Innovazione e sostenibilitá in oncologia: approccio multidisciplinare nella gestione delle target therapy

I nuovi principi attivi (horizon scanning), il loro collegamento con le caratteristiche genetiche-epigenetiche del paziente e la ricerca clinica

(ricerca traslazionale)

Roberto Fantozzi, MDFarmacologo, Università degli Studi di Torino

Milano, 16 Dicembre 2015

«…Il servizio sanitario nazionale è costituito dal complesso delle funzioni, delle

strutture, dei servizi e delle attività destinati alla promozione, al mantenimento ed al

recupero della salute fisica e psichica di tutta la popolazione senza distinzione di

condizioni individuali o sociali e secondo modalità che assicurino l'eguaglianza dei

cittadini nei confronti del servizio…»

Art. 1

LEGGE 23 dicembre 1978, n. 833Istituzione del servizio sanitario nazionale.

 (GU n.360 del 28-12-1978 - Suppl. Ordinario )

Art. 29

(Disciplina dei farmaci)

«…La produzione e la distribuzione dei farmaci devono essere regolate

secondo criteri coerenti con gli obiettivi del servizio sanitario

nazionale, con la funzione sociale del farmaco e con la prevalente

finalità pubblica della produzione…»

LEGGE 23 dicembre 1978, n. 833Istituzione del servizio sanitario nazionale.

 (GU n.360 del 28-12-1978 - Suppl. Ordinario )

Farmaco

Efficacia

Sicurezza

Qualità

Sostenibilità

The precision-medicine ecosystem

The goal of precision medicine is to enable clinicians to quickly, efficiently and

accurately predict the most appropriate course of action for a patient. To achieve

this, clinicians are given tools — in the form of tests and information-technology

support — that are both compatible with their clinical workflow and economically

feasible to deploy in the modern health-care environment. These tools help to

simplify the process of managing the extreme biological complexity that underlies

human disease. To support the creation and refinement of these tools, a precision-

medicine ‘ecosystem’ is developing. This ecosystem is beginning to link clinicians,

laboratories, research enterprises and clinical-information-system developers

together in new ways.Aronson & Rehm, 2015

Pharmacogenomics focuses on the identification of genetic variants that influence drug

effects, typically through alterations in pharmacokinetics — that is, how the drug is

absorbed, distributed, metabolized or eliminated — or pharmacodynamics, by modifying

its target or by perturbing the biological pathways that shape a patient’s sensitivity to its

pharmacological effects.

Relling & Evans, 2015

Somatically acquired genomic variation

Genetic variants that are specific to cancer tissue represent a special case of

pharmacogenomics. Somatic variation can identify which types of malignancy are likely to

respond to various anticancer agents.

Relling & Evans, 2015

Relling & Evans, 2015

Haematopoietic-stem-cell gene therapy

HSCs have long been a preferred target for ex vivo gene therapy. Genetic modification of

self-maintaining multipotent HSCs would ensure a steady supply of their gene-corrected

progeny in the body. These cells have the potential to treat conditions that manifest when

mature haematopoietic lineages fail to develop or to function correctly. Given the self-

renewing nature of HSCs and the need to ensure that genetic modifications are passed on

to their progeny, gene correction must be stably introduced into cellular chromatin, either

by vector-mediated transgene insertion or by in situ gene editing.Naldini, 2015

T-cell immunotherapy for cancer

T cells are also popular targets for ex vivo gene therapy. Such therapies aim mostly at

boosting the adaptive immune response against cancer and chronic infections such as

HIV. Autologous T cells can be harvested readily from the peripheral blood and expanded

ex vivo. Cells are then transduced with a γ-RV or lentiviral vector expressing an exogenous

T-cell antigen receptor (TCR) that is specific to a cancer-associated antigen.

Naldini, 2015

More recently, gene transfer was used to introduce synthetic chimaeric antigen receptors (CARs)

to T cells. CARs combine the binding specificity of an antibody against a cancerassociated surface

marker with one or more intracellular signalling domains from the TCR and costimulatory receptor

complexes … these engineered T cells can be fully activated when meeting their target. Trials that

deployed CARs directed against the B-cell surface molecule CD19 reported dramatic benefits in

patients with B-cell malignancies, who experienced durable clinical responses, including complete

remission, with mostly manageable toxicity. These results have spurred enormous interest in

further developing this approach

Naldini, 2015

Epigenetics refers to changes in gene expression

caused by modifications to DNA that occur without

modifying the DNA sequence, such as DNA

methylation or histone modifications.

Mummaneni & Shord, 2014

Mummaneni & Shord, 2014

D

Minelli et al. 2013

Inhibition of DNA repair in cancer cells represents an attractive strategy for potentiating the

cytotoxic effects of chemotherapy and radiation ... Of the known DNA repair inhibitors, Poly (ADP-

ribose) polymerase inhibitors (PARPi) are furthest along in development and appear promising in a

variety of cancer types, including breast and ovarian cancers. The first PARP enzyme was discovered

over 40 years ago and PARP-1 is the most abundant and best-characterised member of the family of

PARP enzymes. PARP-1 has a key role in the repair of single-strand breaks (SSBs), resulting from

oxidative stress via the base excision repair/SSB repair (BER/SSBR) pathway … PARPi were

designed to block the catalytic activity of the enzyme and have structural resemblance to

the by-product, nicotinamide.Javle & Curtin, 2011

Lord et al., 2015

Cancer Control. 2014 Jul;21(3):231-7.

PD-1 is an immunoinhibitory receptor that belongs to the CD28 family and is expressed on T cells, B cells, monocytes, natural killer cells, and many tumor-infiltrating lymphocytes (TILs); it has 2 ligands that have been described (PD-L1 [B7H1] and PD-L2 [B7-DC]). Although PD-L1 is expressed on resting T cells, B cells, dendritic cells, macrophages, vascular endothelial cells, and pancreatic islet cells, PD-L2 expression is seen on macrophages and dendritic cells alone. Certain tumors have a higher expression of PD-L1. PD-L1 and L2 inhibit T-cell proliferation, cytokine production, and cell adhesion. PD-L2 controls immune T-cell activation in lymphoid organs, whereas PD-L1 appears to dampen T-cell function in peripheral tissues ... Blocking this pathway in cancer can augment the antitumor immune response. Like the CTLA-4, the PD-1 pathway down-modulates T cell responses by regulating overlapping signaling proteins that are part of the immune checkpoint pathway; however, they function slightly differently. Although the CTLA-4 focuses on regulating the activation of T cells, PD-1 regulates effector T-cell activity in peripheral tissues in response to infection or tumor progression.

Drugs targeting the PD-1 pathway may provide antitumor immunity, especially

in PD-L1 positive tumors. Various cancers, such as melanoma, hepatocellular

carcinoma, glioblastoma, lung, kidney, breast, ovarian, pancreatic, and

esophageal cancers, as well as hematological malignancies, have positive PD-

L1 expression, and this expression has been correlated with poor prognosis.

Dolan & Gupta, 2014

PD-1 inhibitors

Nivolumab: fully human IgG4 monoclonal antibody

Pembrolizumab: highly selective, humanized IgG4-kappa monoclonal antibody

Pidilizumab: humanized IgG1 monoclonal antibody

Dolan & Gupta, 2014

Experimental studies have shown that blockade of leukocyte α4β1 or

α4β7 integrins or their endothelial receptors mucosal addressin cell adhesion

molecule 1 (MAdCAM-1) or vascular cell adhesion molecule 1 (VCAM-1) has a

consistent and potent effect in preventing or reversing established inflammation

in various models.

Danese & Panés, 2014

Natalizumab, originally developed and approved for the treatment of multiple

sclerosis, is a recombinant humanized IgG4 monoclonal antibody targeting the α4-

integrin subunit. It acts to block both the α4β1 and α4β7 integrins expressed on all

leukocytes except neutrophils. The interaction between the α4β7 integrin and

MAdCAM-1 is specific to the gut, whereas interaction between α4β1 and VCAM-1

mediates lymphocyte migration in all organs, including the central nervous system

(CNS). Danese & Panés, 2014

Vedolizumab, a humanized IgG1 monoclonal antibody against the α4β7 integrin that

selectively blocks the interaction of this integrin with MAdCAM-1. Vedolizumab binds

only to the dimer α4β7 and is therefore expected to have a highly selective effect in the

gastrointestinal tract without affecting the trafficking of lymphocytes in other organs

and the CNS because the counterreceptor of α4β7, MAdCAM-1, is predominantly

expressed in the gastrointestinal tract. Therefore, vedolizumab would not be expected

to carry a risk of PML (progressive multifocal leukoencephalopathy).Danese & Panés, 2014

Dianzani et al. 2016

Camptothecin (CPT), a pentacyclic alkaloid, is an inhibitor of DNA Topoisomerase-I and shows a wide spectrum of anticancer activities. The use of CPT has been hampered by poor aqueous solubility and a high degradation rate. Previously, it has been reported that CPT encapsulated in β-cyclodextrin-nanosponges (CN-CPT) overcomes these disadvantages and improves the CPT's inhibitory effect on DU145 prostate tumor cell lines, and PC-3 growth in vitro. This work extends these observations by showing that CN-CPT significantly inhibits the adhesion and migration of these tumor cells and their STAT3 phosphorylation. The anti-adhesive effect is exerted also in human endothelial cells, in which CN-CPT also inhibits the angiogenic activity as assessed by the tubulogenesis and sprouting assays. Finally, CN-CPT substantially delays the growth of PC-3 cell engraftment in SCID mice in vivo without apparent toxic effects. These results support the use of β-cyclodextrin nanosponge nanotechnology as a potential nanocarrier for delivery of anticancer drugs in the treatment of prostate cancers.

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In Vitro and In Vivo Therapeutic Evaluation of Camptothecin-Encapsulated β-Cyclodextrin Nanosponges in Prostate Cancer