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Role of the SWI/SNF complex in tumor suppression

Award Number: R01CA172152
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2013
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Role of the SWI/SNF complex in tumor suppression - Project Summary/Abstract: A role for SWI/SNF complexes in cancer was first suggested when SMARCB1 was identified as inactivated in virtually all malignant rhabdoid tumor (RT) cases, a highly aggressive pediatric cancer. It is now clear that mutations in genes encoding subunits of SWI/SNF (BAF) chromatin-remodeling complexes are frequent, collectively occurring in over 20% of all cancers. Our group established SMARCB1 as a bona fide and potent tumor suppressor. We later made high-impact discoveries that helped define mechanisms by which SWI/SNF mutations lead to dysregulated cell proliferation. Our findings suggest a model whereby SWI/SNF- facilitated control of transcription underlies cellular fate specification, with disruption of this control being the basis for cancer formation. Our long-term goals are to elucidate the function of SWI/SNF complexes, to determine how their loss leads to oncogenesis, and to translate this knowledge into novel therapies. Based on our findings, we hypothesized that loss of SMARCB1, while driving cancer growth, also creates unique vulnerabilities. To identify such vulnerabilities, we collaborated with the Pediatric Dependencies Project to perform a rigorous genome-wide CRISPR deletion screen involving 21 RT cell lines compared to over 800 other cancer cell lines. Notably, rhabdoid tumors are typically diploid and contain few other mutations, making them a powerful model with which to study the effects of gene deletions. We have now identified and validated a novel gene that is specifically essential for rhabdoid cell survival from this screen. Our preliminary data reveal that this gene's product, previously only linked to gene repression, has unanticipated connections with SWI/SNF and transcriptional activity. We localize this protein to enhancers and promoters of genes bound by SWI/SNF and hypothesize that this protein performs a key regulatory role in determining whether activating SWI/SNF complexes or repressive complexes are recruited, thus serving a pivotal role in dictating cell fate. We previously demonstrated that SWI/SNF and another repressive protein, EZH2, serve antagonistic roles in chromatin regulation, a discovery that ultimately led to FDA approval of an EZH2 inhibitor (EZH2i) for SMARCB1-mutant cancers. Despite this success, the mechanisms that control the interplay between these complexes are poorly understood, as are the mechanisms that underlie resistance to EZH2i in SWI/SNF-mutant cancers. To establish mechanisms driving drug resistance, we have performed a near genome-wide CRISPR screen in EZH2 inhibitor-treated RTs. We previously identified NSD1 as a gene that, when inactivated, causes resistance to EZH2i. Here, we plan to investigate the mechanism of resistance conferred by mutations in a second chromatin regulatory gene not previously associated with SWI/SNF functions. Together, these experiments have the potential for broad impact including understanding the roles of these critical chromatin remodeling complexes in transcriptional control, in transformation, and as potential therapeutic vulnerabilities.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $450,446 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	003	13	4/4/2025	NON-COMPETING CONTINUATION	$405,401
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	004	13	5/22/2025	NON-COMPETING CONTINUATION	$45,045
2025	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	002	12	3/28/2025	COMPETING CONTINUATION	$47
2025	2022	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	001	11	3/28/2025	NON-COMPETING CONTINUATION	-$47
2025	2022	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	11	2/27/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $450,446

Issue Date FY: 2024 ( Subtotal = $450,446 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	001	12	2/1/2024	COMPETING CONTINUATION	$450,446
2024	2022	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	11	2/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $450,446

Issue Date FY: 2022 ( Subtotal = $390,919 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	11	9/21/2022	NON-COMPETING CONTINUATION	$390,919
														Subtotal = $390,919

Issue Date FY: 2021 ( Subtotal = $399,004 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	10	8/6/2021	NON-COMPETING CONTINUATION	$399,004
														Subtotal = $399,004

Issue Date FY: 2020 ( Subtotal = $399,112 )
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	9	8/27/2020	NON-COMPETING CONTINUATION	$399,112
														Subtotal = $399,112

Issue Date FY: 2019 ( Subtotal = $387,236 )
2019	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	002	8	7/25/2019	NON-COMPETING CONTINUATION	$387,236
2019	2018	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	001	7	12/14/2018	COMPETING CONTINUATION	$38,492
2019	2017	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	6	12/14/2018	NON-COMPETING CONTINUATION	-$38,492
														Subtotal = $387,236

Issue Date FY: 2018 ( Subtotal = $419,188 )
2018	2018	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	7	8/29/2018	COMPETING CONTINUATION	$419,188
														Subtotal = $419,188

Issue Date FY: 2017 ( Subtotal = $357,826 )
2017	2017	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL MAILSTOP # 509	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	6	6/21/2017	NON-COMPETING CONTINUATION	$357,826
														Subtotal = $357,826

Issue Date FY: 2016 ( Subtotal = $335,023 )
2016	2016	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	002	5	6/27/2016	NON-COMPETING CONTINUATION	$335,023
2016	2015	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	001	4	1/8/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$208,753
2016	2015	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	3	1/7/2016	NON-COMPETING CONTINUATION	-$208,753
														Subtotal = $335,023

Issue Date FY: 2015 ( Subtotal = $359,256 )
2015	2015	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	3	5/18/2015	NON-COMPETING CONTINUATION	$359,256
														Subtotal = $359,256

Issue Date FY: 2014 ( Subtotal = $348,478 )
2014	2014	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	2	6/5/2014	NON-COMPETING CONTINUATION	$348,478
														Subtotal = $348,478

Issue Date FY: 2013 ( Subtotal = $359,256 )
2013	2013	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	1	6/26/2013	NEW	$359,256
														Subtotal = $359,256

Grand Total All Awards = $4,656,190

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Role of the SWI/SNF complex in tumor suppression

Award Number: R01CA172152

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2013

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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