Research
Drug resistance and new cancer treatments : C. Gongora

The goal of our group is to understand the mechanisms of drug response, particularly those linked to the development of resistance to anticancer agents. We develop translational research programs focusing on solid cancers (mostly digestive and urothelial cancers) with the aim of proposing alternative therapeutic strategies that could rapidly be transferred to the clinic to improve patients’ survival. Our objectives are the development of new therapeutic strategies to overcome drug resistance. For this purpose, we use specific methods, tools and models such as: cell signaling, phenotypic screening, preclinical models (resistant cell lines, heterotypic spheroids, tumoroids, PDX and orthotopic in vivo models), pharmacogenomics, transcriptomics and bioinformatics. Moreover, for the majority of our projects, we work closely with chemists, in particular to produce and optimize new drug candidates. The close collaboration between basic researchers and clinicians involved in the routine care of cancer patients and in clinical trials represents a real strength of our team as it allows us to develop translational programs with a rapid transfer to early phase clinical trials.

Axe 1: Candidate genes to overcome drug resistance in urological cancers

In prostate cancer, we are studying the role of the nuclear receptor PXR and its target genes in the resistance to the combination of B-RAF/MEK inhibitors. We previously demonstrated that expression of PXR could modulate prostate cancer cell response to various kinase inhibitors, in particular sensitize cancers cells to the EGFR kinase inhibitor Afatinib by regulating expression of a drug. We are also studying the role of Androgen receptor (AR) and its splicing variants in response to enzalutamide and abiraterone acetate.

In urothelial cancer, we have recently identified a mechanism that contributes to the resistance of tumor cells to the action of the immune system. Indeed, we have shown that chemotherapies induced the expression of the transcription factor ATF3 which prevents the production of interferon beta, a cytokine essential for immunity activation. For this project we developed in vitro alternatives models to animal experimentation, namely heterotypic spheroids composed of tumor cells and PBMC (from healthy donors or patients) or TILs. Using these models, we are now studying the response to immune checkpoint inhibitors.

Axe 2: Potential inhibitors of existing targets with original mechanism of action

We are studying the mechanism of action of a new imiqualine derivatives (EAPB02303) that showed anticancer activity toward PDAC. We showed that this compound activity involves a first step of bio activation by the Catechol-O-methyltransferase (a mechanism never before described for a drug), resulting in the production of a methylated compound that effectively inhibits microtubule polymerization.

In the same vein, we are characterizing a new class of DNA mimics that inhibit the catalytic activity of DNA interacting enzymes, including DNA topoisomerase 1. The fact that these mimics can inhibit the growth of cancer cells resistant to Top1 poisons used in the clinic led us to use these molecules as payloads for the synthesis of ADCs that will be used to specifically target CRC tumors and overcome resistance to irinotecan.

Axe 3: New drug combination overcoming resistance in digestive cancers

We previously observed that combination of platin-based treatment with ATR inhibitors was synergistic and remodels the immune landscape of the tumor. Based on these results we currently address the impact of ATR inhibition in combination with oxaliplatin in CRC or in combination with FOLFIRINOX in PDAC added with anti-PD1 immunotherapies.