Genetic and Epigenetic Vulnerabilities of Solid Tumors and Sarcomas

Objectives and Challenges

Our research aims to exploit the genetic and epigenetic vulnerabilities of tumor cells to develop new therapeutic approaches targeting sarcomas and tumors with defects in DNA repair and chromatin remodeling. The major challenge is the development of immuno-oncology treatments and the understanding of tumor heterogeneity, through the integration of preclinical results with multi-omic and clinical patient data.

Research Areas/Major Projects

The main research areas are i) the identification of new genetic dependencies in tumors deficient in DNA repair (e.g., BRCA1/2) or exhibiting abnormalities in the SWI/SNF chromatin remodeling complex (e.g., loss of SMARCB1 in epithelioid sarcomas) through functional genomics, ii) understanding the interactions between these dependencies and the antitumor immune response—particularly the modulation of innate immunity—in order to propose rational therapeutic combinations in immuno-oncology, iii) and the study of tumor heterogeneity in certain sarcomas by performing their multi-omic molecular characterization, which is then integrated into preclinical modeling.

Major Findings and Scientific, Clinical, and Societal Impacts

Our main results include (i) the description of the immunomodulatory potential of PARP inhibitors in tumors where they induce synthetic lethality, (ii) the discovery of synthetic lethality between BRCA1 and ADAR1-mediated epitranscriptomic regulation, mediated by an interferon response, (iii) the characterization of the heterogeneity and multi-omic classification of small round cell desmoplastic tumors and epithelioid sarcomas. The impact of this research is demonstrated by its clinical translation through the development of academic clinical trials conducted at Gustave Roussy Hospital.