Targeting SWI/SNF-related chromatin remodelling defects in solid tumours

Introduction

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 current therapies. To address this highly unmet medical need, it is crucial to determine how to harness vulnerabilities induced by SWI/SNF defects.

Background

Recent evidence shows that SWI/SNF influences the DNA damage response and is involved in shaping tumour immunogenicity. However, whether there is a link between these observations, and whether the latter may be therapeutically exploited is unknown. Furthermore, the impact of SWI/SNF defects on tumour heterogeneity, a major determinant of resistance to treatment, remains unaddressed.

Research Proposal

I therefore propose to identify and understand synthetic lethal vulnerabilities associated with two selected SWI/SNF defects of unmet need (PBRM1 and SMARCB1). Additionally, I will study how these vulnerabilities can be exploited to stimulate the anti-tumour immune response.

Methodology

By using hypothesis-testing and -generating approaches, including high-throughput screening on in-house developed isogenic and non-isogenic models, I will:

1. Identify and decipher novel synthetic lethal vulnerabilities associated with PBRM1 and SMARCB1 defects.
2. Perform molecular biology, high-content imaging, and in vivo experiments to study the effects of drugs that cause synthetic lethality, both on intra-cellular signalling and on the anti-tumour immune response.
3. Characterise the impact of SMARCB1 defects on tumour heterogeneity using single-cell sequencing on preclinical models and human tumour samples.

Data Integration

Preclinical data will be integrated with tumour profiling and clinical data, which will guide the development of proof-of-concept clinical studies, as I previously did.

Conclusion

The overall research program will identify, decipher mechanistically, and evaluate clinically novel immuno-oncology therapeutic strategies for selected SWI/SNF-deficient tumours of unmet need.