Over the past decades, cancer treatment has switched from a “one-size-fits-all” approach to a precision medicine-based approach, i.e. customising therapy to the patient’s tumour characteristics. Such molecularly targeted treatments have shown tremendous efficacy against some cancer genetic alterations, but not others. Notably, defects in a multi-subunit complex called SWI/SNF, which remodels the tumour cell chromatin and thereby modifies gene expression, are found in 20% of solid tumours, but there is currently virtually no effective therapy to treat them. We therefore want to explore the consequences of SWI/SNF defects in cancer and hopefully identify novel therapeutic approaches for this patient population.
More specifically, we will focus on selected SWI/SNF subunits, including SMARCB1. SMARCB1 is a core subunit, the loss of which plays a key role in the development of a highly aggressive malignancy called epithelioid sarcoma. Using high-throughput screening and functional molecular biology approaches, integrated with patient molecular and clinical data, we aim at (i) identifying novel therapeutic approaches, notably be based on synthetic lethality, i.e. a genetic interaction where the simultaneous loss of two genes results in cell death, while the loss of either gene alone is non-lethal; (ii) understanding the tumour heterogeneity, i.e. the fact that all tumour cells are not identical; (iii) building a novel molecular classification for epithelioid sarcoma, to better guide patient treatment, and ultimately (iv) evaluating at least one of our main findings in a proof-of-concept clinical trial.
Overall, by integrating laboratory work with patient data using breakthrough technological approaches, we will identify novel, targeted, therapeutic strategies to treat some SWI/SNF-defective tumours and improve our understanding of epithelioid sarcoma biology, to hopefully ultimately improve patient outcome.
