Non-canonical SWI/SNF complex and uses thereof
Inventors
Kadoch, Cigall • Michel, Brittany C. • D'Avino, Andrew
Assignees
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Publication Number
US-12729225-B2
Publication Date
2026-09-08
Expiration Date
Abstract
The present invention provides compositions and methods for treating cancers with canonical BAF (cBAF) complex perturbations (e.g. synovial sarcoma or malignant rhabdoid tumor) using an agent that inhibits the formation, activity, and/or stability of the ncBAF complex.
Core Innovation
The disclosure describes non-canonical BAF complexes as synthetic-lethal targets in cancers characterized by reduced copy number, amount, or activity of a core cBAF component, specifically ARID1A, ARID1B, or SMARCE1. The non-canonical BAF complex is biochemically distinct from cBAF and PBAF, associating specifically with GLTSCR1 and BRD9 while lacking core subunits such as SMARCE1. Genomic and proteomic analyses identify GLTSCR1 as an essential component maintaining gene expression at promoters and CTCF sites.
A GLTSCR1-homologous nucleic acid agent, including siRNA, shRNA, or gRNA, downregulates GLTSCR1 to inhibit non-canonical BAF complex formation, activity, stability, or binding to chromatin and other proteins. This downregulation serves as a synthetic-lethal strategy to treat afflicted subjects or reduce cancer-cell viability and proliferation. Disclosed cancer models exhibiting sensitivity to GLTSCR1 depletion include synovial sarcoma and malignant rhabdoid tumors with core canonical BAF perturbations.
Claims Coverage
The claim coverage includes two independent claims directed to treating cancer and reducing cancer-cell viability or proliferation, encompassing four inventive features across the claims.
Treatment of cancer with reduced core cBAF component
The claim provides administering a therapeutically effective amount of a GLTSCR1-homologous nucleic acid agent, such as an siRNA, shRNA, or gRNA, to a subject with cancer having reduced copy number, amount, or activity of ARID1A, ARID1B, or SMARCE1 to downregulate GLTSCR1 and inhibit ncBAF complex formation, activity, stability, or binding to chromatin or other proteins.
Reduction of cancer-cell viability or proliferation
The claim provides contacting cancer cells having reduced copy number, amount, or activity of ARID1A, ARID1B, or SMARCE1 with a GLTSCR1-homologous nucleic acid agent to downregulate GLTSCR1 and inhibit ncBAF complex formation, activity, stability, or binding to chromatin or other proteins in vivo, ex vivo, or in vitro.
Combination with immunotherapy or cancer therapy
The claims provide administering immunotherapy or cancer therapy before, after, or concurrently with the nucleic acid agent, wherein the cancer therapy includes radiation, a radiosensitizer, or chemotherapy, and the immunotherapy includes cell-based immunotherapy, a cancer vaccine, a virus, or immune checkpoint inhibition.
Cancer-cell and tumor reduction outcomes
The claims provide outcomes comprising reducing viable or proliferating cancer cells, reducing tumor volume or size, formulating the agent in a pharmaceutically acceptable formulation, and contacting cancer cells in vivo, ex vivo, or in vitro.
Together, the claims cover GLTSCR1-homologous nucleic acid methods for treating cancer and reducing cancer-cell viability or proliferation in malignancies with reduced core cBAF components ARID1A, ARID1B, or SMARCE1, along with associated therapeutic combinations and delivery formats.
Stated Advantages
The claims state that the methods reduce the viability or proliferation of cancer cells and reduce tumor volume or size.
The reported findings support a selective ncBAF vulnerability in cancers with perturbed core cBAF function.
Downregulating GLTSCR1 inhibits ncBAF complex formation, activity, or stability, or its binding to chromatin or other proteins.
Documented Applications
Treatment of a subject with cancer associated with reduced copy number, amount, or activity of ARID1A, ARID1B, or SMARCE1, including synovial sarcoma and malignant rhabdoid tumor.
Reduction of viability or proliferation of cancer cells with reduced core cBAF components ARID1A, ARID1B, or SMARCE1 in vivo, ex vivo, or in vitro.
Combination treatments employing the GLTSCR1-homologous nucleic acid agent with radiation, radiosensitizers, chemotherapy, or immunotherapy.
Screening assays for identifying agents that inhibit ncBAF functions and reduce cancer-cell viability or proliferation.
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