Periodic Reporting for period 1 - TargetSWItch (Targeting SWI/SNF-related chromatin remodelling defects in solid tumours)
Periodo di rendicontazione: 2023-05-01 al 2025-10-31
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.
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.
Molecular classification of epithelioid sarcoma: To establish a molecular classification of epithelioid sarcoma and explore molecular determinants of this disease’s heterogeneity, we used multi-omics profiling and integrated the genomic, transcriptional and methylome landscapes with single-cell and spatial transcriptomics, i.e. a technology that provides a comprehensive view of which genes are active and where they are located within the tumour. We identified two epithelioid sarcoma molecular subtypes distinct from the traditional clinicopathological ones, which we called “distal-like" and "proximal-like". “Distal-like” tumours harbour a cancer cell-specific epithelial-to-mesenchymal transition signature which associates with improved patient survival, higher peri-tumoral CD8+ lymphocyte infiltrates with specific tumour-immune interactions. We found that “proximal-like” epithelioid sarcoma display a higher inter-tumoral heterogeneity, increased intra-tumoral immunosuppressive macrophages, and some similarities with other SMARCB1-deficient tumours. Our study, now published in Cancer Communications, proposes a novel molecular classification for epithelioid sarcoma that extends beyond traditional clinicopathological one and paves the way for precision medicine-based therapeutic strategies.
Epitranscriptomic-related synthetic lethality: Epitranscriptomics is a new field in cancer research which focused on modifications (aka editing) of the RNA. While exploring the molecular mechanisms of PARP inhibitor-associated genetic vulnerabilities, we discovered a new synthetic lethality between the BRCA1/2 DNA repair genes and RNA editing enzyme ADAR1. We found that this synthetic lethality was operating in multiple species and cellular contexts. Mechanistically, we identified that ADAR1 depletion notably triggered a cell-autonomous interferon response, which eventually caused cell death through interferon poisoning. This finding, now published in Nature Communications, introduces a conceptually novel approach to synthetic lethal treatments, which exploits tumour cell-intrinsic cytosolic immunity as a targetable vulnerability of cancer cells.
Epitranscriptomic-related synthetic lethality: Epitranscriptomics is a new field in cancer research which focused on modifications (aka editing) of the RNA. While exploring the molecular mechanisms of PARP inhibitor-associated genetic vulnerabilities, we discovered a new synthetic lethality between the BRCA1/2 DNA repair genes and RNA editing enzyme ADAR1. We found that this synthetic lethality was operating in multiple species and cellular contexts. Mechanistically, we identified that ADAR1 depletion notably triggered a cell-autonomous interferon response, which eventually caused cell death through interferon poisoning. This finding, now published in Nature Communications, introduces a conceptually novel approach to synthetic lethal treatments, which exploits tumour cell-intrinsic cytosolic immunity as a targetable vulnerability of cancer cells.
Our project has also resulted in a valuable collection of multi-omics and molecular profiling data, which is now available to the scientific community. We have notably uploaded datasets from the epithelioid sarcoma cohort which served as basis for the molecular classification into the European Genome-phenome Archive (EGA) database.
Our project has also resulted in the discovery of a conceptually novel approach to synthetic lethal treatments, which exploits tumour cell-intrinsic cytosolic immunity as a targetable vulnerability of cancer cells. Such synthetic lethal interactions may also operate in other genetic contexts, thereby extending the traditional applications of synthetic lethality. These may also represent novel therapeutic opportunities to either sensitise tumours to immune therapies or favouring more tolerable drug combinations which leveraging on two different hallmarks of cancer, thereby limiting overlapping toxicities. More specifically for the BRCA1/2 – ADAR1 synthetic lethality, this discovery may result in novel treatment opportunities for patients with BRCA1/2-defective cancers, since ADAR1-targeting compounds are being developed by multiple companies.
Finally, preliminary synthetic lethal interactions identified preclinically with SWI/SNF defects may in the future result in novel therapeutic approaches. To first make the proof-of-concept that SWI/SNF defects can be targeted using a biomarker-, precision medicine-based strategy, we are currently working on the development of one academic clinical trial, which will evaluate one previously validated synthetic lethal drug; it should hopefully open in 2026, pending regulatory authority approval.
Overall, our research enabled the identification of potential novel therapeutic strategies for patients and contributed to public repositories for further research performed by the scientific community.
Our project has also resulted in the discovery of a conceptually novel approach to synthetic lethal treatments, which exploits tumour cell-intrinsic cytosolic immunity as a targetable vulnerability of cancer cells. Such synthetic lethal interactions may also operate in other genetic contexts, thereby extending the traditional applications of synthetic lethality. These may also represent novel therapeutic opportunities to either sensitise tumours to immune therapies or favouring more tolerable drug combinations which leveraging on two different hallmarks of cancer, thereby limiting overlapping toxicities. More specifically for the BRCA1/2 – ADAR1 synthetic lethality, this discovery may result in novel treatment opportunities for patients with BRCA1/2-defective cancers, since ADAR1-targeting compounds are being developed by multiple companies.
Finally, preliminary synthetic lethal interactions identified preclinically with SWI/SNF defects may in the future result in novel therapeutic approaches. To first make the proof-of-concept that SWI/SNF defects can be targeted using a biomarker-, precision medicine-based strategy, we are currently working on the development of one academic clinical trial, which will evaluate one previously validated synthetic lethal drug; it should hopefully open in 2026, pending regulatory authority approval.
Overall, our research enabled the identification of potential novel therapeutic strategies for patients and contributed to public repositories for further research performed by the scientific community.