Drug discovery is an inherently inefficient process, particularly in oncology. The difficulty in matching the immense and complex chemical world with a desired physiological effect is illustrated by limitations such as harmful side effects and drug resistance, which defy the most powerful chemotherapeutics available.
Novel therapeutic targets and new ways to identify, to characterize and to develop anti-cancer drugs are needed. Most drug discovery efforts by pharmaceutical companies concern the development and / or expansion of their pre-clinical and clinical pipeline primarily targeting G protein-coupled receptors, nuclear receptors, ion channels and the active sites of enzymes (eg kinases).
Although this strategy is understandable for historical reasons and risk management, inhibitors of protein-protein interaction represents an alternative and almost unexplored reservoir for drug development in oncology. Thus, targeting protein-protein interaction interfaces appears a valuable and promising strategy, which is further underscored by an expected reduced occurrence of resistance that might arise due to mutations in the protein-protein interface.
In this context, our objectives are to identify, to understand, to validate and to target protein-protein interaction interfaces critically involved in tumor cell signaling, with the specific purpose of facilitating the transfer of therapeutic and pharmacological targets into preclinical and clinical development programs in oncology.
From Left to Right: Etienne Rebuffet, Xavier Morelli, Yves Collette, Hélène Launay, Brigitt Raux, Elsa Drivet, Stéphane Betzi, Sébastien Combes, Iuliia Voitovich, Laurent Hoffer, Véronique Brechot, Karine Barral, Sabine Milhas, Philippe Roche, Carine Derviaux, Marie-Jeanne Basse, Mathias Vanhems.
Not in the picture: Jean-Michel Brunel, Fatiha Benmansour
- Since 2012 : Group Leader of the team iSCB, CRCM – Marseille, France
- 2008-2012 : Group Leader of the team ID3, CNRS/IMR Laboratory – Marseille, France
- since 2006 : Researcher CR1 CNRS section 21
- 2002-2006 : Researcher CR2 CNRS section 21
- 2000-2002 : Postdoctoral Fellow, Division of Thrombosis and Hemostasis, Harvard Medical School, Boston, USA (Supervisor : Bruce Furie)
- 1996-1999 : PhD in Structural Biology, University of Paris XI, France
- French Pionneer in the discovery of Protein-Protein Interaction Inhibitors (research article published in PNAS in 2007)
- Chemical databases dedicated to Protein-Protein Interactions
- Co-founder of ZymGen, a startup in thrombosis in 2002.
- National Secretary of the French Society of Chemoinformatics
- Associate editor of the journal ‘BMC Pharmacology & Toxicology’
- Member of the national scientific commitee of the ARC.
- Since 2012 : Group Leader of the team iSCB, CRCM – Marseille, France
- Since 2007: Director of the TrGET preclinical platform CRCM/IPC– Marseille, France
- Since 2007 : Researcher DR2 INSERM
- 2002-2007 : Researcher CR1 INSERM
- 1998-2002 : Researcher CR2 INSERM
- 1994-1997: European Community Postdoctoral Fellow, Immunity and Cancer Laboratory, INSERM U119, France (Supervisor : Pr Daniel Olive)
- 1989-1994 : PhD in Virology, Free University of Brussel, Belgium (Supervisor : Pr Arsène Burny)
- Development of original chemical-biology approaches to discover, to study and to target pathological signaling
- Co-discover of HIV-1 Nef Protein-Protein Interaction Inhibitors
- Set up of a preclinical platform at Institut Paoli Calmettes
- INSERM Contrat d’interface with Institut Paoli Calmettes (2008-2013)
- Member of the national coordinated action 14.3 of the ANRS (2000-2007)
- Member of the national scientific commitee of the ANRS (2005-2009)
- Ex ante member of the Belgian national scientific commitee of the FNRS (2010-)
Title: Targeting of the PTK7 tyrosine kinase receptor in breast cancer
Despite undeniable therapeutic advances in recent decades, some breast cancers remain medical and scientific challenges. This is the case of triple negative breast cancers so called because of the lack of expression of HER2 and hormone receptors, making patients ineligible for targeted therapies. The search for therapeutic targets in these very aggressive cancers thus remains a priority.
The team of Jean-Paul Borg has shown that the PTK7 tyrosine kinase receptor belonging to the Wnt/planar cell polarity pathway is overexpressed in many cancers, including triple-negative breast cancers, and associated with poor prognosis and metastasis development. A characteristic of PTK7 is the absence of catalytic activity of its kinase domain, making the use of kinase inhibitors inaccessible. PTK7 is currently only targeted by an antibody-drug conjugate currently in early clinical development. This approach is interesting but does not clear PTK7 from the tumor cell. In this thesis project, the teams propose to target PTK7 by a recently described PROTAC (Proteolysis Targeting Chimera) approach promoting the degradation of proteins of interest by the proteasome. This technology has been shown to be effective in removing oncoproteins in tumor cells (BCR-ABL in acute myeloid leukemia). The project will consist first in the production and purification of the PTK7 kinase domain. Second, thanks to a screen of libraries developed by the Xavier Morelli/Yves Collette team expert in structural biology and chemistry and assays developed for drug design (isothermal titration calorimetry and thermal shift assay), the student will identify chemical compounds specific for PTK7 that will be functionalized to recruit an E3 ubiquitin ligase capable of degrading the receptor. Third, these compounds will be tested in vitro and in vivo using models of breast cancer cells developed at the CRCM.
Références de deux ou trois publications pour éclairer le doctorant sur le sujet proposé
Daulat A.M. and Borg J.-P. Wnt/Planar Cell Polarity signaling: new opportunities for cancer treatment. (2017) Trends in Cancer, 7: 113-125.
Lhoumeau A.-C., Arcangeli M.-L., Giordano M., Orsoni J.-C., Lembo F., Bardin F., Marchetto M., Aurrand-Lions M. and Borg J.-P. Ptk7 deficient mice have decreased hematopoietic stem cell pools as a result of deregulated proliferation and migration. (2016) J. Immunology, 196: 4367-77.
Lhoumeau A.-C., Prébet T., S. Martinez, and Borg J.-P. PTK7 tyrosine kinase receptor family. (2015) "The Receptor Tyrosine Kinase Handbook", Humana press 539-558.
Martinez S., Scerbo P., Giordano M., Daulat A.M., Lhoumeau A.-C., Thomé V., Kodjabachian L. and Borg J.-P. (2015) The PTK7 and ROR2 receptors interact in the vertebrate WNT/PCP pathway. J. Biol. Chem., 290: 30562-72.
Lhoumeau A.-C., Martinez S., Monges G., Castellano R., Poizat F., Saillard C., Viens P., Raoul J.-L., Prebet T., Aurrand-Lions M., Borg J.-P and Gonçalves A. Overexpression of the promigratory and prometastatic PTK7 receptor has an adverse clinical outcome in colorectal cancer. (2015) PLoS ONE, 10: e0123768.
Milhas S., et al. Protein-protein interaction inhibition (2P2I)-oriented chemical library accelerates hit discovery (2016). ACS Chem. Bio. Aug 19;11(8):2140-8.
Raux, B., et al. Exploring Selectivity of the First Bromo and Extra-Terminal (BET) Bromodomain Inhibition (2016). J. Med. Chem. Feb 25;59(4):1634-41.
Basse, M.J., et al. 2P2Idb v2: update of a structural database dedicated to orthosteric modulation of protein–protein interactions (2016). Database Mar 15;2016. pii: baw007.
The student will be involved in an interdisciplinary biology-chemistry program developed in close collaboration with academic (proteomics, drug design) and industrial (IPC drug discovery) platforms set up at CRCM and Institut Paoli-Calmettes.