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ATP-Dependent Chromatin Remodeling in Human Malignancy

Award Number: R01CA163915
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2012
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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ATP-Dependent Chromatin Remodeling in Human Malignancy - Project Summary ATP-Dependent Chromatin Remodeling in Cancer Chromatin and epigenetic regulators have emerged as important contributors to human cancer. The subunits of the mSWI/SNF or BAF ATP-dependent chromatin remodeling complex are mutated in over 20% of human cancers. In addition, several other ATP-dependent remodelers make important contributions to the pathogenesis of specific cancers. These complexes often function as genetically dominant tumor suppressors, however the BAF complex also plays oncogenic roles in synovial sarcoma and squamous cell carcinoma. Despite their prevalent roles in human cancer their oncogenic mechanism(s) remain unclear and a detailed molecular understanding, necessary for therapeutic development, has been elusive. One of the most well documented roles of BAF complexes is their opposition to Polycomb Repressive Complexes (PRC) complexes. Indeed, BAF subunits were discovered in flies as suppressors of PRC1 mutations. In addition, inhibition of PRC is therapeutic in some cancers having loss of function mutations in the BAF complex. However, the mechanisms underlying the opposition between BAF chromatin remodeling complexes and Polycomb complexes is still unclear. We will obtain a detailed understanding of the physical interaction between these complexes and explore their oncogenic roles with the goal of identifying potential sites of therapeutic intervention. One possible mechanism underlying the BAF-PRC opposition is the potential of BAF complexes to exchange or evict nucleosomes modified by PRC1 and 2. Measured rates of nucleosome exchange by several techniques and by several groups show that nucleosomes exchange several times per cell cycle. This observation seems inconsistent with the widely held concept that histone and/or nucleosome modifications are the basis of epigenetic and phenotypic stability. Another way of stating this is “why do the 32 SNF2-like ATP-dependent remodelers encoded in the mammalian genome not quickly erase all histone modifications by nucleosome exchange? This conflict would be resolved if nucleosome exchange by ATP- dependent remodelers was selective to a specific remodeler and a specific nucleosomal modification. Thus, we are developing two new techniques that will fill this gap in our knowledge by measuring exchange of specifically modified nucleosomes and attributing them to specific remodelers, including their post translational or oncogenic modifications. These techniques should allow the understanding of the paradox that rates of nucleosome exchange appear to be far faster than the rate of change of histone modifications. We will use these techniques to assign changes in the epigenetic landscape to specific ATP-dependent chromatin regulators and to understand the stability of epigenetic histone modifications in normal and malignant cells. At the conclusion of our studies, we hope to have a deeper and more detailed understanding of both the normal and oncogenic mechanisms related to mutation or dysfunction of the mSWI/SNF or BAF chromatin remodeling complex.


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 = $386,000 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	13	3/20/2025	NON-COMPETING CONTINUATION	$347,400
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	001	13	5/22/2025	NON-COMPETING CONTINUATION	$38,600
														Subtotal = $386,000

Issue Date FY: 2024 ( Subtotal = $366,700 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	12	2/13/2024	NON-COMPETING CONTINUATION	$347,400
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	001	12	4/19/2024	NON-COMPETING CONTINUATION	$19,300
														Subtotal = $366,700

Issue Date FY: 2023 ( Subtotal = $387,313 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	11	3/7/2023	COMPETING CONTINUATION	$387,313
														Subtotal = $387,313

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	10	8/10/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $377,979 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	10	3/25/2021	NON-COMPETING CONTINUATION	$377,979
														Subtotal = $377,979

Issue Date FY: 2020 ( Subtotal = $377,649 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	9	5/20/2020	NON-COMPETING CONTINUATION	$377,649
														Subtotal = $377,649

Issue Date FY: 2019 ( Subtotal = $577,972 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	8	4/2/2019	SUPPLEMENT FOR EXPANSION	$211,950
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	8	3/29/2019	NON-COMPETING CONTINUATION	$455,068
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	002	8	4/23/2019	NON-COMPETING CONTINUATION	-$89,046
														Subtotal = $577,972

Issue Date FY: 2018 ( Subtotal = $589,008 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	7	4/6/2018	SUPPLEMENT FOR EXPANSION	$211,950
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	002	7	5/23/2018	NON-COMPETING CONTINUATION	$37,707
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	7	3/28/2018	NON-COMPETING CONTINUATION	$339,351
														Subtotal = $589,008

Issue Date FY: 2017 ( Subtotal = $376,791 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	6	3/22/2017	COMPETING CONTINUATION	$471,371
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	001	6	5/26/2017	COMPETING CONTINUATION	-$94,580
2017	2016	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	002	5	8/16/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $376,791

Issue Date FY: 2016 ( Subtotal = $328,914 )
2016	2016	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	5	5/5/2016	EXTENSION WITH OR WITHOUT FUNDS	$328,914
														Subtotal = $328,914

Issue Date FY: 2015 ( Subtotal = $328,272 )
2015	2015	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	4	4/15/2015	NON-COMPETING CONTINUATION	$328,272
														Subtotal = $328,272

Issue Date FY: 2014 ( Subtotal = $317,818 )
2014	2014	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	3	7/15/2014	NON-COMPETING CONTINUATION	$317,818
														Subtotal = $317,818

Issue Date FY: 2013 ( Subtotal = $307,421 )
2013	2013	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	001	2	6/21/2013	NON-COMPETING CONTINUATION	$230,565
2013	2013	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	2	5/3/2013	NON-COMPETING CONTINUATION	$76,856
														Subtotal = $307,421

Issue Date FY: 2012 ( Subtotal = $326,459 )
2012	2012	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Cause and Prevention Research	000	1	7/10/2012	NEW	$326,459
														Subtotal = $326,459

Grand Total All Awards = $5,048,296

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ATP-Dependent Chromatin Remodeling in Human Malignancy

Award Number: R01CA163915

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/10/2012

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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