CV Science

Gilles Pagès PhD Molecular Biology

Course and current status

PhD in molecular biology january 1990

Position as a lecturer in molecular biology May 1990 University Nice FRANCE

Development of a project on MAP Kinases and their role in tumor growth (from 1991 to 1998). Defense of Habilitation to direct research January 1994

Development of a project of the role of ERK on tumor angiogenesis and regulation of VEGF expression as principal investigator.

November 2007. Position as director of research INSERM

Awards from the Ligue National contre le Cancer and Roche company on fundamental research in angiogenesis 2009

Currently implicated in the determination of the mechanisms of resistance to anti angiogenic drugs especially in renal cell carcinoma.

FUNDING CONTRACTS OF THE TEAM (2006-2010)

2005-2007 Subvention AICR (210 kE, GP)

2005-2007 Labellisation Ligue Nationale Contre le Cancer (126 kE, GP)

2007-2008 Contract with Roche society (40 kE, GP)

2006-2007 Subvention French association for cancer research fixe (50 kE, Valérie Vouret-Craviari))

2007-2008 Subvention French association for cancer research fixe (50 kE, Clotilde Gimond)

2008-2009 Subvention French association for cancer research fixe (50 kE, GP)

2008: Subvention BQR University of Nice (5kE Gilles Pagès)

2008 : Subvention Marie de Nice (2 kE GP)

2008-2011: French association for cancer research (140 kE)

2008-2010 INCA translationnal (312 kE, two partners, GP coordinator)

2009-2010 Contract with Roche society (30 kE, GP)

2009-2010 INCA libre (four partners Eric Gilson coordinator, 140 kE for the GP team).

2009  Award “Recherche fondamentale” Roche Society (50 kE)

2011-2013: INCA translational (350 kE, three partners, GP coordinator)

2011-2013: Fondation de France (140 kE).

2011-2013: French association for cancer research (50 kE)

2011: Thematic institute INSERM (15 kE)

Scientific summary

TEAM NORMAL AND PATHOLOGICAL ANGIOGENESIS

ABSTRACT: The phenomena of angiogenesis are finely controlled through an equilibrated balance between pro and anti-angiogenic factors. Any imbalance leads to abnormal angiogenesis often associated with tumor progression. Despite an undeniable effect on progression-free survival of anti VEGF (Bevacizumab, BVZ), only a marginal effect on overall survival was observed. Our project aims to elucidate the partial failure of anti-angiogenic through the approach “from bedside to bench”. Our recent findings have shown that ELR + / ELR-CXCL cytokines are major players implicated in tumor evasion to BVZ. The anti-angiogenic forms of VEGF are also interesting targets since they are recognized by BVZ with the same affinity than VEGF. The aims of our project will be both fundamental and translational and we will focused on: i) redundant angiogenic ELR+CXCL, regulation of their expression and development of specific antibodies targeting the most pertinent one, ii) the regulation of expression of anti-angiogenic forms of VEGF in tumor cells, the means of forcing their expression, their role as pro-apoptotic factors or growth inhibitors and targeting only pro-angiogenic forms of VEGF; iii) Influence of ERK on the balance between pro and anti-angiogenic forms of VEGF. The molecular players involved in maintaining an equilibrated angiogenic balance would serve as pertinent prognosis markers of cancers aggressiveness. Moreover, the targeting of the most relevant pro-angiogenic cytokines (CXCL VEGF) represents a significant therapeutic challenge.

Background of the team

The group was created in 1999 when we moved from the Centre de Biochimie Parc Valrose to the Nice Cancer Centre, Centre Antoine Lacassagne (CAL). Our objectives were to decipher the links between activation of the ERK pathway and abnormal angiogenesis, two mains actors implicated in tumor development. Our localization at the CAL incited us to develop translational research aiming at reinforced the links with clinicians. My team was implicated in the discovery of new pertinent direct targets of ERK and on the molecular links between ERKs and regulation of VEGF expression at transcriptional and post transcriptional levels. Discussions with clinicians and our expertise on angiogenesis have oriented our thematic on the failure of anti-angiogenic therapies. The identification of the phosphorylation of the telomere binding factor TRF2 by ERK has established a new link between telomeric activity and activation of a major signaling pathway involved in tumor development.

RESEARCH PROJECT

I)    PROBLEMATIC, HYPOTHESIS AND OBJECTIVES

Clear cell renal cell carcinomas (RCC) are vascularized tumors that arise due to mutations in the von Hippel-Lindau gene leading to over-expression of VEGF. Hence RCC should be one of the most responsive tumors to anti-angiogenic therapies. Bevacizumab (BVZ), a humanised monoclonal antibody targeting VEGF has obtained approval for treatment of RCC in association with interferon-a (1). Despite the increased time to progression, no significant effects of BVZ on overall survival have been observed (AVOREN study) (2). The limited effectiveness raises an economic issue, given the high cost of treatment with BVZ. Moreover, some recent papers describe a new phenomenon called treatment evasion and the selection of more aggressive cells with increased metastatic potential (3-4). The aim of our study was to gain insight into the absence of persistent effects of anti-angiogenic therapies (5). Our hypothesis states that this could be due to the presence of anti-angiogenic forms of VEGF called VEGFxxxb, which result from alternative splicing (6) or to the production of redundant angiogenic cytokines. We have focused on the specific regulation of the VEGF/VEGFxxxb balance and on the targeting of cytokines of the CXCL family that have angiogenic and anti-angiogenic potency depending on the presence or absence of the amino acid triplet ELR (ELR+CXCL (1,2,3,5,6,7,8), pro-angiogenic; ELR-CXCL (4,9,10) anti-angiogenic) (7). ELR+CXCL stimulate their G-protein-coupled receptors CXCR-1 and CXCR-2, which activate of the ERK pathway (8). The pro-inflammatory chemokine CXCL8/interleukin-8 promotes angiogenesis, tumorigenesis and metastasis and is over-expressed in many tumors (9) including RCC (10). Ras-dependent secretion of CXCL8 enhances tumor progression by promoting neo-vascularisation (11). Hence, tumor cells may use diverse pro-angiogenic chemokines to mediate angiogenesis and to promote tumor progression. Our goals are:

1)  To determine the pertinence of targeting CXCL rather than VEGF for RCC

2)  To highlight new cytokines implicated in mechanisms of evasion to anti VEGF

3)  To demonstrate that VEGFxxxb are implicated in absence of enduring efficacy to BVZ

4)  To understand the molecular mechanisms implicated in repression of VEGFxxxb in tumor

5)  The development of new therapeutic strategies aiming at decreasing the activity of CXCL, at increasing expression of VEGFxxxb or specifically targeting the pro-angiogenic VEGF.

6)  Patenting therapeutic antibodies issued from our fundamental research.

CONCLUSION

The anti-angiogenic drugs exceptionally improve overall survival. This finding was depressing for both therapeutic purposes and economic impact as huge sums were invested by pharmaceutical companies and these treatments are very expensive for patients or for health insurances. Our project propose to determine the molecular mechanisms involved in this semi-clinical failure and find new ways to improve existing treatments or propose new therapeutic options. Our project should: 1) identify biomarkers predictive of response or non-response to anti-angiogenic drugs for a more relevant prescription of existing therapies, 2) test the relevance of combinations currently used in clinical practices, 3) propose new combination therapies, 4) propose new targets for developing more efficient therapies.