Non-canonical SWI/SNF complex and uses thereof
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.
1 . A method of treating a subject afflicted with a cancer that has a reduced copy number, amount, and/or activity of a core cBAF component, wherein the core cBAF component is selected from the group consisting of ARID1A, ARID1B, and SMARCE1,
the method comprising administering to the subject a therapeutically effective amount of a nucleic acid agent that comprises a nucleotide sequence that is homologous to the nucleotide sequence of GLTSCR1 or a portion thereof,
wherein the nucleic acid agent downregulates the copy number or amount of GLTSCR1 and thereby inhibits the formation, activity, and/or stability of noncanonical BAF (ncBAF) complex, and/or the binding of ncBAF complex to chromatin or other proteins;
wherein the nucleic acid agent (a) is selected from the group consisting of an siRNA, an shRNA, and a gRNA, and (b) comprises a sequence set forth in any one of SEQ ID NOs: 47-50.
2 . The method of claim 1 , wherein the nucleic acid agent
a) reduces the number of viable or proliferating cells in the cancer, and/or reduces the volume or size of a tumor comprising the cancer cells; and/or
b) is administered in a pharmaceutically acceptable formulation.
3 . The method of claim 1 , further comprising administering to the subject an immunotherapy and/or cancer therapy, optionally wherein the immunotherapy and/or cancer therapy is administered before, after, or concurrently with the agent.
4 . The method of claim 3 , wherein the immunotherapy
a) is cell-based;
b) comprises a cancer vaccine and/or virus;
c) inhibits an immune checkpoint, optionally wherein the immune checkpoint is selected from the group consisting of CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, GITR, 4-IBB, OX-40, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, HHLA2, butyrophilins, and A2aR.
5 . The method of claim 3 , wherein the cancer therapy is selected from the group consisting of radiation, a radiosensitizer, and a chemotherapy.
6 . The method of claim 1 , further comprising administering to the subject at least one additional therapeutic agent or regimen for treating the cancer.
7 . The method of claim 1 , wherein the subject is selected from the group consisting of 1) an animal model of the cancer, 2) a mouse model of the cancer, 3) a mammal, 4) a mouse, and 5) a human.
8 . A method of reducing viability or proliferation of cancer cells having a reduced copy number, amount, and/or activity of a core cBAF component, wherein the core cBAF component is selected from the group consisting of ARIDIA, ARID1B, and SMARCE1,
the method comprising contacting the cancer cells with a nucleic acid agent that comprises a nucleotide sequence that is homologous to the nucleotide sequence of GLTSCR1 or a portion thereof,
wherein the nucleic acid agent downregulates the copy number or amount of GLTSCR1 and thereby inhibits the formation, activity, and/or stability of ncBAF complex, and/or the binding of ncBAF complex to chromatin or other proteins;
wherein the nucleic acid agent (a) is selected from the group consisting of an siRNA, an shRNA, and a gRNA, and (b) comprises a sequence set forth in any one of SEQ ID NOs: 47-50.
9 . The method of claim 8 , wherein the nucleic acid agent
a) reduces the number of viable or proliferating cells in the cancer, and/or reduces the volume or size of a tumor comprising the cancer cells;
b) is administered in a pharmaceutically acceptable formulation.
10 . The method of claim 8 , further comprising contacting the cancer cells with an immunotherapy and/or cancer therapy, optionally wherein the immunotherapy and/or cancer therapy contacts the cancer cells before, after, or concurrently with the agent.
11 . The method of claim 10 , wherein the immunotherapy
a) is cell-based;
b) comprises a cancer vaccine and/or virus;
c) inhibits an immune checkpoint, optionally wherein the immune checkpoint is selected from the group consisting of CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, GITR, 4-IBB, OX-40, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, HHLA2, butyrophilins, and A2aR.
12 . The method of claim 10 , wherein the cancer therapy is selected from the group consisting of radiation, a radiosensitizer, and a chemotherapy.
13 . The method of claim 8 , wherein the step of contacting occurs in vivo, ex vivo, or in vitro, optionally wherein the in vivo contact occurs in a subject selected from the group consisting of 1) an animal model of the cancer, optionally wherein the animal model is a mouse model, 2) a mammal, 3) a mouse, and 4) a human.