Recent large-scale genomic profiling studies have uncovered mutations in the SWI/SNF (Switch / Sucrose Non-Fermentable) chromatin remodelling complex subunits in 20% of solid tumours. Most of these tumours resist to current therapies. To address this highly unmet medical need, it is crucial to determine how to harness vulnerabilities induced by SWI/SNF defects and to identify novel, targeted strategies against SWI/SNF-defective cancers. Recent evidence suggests that SWI/SNF interacts with the DNA repair apparatus and is involved in shaping tumour immunogenicity. I therefore propose to identify and understand synthetic lethal vulnerabilities associated with SWI/SNF defects, and study how the latter can be exploited to stimulate the anti-tumour immune response, in order to develop novel, targeted, effective therapeutic approaches that I will ultimately translate into a proof-of-concept clinical protocol.
Parallel hypothesis-testing and -generating approaches will be used to identify and decipher novel synthetic lethal vulnerabilities associated with selected SWI/SNF defects. This will be done using in-house developed isogenic and non-isogenic models of SWI/SNF deficiency and tumour samples. Molecular biology, high-content imaging and in vivo experiments on xenografts and syngeneic models will be performed to study the effects of drugs that are synthetic lethal with SWI/SNF defects both on intra-cellular signalling and anti-tumour immune response. I will further combine high-throughput screening and proteomic approaches to comprehensively characterise SWI/SNF-associated vulnerabilities and interactome. The impact of SWI/SNF defects on tumour heterogeneity will be investigated. Preclinical data will be integrated with in-house generated tumour profiling data and guide the development of clinical studies. The overall research program will identify, decipher mechanistically and evaluate clinically novel immuno-oncology therapeutic strategies for SWI/SNF-deficient tumours.
Madame Sophie Postel-Vinay (U981 INSERM - Gustave Roussy)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
U981 INSERM - Gustave Roussy
Help of the ANR 124,977 euros
Beginning and duration of the scientific project: December 2020 - 24 Months