The research project of Cyril Corbet's group is to characterize the metabolism of therapy-resistant cancer cells (incl. cancer stem cells) and the interplay thereof with the tumor microenvironment in order to develop new targeted therapies overcoming conventional treatment escape.
Resistance to chemotherapy and molecularly targeted therapies is a major issue in cancer research. Mechanisms of resistance to classical cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. Within the tumor heterogeneity, a small subset of cancer cells (the so-called "minimal residual disease") can survive in the patient during and after treatment. These tumor-initiating cells (TICs) or cancer stem cells (CSCs) have the properties of self-renewal, clonal tumor initiation capacity and clonal long-term repopulation potential, all these features suggested to be the underlying causes of tumor recurrence. In addition, the phenotypic heterogeneity within a tumor makes it very likely that resistant cells are present before therapy regardless of the cancer genetic landscape and the selection of the most appropriate oncogene-targeting drug (i.e. de novo drug resistance).
Pre-existing relapse-inducing tumor cells are proposed to reside in niches, which are anatomically distinct regions within the TME. These niches preserve their phenotypic plasticity, protect them from the immune system and anticancer therapies and facilitate their metastatic potential. Altogether, the niche-mediated phenotypic alterations in cancer cells may support tumor progression and affect treatment outcome, highlighting the need to find new therapeutic strategies to target this small fraction of cancer cells within the tumor sites.
With the increasing arsenal of anticancer agents, improving preclinical models (i.e. patient-derived xenografts and/or organoids) and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.
Our main goals
- To identify the metabolic features associated with cancer treatment resistance by using several preclinical models including treatment-resistant cancer cell lines, patient-derived xenografts and organoids
- To characterize the metabolic preferences of treatment-resistant cancer cells/cancer stem cells at the light of their microenvironmental niche (i.e. hypoxia, acidosis, presence of stromal cells...)
- To manipulate the metabolic vulnerabilities of treatment-resistant cancer cells/cancer stem cells in order to improve the efficacy of conventional treatments such as chemo- and radiotherapies as well as targeted therapies