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Summary

Drug resistance and new cancer treatments (DRCT)

Team Leader  : Céline Gongora
 
Institut de Recherche en
Cancérologie de Montpellier
Campus Val d’Aurelle
34298 Montpellier cedex 5
Tél. : 33 (0)4 67 61 37 45
Fax : 33 (0)4 67 61 37 87
celine.gongora@inserm.fr
 
Research topics
 

Keywords: Preclinical research, p38, irinotecan, 5-FU, oxaliplatin, cetuximab, TKI, signaling pathways, drug metabolism, drug combinations, drug resistance, DNA topoisomerases, Autophagy, biomarkers, therapeutic targets, high throughput screening, in silico approaches .


One of the main causes of cancer treatment failure is the development of drug resistance, the mechanisms of which is pleiotropic by nature and involves multiple pathways that need to be targeted to potentiate tumor response. Our new group, emerging from P. Martineau’s has already demonstrated that the two kinase inhibitors sorafenib and the MAPK14 inhibitor SB202190 can overcome irinotecan resistance, and was the first to identify predictive gene signature in CRC for response to treatment using patients’ samples. Our future research project will focus on identification of new alternative strategies for the optimization of anticancer treatment used in colorectal cancer (CCR) and prostate cancer (PCa). Based on specific molecular signatures obtained from patients and from drug-resistant models we are developing functional approaches either exploratory or focused on specific genes of interest.


The main axes of our project will be:


- The identification of new inhibitors of targets that we previously identified as key players in the response to the drugs used in CCR and PCa (MAPK14, Top1/DNA-PKcs complex, Claudin1). Retrospective clinical validation and/or prospective clinical trials using targets’ inhibitors will be conducted. Concomitantly, in vitro assessment for potential synergistic effects of drug combinations will be performed using a novel approach derived from Lehar methods. This part of the project will be implemented by PK/PD studies taking into account the ADME profile of each drug.
- Synthetic lethality screen and transcriptomic analyses using well characterized samples (as our drug-resistant models and patient tumor samples) to explore drug resistance/sensitivity and the genes involved in such mechanisms.
- Novel rational in silico approach using specific PCa or CCR expression classifiers combined with in vitro drug sensitivity signatures (NCI-60 panel database) to identify potential alternative treatments to existing therapies.
- Deciphering the role of autophagy in drug resistance in CCR and PCa. We will study the mechanism(s) by which BAT3 and p38-mediated irinotecan-induced autophagy is contributing to CCR resistance, in particular the role of protein acetylation and lipid metabolism.
 

 

 
Recent Publications

 

Mbatchi LC, Gassiot M, Pourquier P, Goberna A, Mahammedi H, Mourey L, Joly F, Lumbroso S, Evrard A, Houede N. Association of NR1I2, CYP3A5 and ABCB1 genetic polymorphisms with variability of temsirolimus pharmacokinetics and toxicity in patients with metastatic bladder cancer. Cancer Chemother Pharmacol. 2017 Jul 4. doi: 10.1007/s00280- 017-3379-5. [Epub ahead of print]

 

Cherradi S, Ayrolles-Torro A, Vezzo-Vié N, Gueguinou N, Denis V, Combes E, Boissière F, Busson M, Canterel-Thouennon L, Mollevi C, Pugnière M, Bibeau F, Ychou M, Martineau P, Gongora C, Del Rio M. Antibody targeting of claudin-1 as a potential colorectal cancer therapy. J Exp Clin Cancer Res. 2017 Jun 28;36(1):89. doi: 10.1186/s13046 -017-0558-5.

 

Joffre C, Djavaheri-Mergny M, Pattingre S, Giuriato S. The yin and the yang of autophagy in cancer cells. Med Sci (Paris). 2017 Mar;33(3):328-334. doi: 10.1051 /medsci/20173303021.

 

Del Rio M, Mollevi C, Bibeau F, Vie N, Selves J, Emile JF, Roger P, Gongora C, Robert J, Tubiana-Mathieu N, Ychou M, Martineau P. Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies. Eur J Cancer. 2017 Mar 8;76:68-75. doi: 10.1016/j.ejca.2017.02.003. [Epub ahead of print]

 

Lehmann-Che J, Poirot B, Boyer JC, Evrard A. La génétique somatique des tumeurs solides, un incontournable à l’ère de la médecine de précision. Therapie. 2017 Jan 3. pii: S0040-5957(16)31284-7. doi: 10.1016/j.therap.2016.09.009. [Epub ahead of print]


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