The goal of our group is to understand the mechanisms of drug response, particularly those linked to the development of resistance to specific classes of anticancer agents that are routinely used in the clinic. The strength of our team resides in the close collaboration between basic researchers and clinicians, who are involved in early phase clinical trials and in the routine care and management of patients with cancer. This allow us to develop translational research programs that focus on solid cancer (mostly colorectal and prostate cancer) with the aim of proposing alternative therapeutic strategies that could rapidly be implemented in the clinic to improve patients’ survival.
Our objectives are the identification of new predictive markers of drug response and the development of new therapeutic strategies to overcome drug resistance. Our main project are:
1-Transcriptome analysis to define signatures correlated with drug responses and identify new targets
We collected a large and unique type of tumor collection from patients with colon cancer with normal mucosa, primary CRC and metastasis samples from the same patients and the complete clinical annotations including response to treatment. Using gene expression signatures established from these samples we identified (1) A gene-signature that predict response to FOLFIRI (2) Genes specifically deregulated in hepatic metastasis and (3) A classification of mCRC patients in the new molecular subtypes recently described. In particular, we identified a molecular subtype (C5 from Marisa's classification), representing 28% of the patients, that shows an exceptionally high response rate to FOLFIRI (87.5%) and a better OS and PFS than the other subtypes.
We also identified claudin-1 (CLDN1), a major tight junction transmembrane protein, as a potential therapeutic target in CCR, since it is overexpressed in CRC tumor. Then, we generated an antibody targeting the CLDN1 extracellular part and we are currently investigating the anti-tumoral effect of this antibody (or its ADC counterpart) in vitro and in vivo.
2-Role of genetic variation of ADME genes on drug pharmacokinetics by using in vitro and clinical samples.
We identify NR1I2 (Pregnane X Receptor, PXR) as a Very Important Pharmacogene (VIP, as defined by PharmGkB, the pharmacogenomics knowledge database) responsible for interindividual variability of response/toxicity to various anticancer agents at the pharmacokinetics (PK) level (SNPs affecting drug concentration in blood) and at the tumoral level (expression affecting sensitivity to TKIs in prostate cancer cells). We also identified the high affinity of some TKIs for the ligand binding pocket of PXR, giving thus biological rational for new drug combinations and drug-drug interactions both at the PK and tumoral levels.
3- Identification of proteins involved in ADT resistance in prostate cancer
We have assessed the phosphoproteome modifications induced by enzalutamide or abiraterone acetate in vitro and observed that few signaling pathways and kinases are activated. We are currently working on involvement of these signaling pathways and coactivators on resistance to ADT in vitro and in vivo.
4- Synthetic lethality screening to identify new factors involved in chemoresistance in colorectal cancer
We recently used a genetic screen based on RNA interference (shRNA library from NKI, coll. R. Beijersbergen) to identify genes the inhibition of which confers sensitivity to SN38/irinotecan and oxaliplatin. This screen led to the identification of candidate genes such as ATR for oxaliplatin. We then confirmed the role of ATR in oxaliplatin resistance in CCR and showed that ATR inhibition combined to oxaliplatin sensitize cells to chemotherapy, creating dramatic DNA damages and stimulating anti-tumour immunity.
5- Autophagy and mitophagy as a determinant of drug resistance in colorectal cancer
We demonstrated that BAG6 is a key regulator of autophagy through the modulation of EP300 dependent acetylation. We are currently assessing the role of BAG6 in mitophagy and the role of its intracellular localization in colon cancer.