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Protein Tyrosine Kinase Inhibitors
Speaker Huang Kuo-Chun
Date 2011-11-15
Cells communicate
Gap Junctions and CAMs
bull Protein channels - connexinbull Direct flow to neighbor
ndash Electrical- ions (charge)ndash Signal chemicals
bull CAMs ndash Need direct surface
contactndash Signal chemical
Direct and local cell-to-cell communication
Paracrines and Autocrines
bull Local communication bull Signal chemicals diffuse
to targetbull Example Cytokines
ndash Autocrinendashreceptor on same cell
ndash Paracrinendashneighboring cells
Figure 6-1c Direct and local cell-to-cell communication
bull Signal Chemicalsbull Made in endocrine
cellsbull Transported via
bloodbull Receptors on target
cells
Long Distance Communication Hormones
Long distance cell-to-cell communication
Long Distance Communication Neurons and Neurohormones
Long distance cell-to-cell communication
Signal Pathways
bull Signal molecule (ligand)bull Receptorbull Intracellular signalbull Target proteinbull Response
Signal pathways
bull Ligand- gated channelbull Receptor enzymesbull G-protein-coupledbull Integrin
Membrane Receptor Classes
Membrane Receptor Classes
Four classes of membrane receptors
Signal Transduction
bull Transforms signal energy
bull Protein kinasebull Second messengerbull Activate proteins
ndash Phosporylationndash Bind calcium
bull Cell response
Biological signal transduction
Signal Amplification
bull Small signal produces large cell response
bull Amplification enzymebull Cascade
Signal amplification
Receptor Enzymes
bull Transductionbull Activation
cytoplasmicndash Side enzyme
bull Example Tyrosine kinase
Tyrosine kinase an example of a receptor-enzyme
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Cells communicate
Gap Junctions and CAMs
bull Protein channels - connexinbull Direct flow to neighbor
ndash Electrical- ions (charge)ndash Signal chemicals
bull CAMs ndash Need direct surface
contactndash Signal chemical
Direct and local cell-to-cell communication
Paracrines and Autocrines
bull Local communication bull Signal chemicals diffuse
to targetbull Example Cytokines
ndash Autocrinendashreceptor on same cell
ndash Paracrinendashneighboring cells
Figure 6-1c Direct and local cell-to-cell communication
bull Signal Chemicalsbull Made in endocrine
cellsbull Transported via
bloodbull Receptors on target
cells
Long Distance Communication Hormones
Long distance cell-to-cell communication
Long Distance Communication Neurons and Neurohormones
Long distance cell-to-cell communication
Signal Pathways
bull Signal molecule (ligand)bull Receptorbull Intracellular signalbull Target proteinbull Response
Signal pathways
bull Ligand- gated channelbull Receptor enzymesbull G-protein-coupledbull Integrin
Membrane Receptor Classes
Membrane Receptor Classes
Four classes of membrane receptors
Signal Transduction
bull Transforms signal energy
bull Protein kinasebull Second messengerbull Activate proteins
ndash Phosporylationndash Bind calcium
bull Cell response
Biological signal transduction
Signal Amplification
bull Small signal produces large cell response
bull Amplification enzymebull Cascade
Signal amplification
Receptor Enzymes
bull Transductionbull Activation
cytoplasmicndash Side enzyme
bull Example Tyrosine kinase
Tyrosine kinase an example of a receptor-enzyme
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
Prot
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Gap Junctions and CAMs
bull Protein channels - connexinbull Direct flow to neighbor
ndash Electrical- ions (charge)ndash Signal chemicals
bull CAMs ndash Need direct surface
contactndash Signal chemical
Direct and local cell-to-cell communication
Paracrines and Autocrines
bull Local communication bull Signal chemicals diffuse
to targetbull Example Cytokines
ndash Autocrinendashreceptor on same cell
ndash Paracrinendashneighboring cells
Figure 6-1c Direct and local cell-to-cell communication
bull Signal Chemicalsbull Made in endocrine
cellsbull Transported via
bloodbull Receptors on target
cells
Long Distance Communication Hormones
Long distance cell-to-cell communication
Long Distance Communication Neurons and Neurohormones
Long distance cell-to-cell communication
Signal Pathways
bull Signal molecule (ligand)bull Receptorbull Intracellular signalbull Target proteinbull Response
Signal pathways
bull Ligand- gated channelbull Receptor enzymesbull G-protein-coupledbull Integrin
Membrane Receptor Classes
Membrane Receptor Classes
Four classes of membrane receptors
Signal Transduction
bull Transforms signal energy
bull Protein kinasebull Second messengerbull Activate proteins
ndash Phosporylationndash Bind calcium
bull Cell response
Biological signal transduction
Signal Amplification
bull Small signal produces large cell response
bull Amplification enzymebull Cascade
Signal amplification
Receptor Enzymes
bull Transductionbull Activation
cytoplasmicndash Side enzyme
bull Example Tyrosine kinase
Tyrosine kinase an example of a receptor-enzyme
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Paracrines and Autocrines
bull Local communication bull Signal chemicals diffuse
to targetbull Example Cytokines
ndash Autocrinendashreceptor on same cell
ndash Paracrinendashneighboring cells
Figure 6-1c Direct and local cell-to-cell communication
bull Signal Chemicalsbull Made in endocrine
cellsbull Transported via
bloodbull Receptors on target
cells
Long Distance Communication Hormones
Long distance cell-to-cell communication
Long Distance Communication Neurons and Neurohormones
Long distance cell-to-cell communication
Signal Pathways
bull Signal molecule (ligand)bull Receptorbull Intracellular signalbull Target proteinbull Response
Signal pathways
bull Ligand- gated channelbull Receptor enzymesbull G-protein-coupledbull Integrin
Membrane Receptor Classes
Membrane Receptor Classes
Four classes of membrane receptors
Signal Transduction
bull Transforms signal energy
bull Protein kinasebull Second messengerbull Activate proteins
ndash Phosporylationndash Bind calcium
bull Cell response
Biological signal transduction
Signal Amplification
bull Small signal produces large cell response
bull Amplification enzymebull Cascade
Signal amplification
Receptor Enzymes
bull Transductionbull Activation
cytoplasmicndash Side enzyme
bull Example Tyrosine kinase
Tyrosine kinase an example of a receptor-enzyme
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
Prot
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
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open
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n
RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
bull Signal Chemicalsbull Made in endocrine
cellsbull Transported via
bloodbull Receptors on target
cells
Long Distance Communication Hormones
Long distance cell-to-cell communication
Long Distance Communication Neurons and Neurohormones
Long distance cell-to-cell communication
Signal Pathways
bull Signal molecule (ligand)bull Receptorbull Intracellular signalbull Target proteinbull Response
Signal pathways
bull Ligand- gated channelbull Receptor enzymesbull G-protein-coupledbull Integrin
Membrane Receptor Classes
Membrane Receptor Classes
Four classes of membrane receptors
Signal Transduction
bull Transforms signal energy
bull Protein kinasebull Second messengerbull Activate proteins
ndash Phosporylationndash Bind calcium
bull Cell response
Biological signal transduction
Signal Amplification
bull Small signal produces large cell response
bull Amplification enzymebull Cascade
Signal amplification
Receptor Enzymes
bull Transductionbull Activation
cytoplasmicndash Side enzyme
bull Example Tyrosine kinase
Tyrosine kinase an example of a receptor-enzyme
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Long Distance Communication Neurons and Neurohormones
Long distance cell-to-cell communication
Signal Pathways
bull Signal molecule (ligand)bull Receptorbull Intracellular signalbull Target proteinbull Response
Signal pathways
bull Ligand- gated channelbull Receptor enzymesbull G-protein-coupledbull Integrin
Membrane Receptor Classes
Membrane Receptor Classes
Four classes of membrane receptors
Signal Transduction
bull Transforms signal energy
bull Protein kinasebull Second messengerbull Activate proteins
ndash Phosporylationndash Bind calcium
bull Cell response
Biological signal transduction
Signal Amplification
bull Small signal produces large cell response
bull Amplification enzymebull Cascade
Signal amplification
Receptor Enzymes
bull Transductionbull Activation
cytoplasmicndash Side enzyme
bull Example Tyrosine kinase
Tyrosine kinase an example of a receptor-enzyme
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Signal Pathways
bull Signal molecule (ligand)bull Receptorbull Intracellular signalbull Target proteinbull Response
Signal pathways
bull Ligand- gated channelbull Receptor enzymesbull G-protein-coupledbull Integrin
Membrane Receptor Classes
Membrane Receptor Classes
Four classes of membrane receptors
Signal Transduction
bull Transforms signal energy
bull Protein kinasebull Second messengerbull Activate proteins
ndash Phosporylationndash Bind calcium
bull Cell response
Biological signal transduction
Signal Amplification
bull Small signal produces large cell response
bull Amplification enzymebull Cascade
Signal amplification
Receptor Enzymes
bull Transductionbull Activation
cytoplasmicndash Side enzyme
bull Example Tyrosine kinase
Tyrosine kinase an example of a receptor-enzyme
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
bull Ligand- gated channelbull Receptor enzymesbull G-protein-coupledbull Integrin
Membrane Receptor Classes
Membrane Receptor Classes
Four classes of membrane receptors
Signal Transduction
bull Transforms signal energy
bull Protein kinasebull Second messengerbull Activate proteins
ndash Phosporylationndash Bind calcium
bull Cell response
Biological signal transduction
Signal Amplification
bull Small signal produces large cell response
bull Amplification enzymebull Cascade
Signal amplification
Receptor Enzymes
bull Transductionbull Activation
cytoplasmicndash Side enzyme
bull Example Tyrosine kinase
Tyrosine kinase an example of a receptor-enzyme
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
Prot
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
Prot
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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rsity
of C
open
hage
n
RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Membrane Receptor Classes
Four classes of membrane receptors
Signal Transduction
bull Transforms signal energy
bull Protein kinasebull Second messengerbull Activate proteins
ndash Phosporylationndash Bind calcium
bull Cell response
Biological signal transduction
Signal Amplification
bull Small signal produces large cell response
bull Amplification enzymebull Cascade
Signal amplification
Receptor Enzymes
bull Transductionbull Activation
cytoplasmicndash Side enzyme
bull Example Tyrosine kinase
Tyrosine kinase an example of a receptor-enzyme
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Signal Transduction
bull Transforms signal energy
bull Protein kinasebull Second messengerbull Activate proteins
ndash Phosporylationndash Bind calcium
bull Cell response
Biological signal transduction
Signal Amplification
bull Small signal produces large cell response
bull Amplification enzymebull Cascade
Signal amplification
Receptor Enzymes
bull Transductionbull Activation
cytoplasmicndash Side enzyme
bull Example Tyrosine kinase
Tyrosine kinase an example of a receptor-enzyme
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Signal Amplification
bull Small signal produces large cell response
bull Amplification enzymebull Cascade
Signal amplification
Receptor Enzymes
bull Transductionbull Activation
cytoplasmicndash Side enzyme
bull Example Tyrosine kinase
Tyrosine kinase an example of a receptor-enzyme
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Receptor Enzymes
bull Transductionbull Activation
cytoplasmicndash Side enzyme
bull Example Tyrosine kinase
Tyrosine kinase an example of a receptor-enzyme
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
Prot
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
More than 70 of the known oncogenes and proto-oncogenes involved in cancer code for PTKs The importance of PTKs in health and disease is further underscored by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes
Protein Tyrosine Kinase
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
Prot
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
Prot
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
Prot
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
腫瘤血管增生
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
腫瘤淋巴管增生
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Signalling Pathways
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
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ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
These enzymes are involved in 1cellular signaling pathways2regulate key cell functionssuch as proliferation differentiation anti-apoptotic signaling and neurite outgrowth
Unregulated activation of these enzymes through mechanisms such as 1point mutations or 2over-expression can lead to various forms of cancer as well as benign proliferative conditions
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
Prot
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
The total number of PTKs does not exceed 1000
There are two main classes of PTKs ( Of the 91 protein tyrosine kinases identified thus far)
1receptor receptor tyrosine kinases ( 59 ) [RTK]and 2cellular or non-receptor tyrosine kinases ( 32 )[The receptor-associated tyrosine kinases ]
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
Prot
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
Prot
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
Prot
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
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Labo
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Receptor PTKs possess an extracellular ligand binding domain a transmembrane domain and an intracellular catalytic domain
TK Intracellular Catalytic Domain
Extracellular Ligand Binding Domain
Transmembrane Domain
membrane
1RTK structure
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
bull RTK family includes the receptors for many growth factorsndash EGF (epidermal growth factor)ndash IGF1 (insulin-like growth factor 1)ndash PDGF (platelet-derived growth factor)ndash FGFs (fibroblast growth factors)ndash VEGF (vascular endothelial growth factor)ndash And the like
2 Ligands of RTK
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
Prot
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
The transmembrane domain anchors the receptor in the plasma membrane while the extracellular domains bind growth factors
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
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ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
The extracellular domains are comprised of one or more identifiable structural motifs including cysteine-rich regions fibronectin III-like domains immunoglobulin-like domains EGF-like domains c-adherin-like domains Factor VIII-like domains glycine-rich regions leucine-rich regions acidic regions kringle-like domains and discoidin-like domains
3Extracellular domain
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
Prot
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
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ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
RTK Subclasses
EGFRHER2neuHER2HER4
I-RIGF-1RIRR
PDGFRαPDGFRβCSF-1RKITFLK2FLT3
VEGFR1VEGFR2VEGFR3
FGFR-1FGFR-2FGFR-3FGFR-4
CCK4 TRKATRKBTRKC
METRON
EPHA1-EPHA8EPHB1-EPHB7
AXLMERTYRO3
TIETEK
RYK DDR-1DDR-2
RET ROS LTKALK
ROR1ROR2
MUSKMDK4
AATYKAATYK2AATYK3
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
Prot
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
Prot
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
Prot
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n
RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
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rsity
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open
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n
RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
20151021 24
Type I 含半胱胺酸的2個重複序列Tyep II 異四聚體結構Tyep III由5個Ig構成Type IV 由3個Ig構成
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
4 Three ways to cross-link receptors
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
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ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
The intracellular kinase domains of receptor PTKs can be divided into two classes those containing a stretch of amino acids separating the kinase domain and those in which the kinase domain is continuous
5 Intracellular domain
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
ligand induced dimerizationautophosphorylation by cross-phosphorylation
Dimerization and Autophosphorylation of Receptor Protein-Tyrosine Kinases
Activation of the kinase is achieved by ligand binding to the extracellular domain which induces dimerization of the receptors Receptors thus activated are able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation The results of this auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking sites for proteins which transduce signals within the cell
6 Dimerization
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
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ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
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Ligand-binding results in receptor dimerization or activation of a pre-existing dimer
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
These enzyme domains are normally inactive but when brought together by receptor clustering they are able to activate each other by trans-phosphorylation Once activated these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules
Receptor Protein-Tyrosine KinasesReceptor with Intrinsic Tyrosine Kinase Activity
7 Intrinsic Tyrosine Kinase Activity
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
Prot
ein
Labo
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of C
open
hage
n
EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
ein
Labo
rato
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rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
8Role of PTPs in c-Src Activation
From Hunter (2001) Nature 411355
Extracellular signal
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Signaling proteins which bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include 1RasGAP 2phosphatidylinositol-3acute-kinase (PI3-kinase) 3phospholipase C-γ 4phosphotyrosine phosphatase SHP and 5adaptor proteins such as Shc Grb2 and Crk6And downstream effects including stimulation of other tyrosine kinases elevation of intracellular calcium levelsactivation of serinethreonine kinases
9 Bind to Kinase domain
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Association of Downstream Signaling Molecules with Receptor Protein-Tyrosine
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
Prot
ein
Labo
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open
hage
n
EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
Prot
ein
Labo
rato
ry U
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rsity
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open
hage
n
RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
ein
Labo
rato
ry U
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rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Adaptor Proteins
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
SH2 amp pY peptide
phosphorylation
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
pY
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
Prot
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Adaptor proteins are specialized signaling molecules that usually have no enzymatic activity themselves
Adaptor Proteins
Prot
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
Ex
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
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EGF-receptor signaling
Human carcinomas frequently express high levels of receptorsin the EGF receptor family In the last two decades monoclonalantibodies (MAbs) which block activation of the EGFR andErbB2 have been developed A humanized anti-ErbB2 MAbis active and was recently approved in combination withpaclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer
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RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
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RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Prot
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n
RASSignaling downstream of Ras activation
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
ein
Labo
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open
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n
RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
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AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
RTKRTK can also activatephospholipid kinase ndashPI-3 kinase
RTK can also activatePLCγ
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
VEGFR binding and activation
Endothelial cellactivation
VEGF A Key Mediator of Angiogenesis
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Cellular PTKs are located in the cytoplasm nucleus or anchored to the inner leaflet of the plasma membrane They are grouped into eight families SRC JAK ABL FAK FPS CSK SYK and BTK Each family consists of several members Structures 1homologous kinase domains (Src Homology 1 or SH1 domains) 2some protein- protein interaction domains (SH2 and SH3 domains)Other unique domains
Functions 1SRC are involved in cell growth2 FPS PTKs are involved in differentiation 3ABL PTKs are involved in growth inhibition 4FAK activity is associated with cell adhesion 5JAKs which phosphorylate the transcription factors STATs Which interact with Some members of the cytokine receptor pathway
6Still other PTKs activate pathways whose components and functions remain to be determined
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
AnnuRevCell DevBiol135131997
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Schematic presentation of the cytoplasmic protein tyrosine kinase families The major domains of the mammalian nontransmembrane protein tyrosine kinases are indicated SH Src homology domain
1
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Prot
ein
Labo
rato
ry U
nive
rsity
of C
open
hage
n
AktPKB ndash cell survival kinase
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Mechanism of PTK Activation
bull Autophosphorylation serves two distinct functions in the receptor activation processndash Receptor catalytic activity through proper
active site configurationndash Creation of binding site for downstream
signaling proteins phosphotyrosines are available as recruitment sites for proteins
bull Containing Src homology 2 (SH2) domain or phosphotyrosine-binding domains
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Autoinhibition and Activation
20151021 50
Downstream signaling proteins
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
為什麼 Signal Transduction
總是圍繞在Phosphorylation
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Signalling Pathways
Cell 100 57ndash70 2000
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Role of Ras protein in a central growth factor activationpathway
Tyrosine
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Why phosphorylation
1 Causes allostericchanges in protein
2 negative charges3 Attracts positive side
chains (Lys Arg)4 Occurs on Serine
threonine and tyrosine
Structure function relationship
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
General kinase structure
1 Often N and C-terminal lobes2 N-terminal ATP binding site3 Activating catalytic loop
(phosphorylated)4 Short sequences (red
arrowheads) are unique to specific kinase and may determine substrate specificity
Cyclic AMP-dependent kinase (PKA)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
ErbB Receptor Signaling Network
Yarden and Sliwkowski nature reviews 2001
bull EGFR (ErbB1) is one of four members of ErbB receptor family
bull ErbB family trigger a rich signaling network including Erk and Akt pathways
12 3 4
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
The phosphotyrosines are dockingsites for a variety of proteins
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Enzyme-Linked Receptors
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Mechanisms and Models of ErbB Receptor Signaling
Zhang et al Cell 2006
Peptide Moiety
ATP Moiety
EGFR Protein Kinase Structure Sordella et al Science 2004
EGFR
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Role of the activation Loopin RTK Regulation
20151021
Insulin receptor
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Role of the activation Loopin RTK Regulation
bull RTK contain between one and three tyrosines in the kinase activation loop
bull Autophosphorylation of activation loop tyrosinesndash Shown to be essential for simulation of catalytic
activity for RTKs bull Such as insulin receptor IGF1 receptor FGF receptor
Met Ros Nyk TrkA TrkB
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Role of the activation Loopin RTK Regulation
bull Phosphorylation of the activation loop stabilizes a conformationndash The active site is accessible to both substrates
MgATP and tyrosine-containing peptidendash Residues in the activation loop important for
catalysis (DFG sequence) and for peptide binding (end of the activation loop) are optimally positioned
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Regulation of Catalytic through Activation Loop Autophosphorylation
Autoinhibitory conformation of the unphosphorylated activation loop
Re-positioning of the activation loop upon autophosphorylation
The ATP analog the active site
substrate
The ATP analog the active site Mg2+ and the tyrosine-
containing [Y(P)] peptide substrate
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
PKA ERK2
PKA comparison with ERK2
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Structural Similarities Between Protein Kinases
Structure Function Relationship
But kinases maintain substrate selectivity
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Wang et al (1997) Proc Natl Acad Sci 94 2327-2332
Comparison of MAP kinase members(p38 MAPK and ERK2 structures)
p38 MAP kinase p38 MAP kinase and ERK2
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
MAP Kinase interactions with substrates
1 Proline directed kinases -consensus PXSTP site on substrates -minimum STP
2 Substrate domains a FXFP motif b D-domain - basic residues followed by an LXL motifc Kinase interaction motif (KIM) on phosphatases
3 Docking domains on MAP kinases (ERK and p38)Tanoue et al (2001) EMBO J 20466-479
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Mutants and over-expression
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
EGFR v-erbB
FS699
IV705
FS699
TK718HR811QL840SI932Δ1034Δ 1042-1062YN1091
EGF-R v-erbB-H v-erbB-ES4
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
腫瘤與血管增生
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Regulating MAP kinase function
a MAP kinases involved in cell proliferation and many other physiological responses
b Continuous activation is involved in disease
c Few MAP kinase inhibitors exist
d Most kinase inhibitors target ATP binding thus may lack selectivity Why
e Is it advantageous to selectively inhibit some but not all MAP kinase substrates
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Problem -MAP kinase (ERK) proteins phosphorylate and regulate dozens of substrates (~ 70)
How can one inhibit ERK substrates involved in disease but not normal metabolic processes
Hypothesis -Low MW compounds that bind unique MAP kinase docking domains can selectively inhibit interactions between the kinase and a specific substrate protein
Thus selective inhibition of phosphorylation and protein function
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
ERK
S3 S4
S1 S2
ATP ADP
pS1
pS4pS3
pS2
Cell proliferation
Substrate selective inhibition of ERK functions using small molecules
Test compound
ERK ERKS3 S4
S1 S2
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
2 Screen compounds based on ability to inhibit ERK-specific phosphorylation of substrate proteins and determine ERK binding interactions
3 Evaluate the effectiveness of biologically active compounds in inhibiting ERK-mediated cell proliferation
1 CADD database search of compounds that target ERK2 docking domains (need 3D structure)
Future Optimize lead compounds for selective inhibition of ERK substrates and in vivo studies
General CADD Research Design(for ERK2 inhibitors)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Example ERK2 CD and ED docking domains and computer aided drug design (CADD)
N-terminal
C-terminal
Molecular model of ERK2
ATP
substrate
Blue D316 and D319(common docking CD domain)Green T157 and T158(ED domain)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Herceptin Humanized Anti-HER2 Antibody
Targets HER2 oncoprotein
High affinity (Kd= 01 nM)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
HERCEPTIN History
Cloning ofEGFR cDNA
Relation toV-erbB
1984
Slamon et alScience
HER2 geneamplification
in Breast Cancerand correlation
with diseaseprogression
1987
1985
HER2Sequence published
Coussens et al
1989
Hudziak et alMCB
Anti-tumor effectOf MAb 4D5 and 2C4
Phase IRhu MAb
1992
1993
Phase II
Phase III
1995
ApprovalIn Europe
2000
1998
FDAApproval
2002
MAb 2C4In
Development
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
HERCEPTIN
bull Efficacy of Monotherapy in HER2neu +++ Patients Low (15)
bull Reminder Cancer is NOT a Monogenic Disease
bull Moving Disease Target due to Genetic Plasticity of Tumor Cells
bull Combination Therapy
HERCEPTIN +- Anthracyclines- Taxotere- Platinum Salts - etc
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Inhibitors of mammalian RTKs target different steps of receptor signaling cascades
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Terman et alBiochem Biophys Res Commun1992
Quinn et alProc Natl Acad Sci USA 1993
Millauer et alCell 1993
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Gene Therapy with Dominant-Negative VEGF-R Retrovirus
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Flk-1VEGFR2 Validation as Anti-Angiogenesis Drug Development Target
bull Receptor for VEGF
bull Specifically Expressed in Endothelial Cells
bull Essential for Tumor Angiogenesis
DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
NH
O
NH
Chemical Structure of SU5416 -An Inhibitor of VEGF Receptor Kinase
SU5416 3-[2 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
SU5 416 Response in AIDS Kaposirsquos Sarcoma
Protocol 5416003 Patient 003 R-P
Before treatment with SU5416 After treatment with SU5416
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Patient 018JZH SU5416 ResponseFacial Lesions
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
SU5416
bull Highly Selective
bull Efficacious in Mouse Models
bull Anti - Metastatic
bull Sub ndash Optimal Pharmacological Properties
bull Efficacious in Phase I Kaposi-Sarcoma Trial
bull Colon Cancer Trial Terminated
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Biochemical Effects of SU6668 a VEGFR-2 PDGFR amp FGFR RTK Inhibitor
SU5416SU6668
Flk-1Ki
PDGFR FGFR-1
Km (ATP) Ki Km (ATP) Ki Km (ATP)
01621
043043
0320008
6262
19512
2626
Mean Ki and Km values are shown (M)
EGFR
IC50
gt100gt100
NH
O
NH
NH
O
NH
SU5416 SU6668
bull Both compounds exhibit competitive (with respect to ATP) inhibition
bull Both compounds also inhibit ligand-dependent phosphorylation of c-Kit
NO
N
O
O
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
SU11248
An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and
Anti-Angiogenic Activity
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
SU11248 A Multitargeted Kinase Inhibitor
Receptor Ligand Tumor Expression
PDGFR PDGF Glioma HCC NSCLC OvCa CaP melanoma CMML MDS
VEGFR VEGF CRC OvCa RCC Melanoma NSCLC Sarcomas Breast NET
KIT SCF GIST AML Melanoma SCLC Breast OvCa Cervix Mastocytoma
FLT3 FLT3 Ligand AML MDS T-ALL Neurological
Proliferation driven by mutant receptor
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials
Phase I trials ongoing at multiple international sitesbull Patients heavily pre-treated with progressive disease at entrybull Confirmed partial responses observed
SU11248 is well toleratedbull most common toxicities seen in patients are fatigue GI and hematologic toxicity
Baseline Week 4
Patient with metastatic renal cell carcinoma腎臟癌
Eric Raymond et al 2002 NCIEORTCAACR
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
SU 11248SUTENT
August 2005Pfizer Submits a New Drug Application (NDA) to the
FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST
January 26 2006FDA approves SUTENT for treatment of Gleevec-
resistant GIST and RCCJuly 192006
EMEA Approval for Europe
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Sunitinib in metastatic RCC
Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC)
Adverse side effects are tolerable
Lung lesion response in RCC Courtesy of Dr Ronald Bukowski Cleveland Clinic Foundation
Before Treatment After 4 weeks of Sunitinib
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Sunitinib in Breast Cancer Patients
bull Open multicentric phase II study with 64 patients
bull Patients had been treated with chemotherapy that included at least an anthracycline or a taxanendash In average patients had received 35 different chemotherapiesndash 85 of patients had received adjuvant chemotherapy
bull Primary endpoint Response (RECIST)bull Secondary endpoints 1-year ndash survival duration of response tolerance
Miller et al ASCO 2005 Oral Presentation May 16
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Results
bull Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer
bull Partial response in 14 of patients (who had been treated before with various chemotherapeutic agents)
bull Moderate Side Effects
Miller et al ASCO 2005 Oral Presentation May 16
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
NH
OH
O
NH
O
NH
NH
ONH
NH
O
F
NH
N
O
SU6668 SU11248SU5416
From Mono- to Multi-Targeted Kinase Inhibitors
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
SUTENT History
Flk-1 shown to be VEGF-R(Millauer et al Quinn et al)
Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millauer et al)
1993 1994 1999 2003 2006
SU5416 inhibits tumor growthIn vivo (Fong et al)
SU11248 orally activemulti-targeted drug (OlsquoFarrell et al)
SUTENT approval by FDAand EMEA (Pfizer)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Molecular Targets in Cancer
Receptor Tyrosine Kinase
RAS-GDP
RAF-1
SHC
BAD
SOSGRB-2
14-3-3
BCLXL
Mitochondria
BCLXL
SRC
P
STAT1+3
P
RAS-GTP
SAPK
P
AKT
14-3-3
BADP
RAS-GAPDOK
MYC
PI3K
MEK12P P
P
P
P
MAPK
mTOR
PSU11248 (Pfizer)
PZarnestra (JNJ)
PCT2584 (CTI)
PRAD001 (Novartis)CCI779 (Wyeth)
Rapamune (Wyeth)
PBAY43-9006 (Bayer)
Imatinib (Novartis)PBMS354825 (Bristol-MS)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Molecular-targeted agents under investigation in lung cancer
Phase I
Phase II
Phase III
Approved
GefitinibTarceva
AZD2171
Bortezomib
Vandetanib
Motesanib
SorafenibAvastin
Matuzumab
Cetuximab
Bexarotene
Imatinib
AZD6244
Tipifarnib
Talabostat
PF-3512676
Celecoxib
Sunitinib
AS1404
VEGF TRAP
Lapatinib
RAD001CP-751871
ABT-751
Vatalanib
Panitumumab
Angiogenesis inhibitorsEGFRHER
inhibitors
Other molecular-targeted therapies
HKI-272
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
bull Significantly Expand Cancer Mutation Database
bull Start with Cancer Kinome Analysis
bull Identify New Drugable Cancer Targets
bull Screening of Compound Librarys ndash Drug Discovery and Optimization
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Imatinib Bcr-Abl Novartis Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Erlotinib Erb1 GenentechRoche Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Lapatinib Erb1Erb2 GSK Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Vandetinib RETVEGFR AstraZeneca Small molecule
E7080 Multiple targets RETVEGFR
Esai Small molecule
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Name Target Company Class
Bevacizumab VEGF Genentech Monoclonal antibody
Ranibizumab VEGF Genentech Monoclonal antibody
Pegaptanib VEGF OSIPfizer Small molecule
AstraZeneca Small molecule
Small molecule
Sorafenib multiple targets OnyxBayer Small molecule
Dasatinib multiple targets BMS Small molecule
Sunitinib multiple targets Pfizer Small molecule
Trastuzumab Erb2 GenentechRoche Monoclonal antibody
Lapatinib Erb1Erb2 GSK Small molecule
Cetuximab Erb1 ImcloneBMS Monoclonal antibody
Erlotinib Erb1 GenentechRoche Small molecule
BIBW 2992 EGFR and Erb2 Boehringer Ingelheim Small molecule
Panitumumab EGFR Amgen Monoclonal antibody
Gefitinib EGFR AstraZeneca Small molecule
Imatinib Novartis Small molecule
Nilotinib Bcl-Abr Novartis Small molecule
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Cetuximab (IMC-C225 -- marketed under the name Erbitux) is a chimeric monoclonal antibody an epidermal growth factor receptor (EGFR) inhibitor given by intravenous injection for treatment of metastatic colorectal cancer and head and neck cancer Cetuximabwas discovered by ImClone Systems and is distributed in North America by ImClone and Bristol-Myers Squibb while in the rest of the world distribution is by Merck KGaA
an FDA approval of the drug in 2004 for useCetuximab is believed to operate by binding to the extracellular domain of the EGFR of all cells that express EGFR preventing ligand binding and activation of the receptor This blocks the downstream signaling of EGFR resulting in impaired cell growth and proliferation Cetuximab has also been shown to mediate antibody dependent cellular cytotoxicity (ADCC)Clinical uses[edit] Colorectal CancerCetuximab is used in metastatic colon cancer and is given concurrently with the chemotherapy drug irinotecan (Camptosar) a form of chemotherapy that blocks the effect of DNA topoisomerase I resulting in fatal damage to the DNA of affected cells While there remains some scientific controversy on this assessment for EGFR expression is required for use in Colorectal Cancer but not in Head amp Neck Cancer It is best to refer to updated Prescription Information[2]Head and neck cancerCetuximab was approved by the FDA in March 2006[3] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapyOne of the side effects of Cetuximab therapy is the incidence of possibly severe acne-like rash
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Panitumumab (INN) also ABX-EGF is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor EGFR ErbB-1 and HER1 in humans)
FDA approved for the first time in September 2006EGFR is a transmembrane proteinPanitumumab works by binding to the extracellular domain of the EGFR (epidermal growth factor receptor) preventing its activation This in turn results in halting of the cascade of intracellular signals dependent on this receptor [2]
Panitumumab vs cetuximabAlthough they both target the EGFR panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate ADCC (antibody-dependent cellular cytotoxicity) better than their IgG2 counterparts hence although they have not been documented differences in the responses in treatments with these two antibodies might be expected
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Gefitinib (INN) (originally coded ZD1839) is a drug used in the treatment of certain types of cancer Acting in a similar manner to erlotinib (marketed as Tarceva) gefitinibselectively targets the mutant proteins in malignant cells It is marketed by AstraZeneca and Teva under the trade name Iressa In 2004 AstraZeneca informed the United States Food and Drug Administration (FDA)
Gefitinib is the first selective inhibitor of epidermal growth factor receptors (EGFR) tyrosine kinase domain The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature sourceEGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers
Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited and malignant cells are inhibited
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy
Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib Given the lack of survival advantage for gefitinib and the positive results for erlotinib erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
BIBW 2992 (trade name Tovok) is a candidate drug against non-small cell lung carcinoma developed by Boehringer Ingelheim As of May 2008 it is undergoing a Phase II clinical trialMethod of actionBIBW 2992 is a dual kinase inhibitor meaning it inhibits two receptors for growth factors (EGFR and HER2neu) Consequently it is directed against multi-resistant carcinomas with EGFR and HER2 mutations These occur mainly in women Eastern Asians and non-smokers
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Lapatinib (INN) or lapatinib ditosylate (USAN) (TykerbTyverb GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer[1] During development it was known as small molecule GW572016 Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer[2] Pharmacologically lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals[3] Lapatanib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFRHER2 protein kinase domain preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinaseSignal transduction)[5]
As of 2007 they have only progressed to Phase II trials[3]
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2neu (erbB2) receptor Trastuzumabs principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over-express (that is produce more than the usual amount of) this receptor
The biotech company Genentech gained FDA approval for trastuzumab in September 1998Trastuzumab is a humanized monoclonal antibody which binds to the domain IV of the [4]extracellular segment of the HER2neu receptor Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferationThe initiation of trastuzumab therapy is based upon the identification of HER-2 overexpression
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Sorafenib (NexavarBayer) is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma)Sorafenib was approved by the US Food and Drug Administration (FDA) on December 20
2005 and received a EU marketing authorisation on July 19 2006[2]Sorafenib is a small molecular inhibitor of several protein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous These pathways include Raf kinase PDGF (platelet-derived growth factor) VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor A growing number of drugs target most of these pathways Sorafenib is unique in targeting the RafMekErk pathway
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Dasatinib also known as BMS-354825 is a drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel Dasatinib is an oral dual BCRABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) It is also being assessed for use in metastatic melanoma黑色素瘤The main targets of Dasatinib are SRC Ephrins GFR In a Phase I dose escalation study published in June 2006 dasatinib was tested in patients who were resistant to or who could not tolerate imatinib (Talpaz et al 2006)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Sunitinib (marketed as Sutent and previously known as SU11248) is an oral small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal腎 cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal胃腸基質 tumor (GIST) on January 26 2006 Sunitinib was the first cancer drug simultaneously approved for two different indications [1] Sunitinib has become the standard of care for both of these cancers and is currently being studied for the treatment of many othersSunitinib inhibits cellular signaling by targeting multiple RTKs These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R) which play a role in both tumor angiogenesis and tumor cell proliferation The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularizationand cancer cell death and ultimately tumor shrinkage Sunitinib also inhibits KIT (CD117) the RTK that drives the majority of GISTs In addition sunitinib inhibits other RTKs including RET CSF-1R and flt3 [2]
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Bevacizumab (Avastin GenentechRoche) is a monoclonal antibody against vascular endothelial growth factor (VEGF) It is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis) Bevacizumab was the first clinically available angiogenesis inhibitor in the United StatesBevacizumab has been approved by the US Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body) although some doctors and patients want to use it for non-metastatic cancers In 2004 it was approved for combination use with standard chemotherapy for metastatic轉移性 colon結腸 cancer and non-small cell lung cancer[1] In 2008 it was approved by the FDA for use in breast cancer This was against the recommendation of its advisory panel[2] who objected because it only slowed tumor growth but didnt extend the patients life
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived from the same parent murine antibody as bevacizumab (Avastin) It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A It is an anti-angiogenic抗心絞痛 that has been approved to treat the ldquowetrdquo type of age-related macular 污點degeneration (ARMD) a common form of age-related vision lossRanibizumab was developed by Genentech and is marketed in the United States by Genentech and elsewhere by Novartis [1] under the brand name LucentisRanibizumab binds to and inhibits all subtypes of vascular endothelial growth factor A (VEGF-A) VEGF may trigger the growth of new vessels which may leak blood and fluid into the eye These leaky blood vessels may contribute to macular edema and choroidal neovascularization resulting in the wet type of ARMDBy blocking VEGF-A in the eye ranibizumab may prevent and reverse vision loss caused by wet macular degeneration
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Pegaptanib sodium injection (brand name Macugen) is an anti-angiogenic抗心絞痛medicine for the treatment of neovascular (wet) age-related macular degeneration老年性黃
斑部病變 (AMD) It was discovered by Gilead Sciences and licensed in 2000 to EyeTech Pharmaceuticals now OSI Pharmaceuticals for late stage development and marketing in the United States Outside the USA Macugen is marketed by Pfizer Approval was granted by the FDA in December 2004Pegaptanib is a pegylated anti-VEGF aptamer a single strand of nucleic acid that binds with specificity to a particular target Pegaptanib specifically binds to VEGF 165 a protein that plays a critical role in angiogenesis (the formation of new blood vessels) and increased permeability (leakage from blood vessels) two of the primary pathological processes responsible for the vision loss associated with neovascular AMD
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
httpwwwreactionbiologycompageskinasehtm
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
Targeting VEGFThe Bevacizumab Story
PP
PP
VEGFBevacizumab
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
VEGFBevacizumab
PP
PP
VEGF Activation BLOCKED
Targeting VEGFThe Bevacizumab Story
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
藥 品 詳 細 資 料學名 Paclitaxel
藥商 藥價 30 mg vial = NT 4104 ~ 4396商品英文名稱 Taxol商品中文名稱 汰癌勝 (太平洋紫杉醇)
劑型 靜脈注射劑
藥理作用
1 紫杉醇屬有絲分裂 中的微小管抑制劑紫杉醇具有聚合和穩定細胞內微管的作用致使快速分裂的腫瘤細胞在有絲分裂階段被牢牢固定使微小管不再分開使癌細胞複製受阻斷而死亡 和目前常用的化療藥作用機理不同2 紫杉醇屬有絲分裂中的微小管抑制劑可阻斷細胞於細胞周期之G2與M期3 此藥在由 Cytochrome P-450 isozymes 肝臟代謝嚴重肝功能異常病人降低劑量是合理的
常用劑量
1劑量按 175~200 mgM2 體表面積計算3~4 小時靜脈滴注 (最好使用靜脈 Pump)每3週1次用藥量和用藥次數可酌情增減[註] 不能用於中性白細胞計數少於1500個mm3的患者的治療因此對用藥患者應經常進行白細胞計數用藥量和用藥次數可酌情增減2 當與 CDDP 併用必須先給 Paclitaxel因為相反的次序造更大的毒性
衛生署許可證適應症 晚期或無法手術切除之非小細胞肺癌
健保藥品給付規定
晚期或無法手術切除之非小細胞肺癌
藥 品 詳 細 資 料
副作用
Taxol 所產生之副作用中骨髓抑制過敏反應心律不整及神經毒性作用等較具有臨床上之重要性且為主要限制 Taxol 繼續調昇劑量的因素1 Taxol所造成周邊神經毒性和劑量有關且主要發生在當劑量大於 250mgM2時bull常見為手套和襪樣麻木( glove-stocking numbness)和感覺神經異常的毒性反應 (60) 2 可能發生輕度到中度噁心嘔吐腹瀉少數肝功能指數上升3 輕度到中度的皮膚過敏4 對骨髓的抑制反應和劑量有關常見白血球減少 (gt 80)但對血小板紅血球的影響較小bull白血球減少常發生於使用後 8~11天而於 15~21天恢復5 禿髮是顯而易見的副作用發生在第二或三療程 後這過程是可逆的只要停止治療後 4~ 6週後可能再生6 免疫bull大約 40 與抗組織胺有關的過敏反應bull嚴重而且威脅生命的急性過敏性休克發生 很罕見bull輸注時間太短較容易見到過敏反應7 心室心律不整無症狀的心搏過緩少數傳導阻滯有30可以見到 EKG 變化 (第一次注射 Taxol 藥監測心律)8 肌肉痛和關節痛發生在開始治療的前幾天
備註
1 為防止病人發生過敏反應接受本品的所有病人應事先給予預防用藥bull通常在給藥前30分鐘(or 後)分別口服 或靜脈注射皮質類固醇 ( Dexamethasone 8mg BID D-1 D0 D+1 ) bull抗組織胺 Diphenhydramine 50mg bull 抗潰瘍藥 Cimetidine 300mg IV (or Ranitidine 50 mg IV) 2 使用前將本品稀釋 生理食鹽水或5葡萄糖注射液500ml中用非聚氯乙烯(non-PVC) 材料的輸液瓶和輸液管靜脈滴注3 建議當合併 Taxol 與 Cisplatin 之治療時Taxol需在Cisplatin 之前給藥 (由於Cisplatin可能影響Taxol的血漿清除率)
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