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Plastic States Associated with Cellular Stress and Malignancy: Insights for Prevention and Treatment of Lethal Metaplastic Cancers

Award Number: R35CA197694
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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¿ DESCRIPTION (provided by applicant): Our long-term goals are to find effective preventive and therapeutic approaches for a group of carcinomas that are disproportionately responsible for cancer mortality worldwide. This proposal will seek to identify the cell of origin for a group f aggressive malignancies from disparate sites that share a common etiology of a metaplastic response to chronic inflammation. Our previous studies, and the novel insights they have generated, provide us with a compelling hypothesis that defies the current dogma and classification of these selected malignancies. We propose that select subsets of carcinomas, exemplified in this proposal by esophageal adenocarcinoma, gastric carcinoma of the indeterminate type and metaplastic breast cancers, arise from unique phenotypically plastic cells that confer aggressive phenotypes with extremely poor prognosis. These subsets of carcinomas are typified by the presence of metaplastic tissue derivatives in the pre-malignant and malignant lesions. Metaplasia, a protective adaptive tissue response where one cell type is replaced by another cell type not typically present in that tissue, is indicative of chronic tissue injury and associated with increased incidence of cancer. Unraveling the biology of these "metaplastic carcinomas" will allow us to overcome barriers to the identification of predisposing conditions and the subsequent activation of the cells-of-origin leading to lethal metaplastic carcinomas and to develop biomarkers to identify those premalignant lesions that will progress to invasive cancer. Identification and targeting of signaling pathways that control progression of these cells would allow us to design rational therapeutics that target the invasive state of these carcinomas. Finally, we also propose a novel preventive approach to reduce formation of the pre-malignant state that underlies these malignancies. Realization of our goals would change clinical practice and allow physicians to halt these cancers before they form. We propose to: (1) determine the role of specific stem/regenerative cells in initiation and progression esophageal adenocarcinomas, gastric cancers of indeterminate type and a subset of triple negative breast cancers, i.e. metaplastic breast cancers. We will also (2) identify distinct molecular features (cellular states) and match them with an optimal approach for (3) targeted prevention and (4) therapy. The connection between chronic inflammation and malignancy is well known; however despite an understanding of the causal insults, the incidences of these malignancies are increasing in the modern world and significantly contribute to cancer mortality. If successful, the goals of this proposal would delineate a therapeutic paradigm that could reduce mortality from this subset of cancers and fundamentally alter our approach to cancer prevention.


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: 2023 ( Subtotal = $0 )
2023	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	7	12/27/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $814,975 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	7	12/22/2021	NON-COMPETING CONTINUATION	$748,447
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	002	7	6/8/2022	NON-COMPETING CONTINUATION	$0
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	001	7	5/9/2022	NON-COMPETING CONTINUATION	$66,528
														Subtotal = $814,975

Issue Date FY: 2021 ( Subtotal = $852,086 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	6	12/15/2020	NON-COMPETING CONTINUATION	$809,481
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	001	6	2/5/2021	NON-COMPETING CONTINUATION	$42,605
														Subtotal = $852,086

Issue Date FY: 2020 ( Subtotal = $852,093 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	5	12/3/2019	NON-COMPETING CONTINUATION	$766,883
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	001	5	1/24/2020	NON-COMPETING CONTINUATION	$85,210
														Subtotal = $852,093

Issue Date FY: 2019 ( Subtotal = $844,609 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	4	1/16/2019	NON-COMPETING CONTINUATION	$844,609
														Subtotal = $844,609

Issue Date FY: 2018 ( Subtotal = $892,951 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	000	3	12/7/2017	NON-COMPETING CONTINUATION	$803,655
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	001	3	5/22/2018	NON-COMPETING CONTINUATION	$89,296
														Subtotal = $892,951

Issue Date FY: 2017 ( Subtotal = $904,026 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	000	2	12/16/2016	NON-COMPETING CONTINUATION	$813,622
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	001	2	6/7/2017	NON-COMPETING CONTINUATION	$90,404
														Subtotal = $904,026

Issue Date FY: 2016 ( Subtotal = $929,349 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Biology Research	000	1	1/19/2016	NEW	$929,349
														Subtotal = $929,349

Grand Total All Awards = $6,090,089

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Plastic States Associated with Cellular Stress and Malignancy: Insights for Prevention and Treatment of Lethal Metaplastic Cancers

Award Number: R35CA197694

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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