This translational research project “from genes to personalized medicine” aims to solve core problems in the treatment of selected solid and hematological tumors for which CARPEM teams have recently show their competences in innovative research. Our strategy starts from basic research projects developed using a wide-range of genomic, cellular and animal approaches to identify novel genetic or epigenetic drivers that would be critical for a more personalized therapeutic approach. Findings obtained from human tissue samples applying high-end technology will be confirmed in experimental models and translated into novel biomarkers and targets for high impact clinical use.
The main concepts supporting this proposal. Four major advancements in genomic could critically improve the outcome of patients with cancer:
1/ The identification of critical molecular subclasses with different prognostic implications. In most of the tumors, prognosis prediction still relies mainly on clinical and histological parameters. However, molecular data represents a critical bottleneck for improving cancer patient outcome and will contribute to guide therapeutic decision-making. Biomarkers able to define subgroups of patients with particularly dismal prognosis will translate into a better therapeutic strategies and allocation of resources.
2/ The identification of the key genetic or epigenetic drivers of specific subclasses, will point to a more personalized treatment algorithms. Both challenges are bounded by the complexity of the molecular basis of these neoplasms and this project is designed to overcome the limitations in currently knowledge to open up a new range of management options. In this line, it is crucial that fundamental academic research owing to understand the molecular and cellular mechanisms that underline the differentiation pathways will be combined with more translational research, since it is now well known that many mechanisms that established cellular identity during development are deregulated during carcinogenesis.
3/ By definition, the drugs used to treat cancer are toxic and, in view of the seriousness of the illness being treated, some degree of toxicity is acceptable. This means that these drugs have a narrow therapeutic window; and so it is essential to identify the factors that can alter drug response and modify the efficacy/toxicity equilibrium. Toxicity and efficacy of a anticancer drug can depend on germline polymorphisms. The study of genetic polymorphisms (pharmacogenetics) will help to choose the treatment the most efficiency and the less toxic
4/ Most of the targeted treatments pinpoint a specific pathway activated in tumor regardless of the cause of this alteration. A new step in personalized medicine was recently achieved with the development of targeted therapy directed against a specific genetic alteration in contrast to previous targeted therapies that inhibit a pathway activated in the tumor. A specific inhibitor of mutated V600E BRAF has demonstrated an impressive clinical efficiency with few adverse events in a recent phase I/II study in melanoma. A predictive molecular tool could also be used to identify patients who are poor candidates for a particular biotherapy. In metastatic colorectal cancer, Pierre Laurent-Puig team’s showed for the first time that the presence of KRAS or BRAF activating mutations are predictive of non-response to monoclonal antibody directed against EGFR (cetuximab or panitumuab). In the future, we can anticipate that identifying the genes mutated in the tumor before treatment or after treatment failure will be necessary to adapt therapies and for the clinical management of cancer. In addition, a better understanding of the interactions between signaling pathways in each tissue context is required to refine targeted therapies.
Project will be developed using different 4 tasks in functional genomics: