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Pathogenesis and Treatment of NUT midline carcinoma

Award Number: R01CA124633
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/30/2007
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Pathogenesis and Treatment of NUT midline carcinoma - Project Summary Abstract. NUT carcinoma (NC, formerly NUT midline carcinoma) is an aggressive squamous carcinoma, affecting all ages, that is highly (>90%) lethal. The over-arching goal of this proposal is to improve survival of these patients through mechanism-driven identification of key oncogenic targets. NC is defined by NUTM1-fusion oncogenes, most commonly (~78%) encoding the BRD4-NUT protein. BRD4-NUT drives NC growth through the blockade of differentiation and maintenance of proliferation by forming very large (100kb-2MB), acetyl-histone-rich super-enhancers called megadomains (MD) that we described. MDs arise from the recruitment of p300, a histone acetyl-transferase (HAT), by NUT to acetylated histones bound by the dual bromodomains of BRD4, a BET family protein. We have shown that BRD4-NUT drives transcription of key oncogenic targets through the additional recruitment of numerous transcriptional activators by BRD4. Our demonstration that treatment with BET bromodomain inhibitors (BETi) that competitively inhibit binding of BET bromodomains to chromatin, can inhibit growth of NC in humans led to a new field investigating the role of BRD4 in cancer. Unfortunately, the efficacy of BETi monotherapy is limited by toxicity. In this next phase, we are investigating novel oncogenic mechanisms whose targeting can synergize with BETi therapeutically. Our preliminary data, together with what is established, has led us to formulate a mechanistic two-domain model of how NC growth is epigenetically driven. The model will be tested in the aims below with the overall goal of identifying a therapeutic combination of compounds optimized for maximally selective, synergistic tumor inhibition with minimized toxicity. The model proposes that the first, transcriptionally repressive domain formed by PRC2 enables NC growth by repressing the expression of pro-differentiation, tumor suppressive genes (tested in aim 1). The second, physically separate permissive MD is comprised of BRD4-NUT-p300 bound to acetylated histones that drive transcription of oncogenic genes. In this model, MD formation requires cooperative binding of both BRD4-NUT bromodomains (BD1 and BD2) to acetylated histones (tested in aim 2); and the acetyl- histone-permissive state that enables MD formation requires mono-methylation of H3K79 by DOT1L (aim 3). Inhibition of both of these domains would 1. repress transcription of oncogenic genes, such as MYC, and 2. de- repress transcription of genes critical for differentiation, senescence, and exit from cell cycle. Indeed, we have found that co-inhibition of EZH2 and BRD4-NUT is synergistic in vitro and in vivo. Specific Aim 1. Determine the oncogenic role of EZH2 in NUT carcinoma. Specific Aim 2. Determine the oncogenic roles of BRD4 bromodomains 1 and 2 in NUT carcinoma. Specific Aim 3. What is the role of DOT1L in BRD4-NUT megadomain formation and oncogenic function?


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: 2026 ( Subtotal = $411,640 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	19	4/28/2026	NON-COMPETING CONTINUATION	$411,640
														Subtotal = $411,640

Issue Date FY: 2025 ( Subtotal = $466,025 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	001	18	7/16/2025	NON-COMPETING CONTINUATION	$466,025
2025	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	15	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $466,025

Issue Date FY: 2024 ( Subtotal = $400,229 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	17	6/7/2024	NON-COMPETING CONTINUATION	$400,229
														Subtotal = $400,229

Issue Date FY: 2023 ( Subtotal = $421,996 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	16	4/7/2023	COMPETING CONTINUATION	$421,996
														Subtotal = $421,996

Issue Date FY: 2022 ( Subtotal = $333,298 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	15	7/20/2022	NON-COMPETING CONTINUATION	$333,298
														Subtotal = $333,298

Issue Date FY: 2021 ( Subtotal = $340,100 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	14	5/19/2021	NON-COMPETING CONTINUATION	$340,100
														Subtotal = $340,100

Issue Date FY: 2020 ( Subtotal = $340,100 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	13	4/29/2020	NON-COMPETING CONTINUATION	$340,100
														Subtotal = $340,100

Issue Date FY: 2019 ( Subtotal = $562,034 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	002	12	5/31/2019	NON-COMPETING CONTINUATION	$329,897
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	003	12	7/3/2019	SUPPLEMENT FOR EXPANSION	$232,137
2019	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	001	11	10/23/2018	COMPETING CONTINUATION	$7,981
2019	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	10	10/23/2018	NON-COMPETING CONTINUATION	-$7,981
														Subtotal = $562,034

Issue Date FY: 2018 ( Subtotal = $600,920 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	001	11	6/15/2018	COMPETING CONTINUATION	$340,100
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	002	11	9/12/2018	SUPPLEMENT FOR EXPANSION	$260,820
2018	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	10	6/15/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $600,920

Issue Date FY: 2017 ( Subtotal = $331,829 )
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	003	10	6/7/2017	NON-COMPETING CONTINUATION	$33,184
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	002	10	4/27/2017	NON-COMPETING CONTINUATION	$298,645
2017	2016	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	001	9	10/31/2016	EXTENSION WITH OR WITHOUT FUNDS	$43,604
2017	2015	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	8	10/31/2016	NON-COMPETING CONTINUATION	-$43,604
														Subtotal = $331,829

Issue Date FY: 2016 ( Subtotal = $366,829 )
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	001	9	9/8/2016	EXTENSION WITH OR WITHOUT FUNDS	$35,000
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	9	4/18/2016	EXTENSION WITH OR WITHOUT FUNDS	$331,829
														Subtotal = $366,829

Issue Date FY: 2015 ( Subtotal = $331,163 )
2015	2015	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	8	4/10/2015	NON-COMPETING CONTINUATION	$331,163
														Subtotal = $331,163

Issue Date FY: 2014 ( Subtotal = $321,439 )
2014	2014	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	7	4/18/2014	NON-COMPETING CONTINUATION	$284,179
2014	2014	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	001	7	6/3/2014	SUPPLEMENT FOR EXPANSION	$37,260
														Subtotal = $321,439

Issue Date FY: 2013 ( Subtotal = $292,554 )
2013	2013	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	6	6/26/2013	COMPETING CONTINUATION	$292,554
														Subtotal = $292,554

Issue Date FY: 2011 ( Subtotal = $290,273 )
2011	2011	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	5	5/24/2011	NON-COMPETING CONTINUATION	$290,273
														Subtotal = $290,273

Issue Date FY: 2010 ( Subtotal = $310,998 )
2010	2010	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	4	5/17/2010	SUPPLEMENT FOR EXPANSION	$11,748
2010	2010	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	4	5/12/2010	NON-COMPETING CONTINUATION	$299,250
														Subtotal = $310,998

Issue Date FY: 2009 ( Subtotal = $299,250 )
2009	2009	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	3	5/7/2009	NON-COMPETING CONTINUATION	$299,250
														Subtotal = $299,250

Issue Date FY: 2008 ( Subtotal = $299,250 )
2008	2008	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	2	5/8/2008	NON-COMPETING CONTINUATION	$299,250
														Subtotal = $299,250

Issue Date FY: 2007 ( Subtotal = $299,250 )
2007	2007	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	1	8/30/2007	NEW	$299,250
														Subtotal = $299,250

Grand Total All Awards = $7,019,177

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Pathogenesis and Treatment of NUT midline carcinoma

Award Number: R01CA124633

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/30/2007

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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