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The function of Snf5 (SMARCB1), an epigenetic tumor suppressor

Award Number: R01CA113794
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2005
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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The function of Snf5 (SMARCB1), an epigenetic tumor suppressor - Project Summary/Abstract: SMARCB1 (SNF5/INI1/BAF47) is a conserved subunit of SWI/SNF chromatin remodeling complexes, which utilize the energy of ATP hydrolysis to mobilize nucleosomes. A role for SWI/SNF complexes in cancer was first suggested when SMARCB1 was identified as inactivated in virtually all cases of malignant rhabdoid tumor (RT), a highly aggressive pediatric cancer. It has recently been discovered that nearly 25% of all human malignancies carry mutations in SWI/SNF subunits. We established SMARCB1 to be a bona fide and potent tumor suppressor and later demonstrated broad epigenetic antagonism between SWI/SNF and Polycomb repressor complexes during oncogenic transformation. In subsequent work, including substantial progress in the current funding period, we uncovered novel biological mechanisms and therapeutic vulnerabilities that form the foundation for the aims described in this proposal. For example, we found that SMARCB1 is essential for enhancer regulation, thus identifying a new mechanism underlying the tumor-suppressive activity of SMARCB1. We and others also discovered the existence of a SWI/SNF complex that lacks SMARCB1, previously considered a core subunit. Instead, this non-canonical complex contains the bromodomain protein BRD9, which we also identified as a specific vulnerability in SMARCB1-deficient pediatric RTs. While our findings demonstrate critical interactions of SWI/SNF and Polycomb complexes in transcriptional regulation and cell fate control, the roles and contributions of SWI/SNF sub-families are unknown. Our first aim is therefore to determine how SMARCB1-containing SWI/SNF complexes differ from mutually-exclusive BRD9- containing SWI/SNF complexes in the antagonism of Polycomb interactions and transcriptional regulation. Recent data from our group have shown that SWI/SNF complexes control histone acetylation and enhancer function; however, the mechanism by which this leads to a mitotically heritable cancer phenotype is unknown. Polycomb complexes remain bound to DNA during mitosis, but histone acetylation is erased and the SWI/SNF ATPase, SMARCA4/BRG1 is phosphorylated and degraded. Thus, for our second aim, we propose to determine how SWI/SNF complexes contribute to epigenetic memory during mitosis, including interrogating a potentially paradigm-shifting model that is supported by preliminary data described in this proposal. Finally, we identified the Polycomb subunit EZH2 as a vulnerability in RTs, inspiring the development of several clinical trials and leading to recent FDA approval of EZH2 inhibitors for SMARCB1-deficient sarcomas. While impactful, resistance to these inhibitors has emerged. To establish mechanisms driving drug resistance, we have performed a near genome-wide CRISPR screen in EZH2 inhibitor-treated RTs, and for our third aim plan to investigate the mechanism of resistance conferred by mutations in a gene not previously associated with SWI/SNF functions. Taken together, these questions have potential for broad and substantive impact in understanding the roles of these critical chromatin remodeling complexes in normal cells and in transformation.


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 = $423,510 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	001	21	6/13/2025	NON-COMPETING CONTINUATION	$42,351
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	21	11/21/2024	NON-COMPETING CONTINUATION	$381,159
														Subtotal = $423,510

Issue Date FY: 2024 ( Subtotal = $402,334 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	20	11/14/2023	NON-COMPETING CONTINUATION	$381,159
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	001	20	4/18/2024	NON-COMPETING CONTINUATION	$21,175
														Subtotal = $402,334

Issue Date FY: 2023 ( Subtotal = $423,510 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	002	19	9/15/2023	NON-COMPETING CONTINUATION	$8,471
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	19	11/10/2022	NON-COMPETING CONTINUATION	$381,159
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	001	19	3/17/2023	NON-COMPETING CONTINUATION	$33,880
														Subtotal = $423,510

Issue Date FY: 2022 ( Subtotal = $415,039 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	001	18	5/4/2022	NON-COMPETING CONTINUATION	$33,881
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	18	12/14/2021	NON-COMPETING CONTINUATION	$381,158
														Subtotal = $415,039

Issue Date FY: 2021 ( Subtotal = $442,391 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	17	11/30/2020	COMPETING CONTINUATION	$442,391
2021	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	001	16	3/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $442,391

Issue Date FY: 2019 ( Subtotal = $358,663 )
2019	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	16	5/10/2019	NON-COMPETING CONTINUATION	$358,663
														Subtotal = $358,663

Issue Date FY: 2018 ( Subtotal = $369,757 )
2018	2018	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	000	15	4/23/2018	NON-COMPETING CONTINUATION	$369,757
														Subtotal = $369,757

Issue Date FY: 2017 ( Subtotal = $369,757 )
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	14	5/22/2017	NON-COMPETING CONTINUATION	$369,757
														Subtotal = $369,757

Issue Date FY: 2016 ( Subtotal = $369,534 )
2016	2016	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	002	13	5/5/2016	NON-COMPETING CONTINUATION	$369,534
2016	2015	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Cancer Cause and Prevention Research	001	12	12/2/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$194,007
2016	2015	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	11	12/1/2015	COMPETING CONTINUATION	-$194,007
														Subtotal = $369,534

Issue Date FY: 2015 ( Subtotal = $369,063 )
2015	2015	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	11	4/3/2015	COMPETING CONTINUATION	$369,063
														Subtotal = $369,063

Issue Date FY: 2014 ( Subtotal = $316,886 )
2014	2014	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	10	4/22/2014	NON-COMPETING CONTINUATION	$316,886
														Subtotal = $316,886

Issue Date FY: 2013 ( Subtotal = $307,107 )
2013	2013	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	9	6/10/2013	NON-COMPETING CONTINUATION	$307,107
														Subtotal = $307,107

Issue Date FY: 2012 ( Subtotal = $326,730 )
2012	2012	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	8	4/27/2012	NON-COMPETING CONTINUATION	$326,730
														Subtotal = $326,730

Issue Date FY: 2011 ( Subtotal = $326,750 )
2011	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	001	7	5/13/2011	NON-COMPETING CONTINUATION	$23,580
2011	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	7	4/20/2011	NON-COMPETING CONTINUATION	$303,170
														Subtotal = $326,750

Issue Date FY: 2010 ( Subtotal = $335,974 )
2010	2010	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	6	6/29/2010	COMPETING CONTINUATION	$335,974
2010	2009	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Control	001	5	6/29/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $335,974

Issue Date FY: 2009 ( Subtotal = $320,225 )
2009	2009	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Control	001	5	3/24/2009	NON-COMPETING CONTINUATION	$320,225
2009	2007	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	3	12/11/2008	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $320,225

Issue Date FY: 2008 ( Subtotal = $320,225 )
2008	2008	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Control	000	4	5/12/2008	NON-COMPETING CONTINUATION	$320,225
														Subtotal = $320,225

Issue Date FY: 2007 ( Subtotal = $374,945 )
2007	2007	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Control	000	3	4/23/2007	NON-COMPETING CONTINUATION	$320,225
2007	2007	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	3	7/24/2007	SUPPLEMENT FOR EXPANSION	$54,720
														Subtotal = $374,945

Issue Date FY: 2006 ( Subtotal = $329,307 )
2006	2006	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	5/2/2006	NON-COMPETING CONTINUATION	$329,307
														Subtotal = $329,307

Grand Total All Awards = $7,237,457

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The function of Snf5 (SMARCB1), an epigenetic tumor suppressor

Award Number: R01CA113794

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2005

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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