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MAOA and AR Reciprocal Crosstalk in Prostate Cancer

Award Number: R37CA233658
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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MAOA and AR Reciprocal Crosstalk in Prostate Cancer - Project Summary/Abstract (Parent Grant Application) Prostate cancer (PC) is the most common non-skin cancer in American men, with a lifetime incidence of 1 in 7, and also the second leading cause of cancer death in American men. Androgen receptor (AR) is the primary oncogenic driver of PC growth, survival and progression. AR-directed therapy is currently the principal treatment regimen. Despite initial response rates exceeding 90%, PC eventually relapses and progresses to fatal castration-resistant PC (CRPC), where reactivation of AR signaling occurs in a low-androgen environment. Recent introduction of FDA-approved next-generation antiandrogens, including enzalutamide (ENZ) and abiraterone acetate (ABI), have improved the CRPC treatment landscape, but emergence of drug resistance remains nearly universal, with no AR-targeted therapeutic options afterwards. These dismal facts underscore the pressing clinical need to identify new molecular targets and develop effective therapies to combat advanced PC. Through integrated analysis of publicly available clinical PC data sets coupled with functional studies in AR-positive PC cells, we propose monoamine oxidase A (MAOA), which synergizes with AR to promote PC, as an ideal therapeutic candidate to complement AR-targeted therapy in CRPC. We identified a novel reciprocal interaction between MAOA and AR in PC cells. MAOA expression is induced by androgen treatment; and conversely, MAOA silencing significantly reduces AR activity by lowering AR target gene expression and responsiveness to androgen stimulation in PC cells under both androgen-replete and depleted conditions as well as in a CRPC xenograft model. We showed significant positive co-expression of MAOA and AR target genes (PSA, TMPRSS2, NKX3.1) in multiple clinical data sets, including CRPC. Importantly, we found MAOA genomic amplification and/or epigenetic activation in 64% of samples in a CRPC data set, reinforced by elevated MAOA protein expression in our CRPC patient cohort. Additionally, we demonstrated that inhibition of MAOA by genetic or pharmacological approaches enhanced the growth-inhibiting effects of ENZ and ABI in androgen-sensitive, CR and antiandrogen-resistant PC cells. Based on these findings, we will test the hypothesis that MAOA synergizes with AR through reciprocal crosstalk and convergent downstream signaling to amply MAOA/AR effects promoting AR-driven PC growth and progression, and that co-targeting MAOA/AR is an actionable, effective strategy to treat CRPC and reverse antiandrogen drug resistance. To address this hypothesis, three aims are proposed. In Aim 1, we will elucidate the mechanistic basis of MAOA- AR reciprocal interaction in PC cells. In Aim 2, we will characterize the role of MAOA in regulating the development and progression of CRPC in xenograft models. In Aim 3, we will determine the efficacy of MAOA inhibitors for treating CRPC and reversing resistance to next-generation antiandrogens in vitro and in vivo. These studies will provide fundamental innovative insights into AR regulation in CRPC and illuminate a path toward the development of new combination therapy for advanced PC.


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 = $490,502 )
2025	2025	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	003	7	6/25/2025	NON-COMPETING CONTINUATION	$349,988
2025	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	002	6	6/16/2025	EXTENSION WITH OR WITHOUT FUNDS	$119,395
2025	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	000	5	5/12/2025	NON-COMPETING CONTINUATION	$140,514
2025	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	001	5	6/16/2025	NON-COMPETING CONTINUATION	-$119,395
														Subtotal = $490,502

Issue Date FY: 2024 ( Subtotal = $332,489 )
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	000	6	2/8/2024	EXTENSION WITH OR WITHOUT FUNDS	$314,989
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	001	6	6/12/2024	EXTENSION WITH OR WITHOUT FUNDS	$17,500
														Subtotal = $332,489

Issue Date FY: 2023 ( Subtotal = $342,988 )
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	001	5	3/17/2023	NON-COMPETING CONTINUATION	$27,999
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	000	5	12/22/2022	NON-COMPETING CONTINUATION	$314,989
														Subtotal = $342,988

Issue Date FY: 2022 ( Subtotal = $349,988 )
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	001	4	5/19/2022	NON-COMPETING CONTINUATION	$34,999
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	000	4	12/23/2021	NON-COMPETING CONTINUATION	$314,989
														Subtotal = $349,988

Issue Date FY: 2021 ( Subtotal = $349,988 )
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	000	3	12/18/2020	NON-COMPETING CONTINUATION	$332,488
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	001	3	1/25/2021	NON-COMPETING CONTINUATION	$17,500
														Subtotal = $349,988

Issue Date FY: 2020 ( Subtotal = $349,988 )
2020	2020	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	001	2	1/14/2020	NON-COMPETING CONTINUATION	$34,999
2020	2020	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	000	2	12/4/2019	NON-COMPETING CONTINUATION	$314,989
														Subtotal = $349,988

Issue Date FY: 2019 ( Subtotal = $349,988 )
2019	2019	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Biology Research	000	1	12/26/2018	NEW	$349,988
														Subtotal = $349,988

Grand Total All Awards = $2,565,931

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MAOA and AR Reciprocal Crosstalk in Prostate Cancer

Award Number: R37CA233658

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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