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Analog Studies of 4-HPR and its Glucuronide

Award Number: R01CA049837
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/1991
PERIOD OF PERFORMANCE END DATE: 02/28/2014

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Analog Studies of 4-HPR and its Glucuronide - DESCRIPTION (provided by applicant): All-trans Retinoic acid (RA) and its analogs have emerged as dermatological agents and as potential cancer chemopreventive/chemotherapeutic agents. As a class, these compounds share teratogenic potential and the tendency to cause vitamin A toxicities. However, the O-acyl glucuronide metabolite of RA has been suggested to be a less toxic, active material. The synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) shows some unique activity as a breast cancer chemopreventive with further reduced toxicity and teratogenicity. Our own studies with 4-HPR-O-glucuronide (4-HPROG) have shown it to be an even less toxic, more effective preventive and therapeutic for DMBA-induced rat mammary tumors relative to 4-HPR. However, these glucuronides as well as the retinamide 4-HPR are unstable to hydrolysis back to the parent retinoid making it unclear what the active forms of the molecules are. We have been synthesizing stable C-linked analogs of 4- HPR and 4-HPROG for evaluation as breast cancer chemopreventive/chemotherapeutic agents. A number of these analogs show increased potency preventing DMBA-induced tumors and further reduced toxicity relative to 4-HPR. Like 4-HPR, these analogs bind weakly to the known nuclear retinoid receptors and, unlike RA, cause apoptosis in tumor cells in a manner that is not inhibited by retinoid receptor antagonists, leaving their mechanism of action incompletely understood. The specific aims of our proposed continued research are: 1) to scale up production of our preferred analog (4-HBR, 4-HBRCG, or 4-HBRCglucose) based on a current chemotherapy/chemoprevention experiment underway, 2) to complete chemoprevention evaluation of the chosen analog in the DMBA-induced rat mammary tumor model, 3) to begin study of the chosen analog in a second (MMTV/ErbB2 mouse) mammary tumor model, 4) to conduct predictive teratology studies of the chosen analog(s), and 5) to explore mechanism of action issues with the chosen analog(s) focusing on our observations that 4-HPR and our analogs appear to induce ER stress. We will focus here on establishing the necessity of these phenomena for the actions of these compounds as well as determining molecular players upstream of these processes which trigger these events. PUBLIC HEALTH RELEVANCE: Despite recent advances, breast cancer-associated morbidity and mortality remains a serious problem in the USA. The analogs of 4-HPR we are developing, show real promise as more effective and less toxic preventive and therapeutic agents for breast cancer. A clearer understanding of how these promising molecules function would further enhance our ability to develop and exploit them.


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: 2015 ( Subtotal = $0 )
2015	2013	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	19	2/22/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $311,800 )
2013	2013	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	19	2/5/2013	NON-COMPETING CONTINUATION	$149,266
2013	2013	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	001	19	7/2/2013	NON-COMPETING CONTINUATION	$162,534
														Subtotal = $311,800

Issue Date FY: 2012 ( Subtotal = $331,716 )
2012	2012	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	18	3/14/2012	NON-COMPETING CONTINUATION	$331,716
														Subtotal = $331,716

Issue Date FY: 2011 ( Subtotal = $329,299 )
2011	2011	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	17	2/18/2011	NON-COMPETING CONTINUATION	$305,535
2011	2011	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	001	17	5/13/2011	NON-COMPETING CONTINUATION	$23,764
														Subtotal = $329,299

Issue Date FY: 2010 ( Subtotal = $322,452 )
2010	2010	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	003	16	3/15/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$322,452
2010	2010	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	005	16	4/14/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$322,452
2010	2010	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	004	16	4/9/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$322,452
2010	2010	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	16	3/1/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$322,452
2010	2010	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	002	16	3/11/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$322,452
2010	2009	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	001	15	3/1/2010	COMPETING CONTINUATION	$0
														Subtotal = $322,452

Issue Date FY: 2009 ( Subtotal = $352,401 )
2009	2009	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	003	15	4/29/2009	COMPETING CONTINUATION	$352,401
2009	2007	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	14	2/26/2009	NON-COMPETING CONTINUATION	$0
2009	2007	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	001	14	4/6/2009	NON-COMPETING CONTINUATION	$0
2009	2007	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	002	14	4/29/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $352,401

Issue Date FY: 2007 ( Subtotal = $282,094 )
2007	2007	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	14	12/15/2006	NON-COMPETING CONTINUATION	$282,094
														Subtotal = $282,094

Issue Date FY: 2006 ( Subtotal = $268,719 )
2006	2006	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	13	12/5/2005	NON-COMPETING CONTINUATION	$268,719
														Subtotal = $268,719

Issue Date FY: 2005 ( Subtotal = $297,510 )
2005	2005	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	12	12/16/2004	NON-COMPETING CONTINUATION	$297,510
														Subtotal = $297,510

Issue Date FY: 2004 ( Subtotal = $297,510 )
2004	2004	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	11	12/19/2003	NON-COMPETING CONTINUATION	$297,510
														Subtotal = $297,510

Issue Date FY: 2003 ( Subtotal = $309,385 )
2003	2003	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	10		COMPETING CONTINUATION	$309,385
														Subtotal = $309,385

Issue Date FY: 2001 ( Subtotal = $269,131 )
2001	2001	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	9	3/1/2001	NON-COMPETING CONTINUATION	$269,131
														Subtotal = $269,131

Issue Date FY: 2000 ( Subtotal = $258,392 )
2000	2000	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	8	3/24/2000	NON-COMPETING CONTINUATION	$258,392
														Subtotal = $258,392

Issue Date FY: 1999 ( Subtotal = $262,368 )
1999	1999	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	7	3/25/1999	COMPETING CONTINUATION	$262,368
														Subtotal = $262,368

Grand Total All Awards = $3,892,777

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Analog Studies of 4-HPR and its Glucuronide

Award Number: R01CA049837

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/1991

PERIOD OF PERFORMANCE END DATE: 02/28/2014

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