Our project

The overall purpose of our project as a whole is to understand and predict the effects of xenobiotics in Man. The response to xenobiotics (pharmacological efficacy, toxicity) is extremely variable due to the metabolism and transport of xenobiotics, to their targets or to the body's reaction. Our project, following on from that of U775, consists in 1) using clinical approaches to validate and use biomarkers of this response with a view to personalized medicine and 2) using fundamental approaches to elucidate the mechanisms of this response The translational research aspect will consist of pharmacogenetic studies of 4 classes of drug: immuno-suppressants, anti-coagulants, psychotropics and anti-cancer drugs. Assumptionfree as well as gene-candidate approaches will be used in studies running alongside clinical trials to ensure the quality standard of the data obtained. In the case of anti-cancer drugs, we intend to extend this concept to the characterization of somatic genetic anomalies that could modify the efficacy of targeted chemotherapies in two types of cancer (colorectal and lung). This research has already allowed us (see Assessment) to identify new genetic biomarkers, to validate them and use them in the hospital context, and will allow us to continue to do so in the future. The fundamental research part will consist of two topics: 1) the metabolism of xenobiotics and 2) molecular toxicology. 1) We will investigate, in both normal and diseased brains, the distribution and enzymatic function of cytochromes P450 in order to determine their physiological, pathological, and pharmacological role in this organ. At the molecular level we will also study the effects of a fusion of NADPH cytochrome P450 reductase on the catalytic activity of CYP2B6, and of some of its mutants to extend the strategy of improving and targeting the treatment of solid tumors with cyclophosphamide. 2) we will attempt to characterize i) EGFR signaling pathways in tumors in order to understand the phenomenon of resistance to treatment, and to identify new biomarkers. ii)the mechanisms of the molecular toxicity of immunosuppressants that induce chronic nephropathy in the transplant, iii) the effects of pollutants on the adipose tissue, and their consequences using assumption-free general methods (transcriptome, metabolome) and iv) the initial immuno-toxicological mechanisms induced by hepatotoxic drugs, based on clearly established examples (tielinic acid, dihydralazine) in animal models and These various approaches will make it possible to elucidate the molecular mechanisms of the responses to xenobiotics, and to develop early predictive biomarkers of this response that we will go on to validate and use in our hospital practice.