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Delineating the mechanisms of androgen receptor activation function-1 antagonists for development of novel prostate cancer therapeutics

Award Number: R01CA105304
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Treatment for advanced prostate cancer involves the reduction of the patients' levels of testosterone (androgen) by surgical and pharmacological castration. Unfortunately, this form of therapy is not curative and eventually the disease will return in a castration resistant form. Once the disease is castration resistant, the survival time is approximately two years before the patient will succumb to his disease. To develop new therapies, a target must be known. Our laboratory identified the N-terminal domain of the androgen receptor as a novel therapeutic target for drug development. This target is supported by data showing that targeting this domain of the receptor blocks tumor growth and progression in vivo. We have identified EPI and sintokamide as first in class of antagonists to androgen receptor N-terminal domain. These compounds were both specific and bind to the N-terminal domain of androgen receptor. However, they appear to have different mechanisms of action. Now we draw on this progress and in Aim 1 we propose to characterize the mechanism of sintokamide that causes inhibition of androgen receptor activity. Aim 2 will determine the molecular mechanisms of androgen-repressed genes to yield clues about potential acquired resistance, possible combination therapies, and pharmacodynamic biomarkers. Aim 3 will elucidate binding characteristics. Aim 4 will test combinations of compounds versus monotherapies in vivo using human prostate cancer xenografts. These novel inhibitors to the androgen receptor N-terminal domain are the only ones available for an N- terminal domain of any steroid hormone receptor and represent a new class of androgen receptor antagonists. All data generated will be novel and provide new insight into potential mechanisms of resistance, drug development, and reveal possible pharmacodynamic markers.


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	2021	PROVINCIAL HEALTH SERVICES AUTHORITY	600 10TH AVE W	VANCOUVER	BC			CAN	Cancer Treatment Research	000	16	6/28/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $275,849 )
2021	2021	PROVINCIAL HEALTH SERVICES AUTHORITY	600 10TH AVE W	VANCOUVER	BC			CAN	Cancer Treatment Research	000	16	2/11/2021	NON-COMPETING CONTINUATION	$275,849
														Subtotal = $275,849

Issue Date FY: 2020 ( Subtotal = $275,849 )
2020	2020	PROVINCIAL HEALTH SERVICES AUTHORITY	600 10TH AVE W	VANCOUVER	BC	V5Z 4E6		CAN	Cancer Treatment Research	001	15	2/6/2020	NON-COMPETING CONTINUATION	$275,849
2020	2018	BRITISH COLUMBIA CANCER AGENCY BRANCH	600 10TH AVE W	VANCOUVER	BC	V5Z 4E6		CAN	Cancer Treatment Research	000	12	1/3/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $275,849

Issue Date FY: 2019 ( Subtotal = $267,573 )
2019	2019	PROVINCIAL HEALTH SERVICES AUTHORITY	600 10TH AVE W	VANCOUVER	BC	V5Z 4E6		CAN	Cancer Treatment Research	002	14	2/7/2019	NON-COMPETING CONTINUATION	$267,573
2019	2018	PROVINCIAL HEALTH SERVICES AUTHORITY	600 10TH AVE W	VANCOUVER	BC	V5Z 4E6		CAN	Cancer Treatment Research	001	13	11/29/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$264,811
2019	2018	BRITISH COLUMBIA CANCER AGENCY BRANCH	600 10TH AVE W	VANCOUVER	BC	V5Z 4E6		CAN	Cancer Treatment Research	000	12	11/29/2018	NON-COMPETING CONTINUATION	-$264,811
														Subtotal = $267,573

Issue Date FY: 2018 ( Subtotal = $264,812 )
2018	2018	BRITISH COLUMBIA CANCER AGENCY BRANCH	600 10TH AVE W	VANCOUVER	BC	V5Z 4E6		CAN	Cancer Treatment Research	001	12	5/23/2018	NON-COMPETING CONTINUATION	$26,481
2018	2018	BRITISH COLUMBIA CANCER AGENCY BRANCH	600 10TH AVE W	VANCOUVER	BC	V5Z 4E6		CAN	Cancer Treatment Research	000	12	2/26/2018	NON-COMPETING CONTINUATION	$238,331
														Subtotal = $264,812

Issue Date FY: 2017 ( Subtotal = $260,846 )
2017	2017	BRITISH COLUMBIA CANCER AGENCY BRANCH	600 10TH AVE W	VANCOUVER	BC	V5Z 4E6		CAN	Cancer Treatment Research	001	11	2/15/2017	COMPETING CONTINUATION	$260,847
2017	2014	BRITISH COLUMBIA CANCER AGENCY BRANCH	600 10TH AVE W	VANCOUVER	BC	V5Z 4E6		CAN	Cancer Biology Research	000	10	12/2/2016	NON-COMPETING CONTINUATION	-$1
														Subtotal = $260,846

Issue Date FY: 2014 ( Subtotal = $265,355 )
2014	2014	BRITISH COLUMBIA CANCER AGENCY	600 West 10th Avenue	VANCOUVER				CAN	Cancer Biology Research	002	10	7/8/2014	NON-COMPETING CONTINUATION	$265,355
2014	2013	BRITISH COLUMBIA CANCER AGENCY	660 WEST 10TH AVENUE	VANCOUVER		00000			Cancer Biology Research	001	9	12/17/2013	EXTENSION WITH OR WITHOUT FUNDS	$0
2014	2012	BRITISH COLUMBIA CANCER AGENCY	660 WEST 10TH AVENUE	VANCOUVER		00000			Cancer Biology Research	000	8	12/16/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $265,355

Issue Date FY: 2013 ( Subtotal = $257,145 )
2013	2013	BRITISH COLUMBIA CANCER AGENCY	600 West 10th Avenue	VANCOUVER				CAN	Cancer Biology Research	000	9	8/1/2013	EXTENSION WITH OR WITHOUT FUNDS	$257,145
2013	2013	BRITISH COLUMBIA CANCER AGENCY	660 WEST 10TH AVENUE	VANCOUVER		00000			Cancer Biology Research	001	9	12/17/2013	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $257,145

Issue Date FY: 2012 ( Subtotal = $248,081 )
2012	2012	BRITISH COLUMBIA CANCER AGENCY	600 West 10th Avenue	VANCOUVER				CAN	Cancer Biology Research	000	8	7/23/2012	NON-COMPETING CONTINUATION	$248,081
														Subtotal = $248,081

Issue Date FY: 2011 ( Subtotal = $248,086 )
2011	2011	BRITISH COLUMBIA CANCER AGENCY	600 West 10th Avenue	VANCOUVER				CAN	Cancer Biology Research	000	7	7/12/2011	NON-COMPETING CONTINUATION	$248,086
														Subtotal = $248,086

Issue Date FY: 2010 ( Subtotal = $222,742 )
2010	2010	BRITISH COLUMBIA CANCER AGENCY	600 West 10th Avenue	VANCOUVER				CAN	Cancer Biology Research	000	6	8/17/2010	COMPETING CONTINUATION	$222,742
														Subtotal = $222,742

Issue Date FY: 2007 ( Subtotal = $209,928 )
2007	2007	BRITISH COLUMBIA CANCER AGENCY	660 WEST 10TH AVENUE	VANCOUVER					Cancer Biology Research	000	4	2/19/2007	NON-COMPETING CONTINUATION	$209,928
														Subtotal = $209,928

Issue Date FY: 2006 ( Subtotal = $216,198 )
2006	2006	BRITISH COLUMBIA CANCER AGENCY	660 WEST 10TH AVENUE	VANCOUVER					Cancer Biology Research	000	3	3/28/2006	NON-COMPETING CONTINUATION	$216,198
														Subtotal = $216,198

Issue Date FY: 2005 ( Subtotal = $221,400 )
2005	2005	BRITISH COLUMBIA CANCER AGENCY	660 WEST 10TH AVENUE	VANCOUVER					Cancer Biology Research	000	2	4/29/2005	NON-COMPETING CONTINUATION	$221,400
														Subtotal = $221,400

Issue Date FY: 2004 ( Subtotal = $221,400 )
2004	2004	BRITISH COLUMBIA CANCER AGENCY	660 WEST 10TH AVENUE	VANCOUVER					Cancer Biology Research	000	1	3/15/2004	NEW	$221,400
														Subtotal = $221,400

Grand Total All Awards = $3,455,264

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Delineating the mechanisms of androgen receptor activation function-1 antagonists for development of novel prostate cancer therapeutics

Award Number: R01CA105304

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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