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Potential therapeutic target & predictive biomarker
Oncogenic IGFBP2
Sonya Song (Sonya Song ( 宋韦宋韦 )) Cancer Research laboratory
Beijing Shijitan Hospital Beijing Shijitan Hospital Department of OncologyDepartment of Oncology
The Capital Medical UniversityThe Capital Medical UniversityBeijing, ChinaBeijing, China
05/22/2010
Biomarker - Important Link
Basic Research
Translational Research
Clinical ResearchClinical
Practice
Biomarker
Biomarker-based patient care
• Diagnosis Diagnosis
• Therapeutic evaluationTherapeutic evaluation
• Recurrence/metastasisRecurrence/metastasis
• PrognosisPrognosis
• Therapeutic targetTherapeutic target
Functions
IGFBP2IGFBP2
• Secreted protein
• Belong to IGFBP family
Insulin-like growth factor binding protein 2
Fuller GN and Zhang W et al. Cancer Res 59:4228-32,1999
First report: IGFBP2 overexpressed in ≥ 80% GBM
High
Low
IGFBP2 Overexpressed in ~10 Tumors TypesIGFBP2 Overexpressed in ~10 Tumors Types
• Glioma
• Colorectal cancer
• Breast cancer
• Prostate Cancer
• Ovarian cancer
• Melanoma
• Lung cancer
• Leukemia
• …
What’s the Role of “Reactivated” IGFBP2
in Tumor?
IGFBP-2
IGFI R
Under the physiological condition
IGFBP2
IGFIGF
X
IGF
IGF-dependent inhibitory role
- Predominant in the fetal
- Low in the adult
Cell proliferation, survival etc
Vector
Low Expressor
High Expresser 1
High Expressor 2
IGFBP2 Promotes Glioma Migration & Invasion
Wang et al. Cancer Res 2003; Song et al. PNAS 2003.
IGFBP2 IGFBP2 + IIp45
H&E
GFP- glioma cells
Song SW et al, PNAS 2003Song SW et al, PNAS 2003
IGFBP2-promoting Migration & InvasionIGFBP2-promoting Migration & Invasion Inhibited by IIp45
Xenograft Mouse Model
IGFBP2 Promotes Glioma Progression in RCAS-tva Transgenic Mice
Dunlap S et al., PNAS, 2007
PDGFbPDGFb
PDGFbPDGFb
++
IGFBP2IGFBP2
O ( grade II)O ( grade II)
(Oligodendroglioma) (Oligodendroglioma)
AO (grade III)AO (grade III)
(Anaplastic Oligodendroglioma)(Anaplastic Oligodendroglioma)
Cerebral cortex
Brain stem
Preoperative Plasma IGFBP2 Correlates with Tumor Grade & Recurrence
Jiang T and Song SW et al , Neuro-Oncology 2009
Gliomas
P<0.001p=0.010 p<0.001
Grade Recurrence Recurrence
Preoperative Plasma IGFBP2 Predicts Prognosis
55.7 wks
41.1 wks
Jiang T and Song SW et al, Neuro-Oncology 2009
Glioma
Molecular Mechanism of IGFBP2 Action in Tumor ?
IGFBP2, oncogenic gene, as therapeutic target and predictive biomarker
Song SW et al, PNAS 2003Song SW et al, PNAS 2003
IGFBP2 Interacts with IIp45 at RGD Domain
IIp45
IGFBP2
IGFBP2-C Terminal: RGD domain (Integrin Binding Site)
Does IGFBP2 Bind to Integrin ?
Wang, G. K. et al. J. Biol. Chem. 2006
IGFBP2 Binds to Integrinα5 IGFBP2 Up-regulates Integrin
IGFBP2 Regulates Integrin Pathway
•β-Catenin induces IGFBP2 expression in transformed intestinal epithelial cells. Oncogene 2005
• IGFBP2 PI3K/Akt pathway in prostate cancer, glioma and breast cancer. PNAS 2007 、 Growth Factors 2010
Other Group Studies on IGFBP2
Model of IGFBP2 Action in Tumor
IGFBP2
IGF-independent Stimulatory Role
Integrin
IIp45RGD
Growth factors
Receptors
Ras
RafPI3K
Akt
FAK-Src
Crk
Motility Invasion Metastasis Survival EMT Angiogenesis Immunity etc
APC/ Wnt / β-Catenin signals+
80% CRC
IGFBP2
IGFBP2 could be an “early driver” oncogenein colorectal carcinogenesis
PI3K / Akt / PTEN
(Glioma , Prostate cancer)
Tumor Initiator
Frequent genetic alterations in colorectal cancer
+
(Early driver)
Smad4/TGFβRII
IGFBP2 as “Early Driver” Oncogene
Potential therapeutic target
& predictive biomarker !
Commits
In Summary
ACKNOWLEDGMENTS
MD Anderson Cancer Center Beijing Tiantan Hospital, CMU
– Dr. Wei Zhang Dr. Tao Jiang
– Dr. Gregory Fuller Dr. Yi Lin
– Dr. Frederick F. Lang Dr. Kaijia Zhou
– Dr. Sara Dunlap Dr. Li Xu
– Dr. George Wang Beijing Shijitan Hospital, CMU
– Dr. Hua Wang Huiyuan Chen
– Hong Zhen Yuchen Li
– Shouming Kong
Thank You!
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