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RXR Rexinoids for Cancer Chemoprevention

Award Number: P01CA210946
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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RXR Rexinoids for Cancer Chemoprevention - Non-melanoma skin cancers (NMSCs), (squamous cell carcinoma [SCC] and basal cell carcinoma [BCC]), are major sources of morbidity in long term survivors of renal transplantation. Due to medications these patients must take to prevent transplant rejection, NMSCs occur more frequently (65-250x the general population for SCC; 10x for BCC), behave more aggressively, and are more likely to metastasize than in the general population. Oral retinoids effectively protect against NMSCs in these patients, but at dosages with unacceptable toxicity. Our team has designed rexinoids with high specificity for the retinoid X receptor (RXR) without signaling through RXR:LXR (liver X receptor) in the liver (or other RXR heterodimers). This eliminates the marked hypertriglyceridemia that is the rate limiting toxicity of bexarotene, the only FDA approved RXR binding rexinoid. Our lead compound, UAB30, prevents UV-induced NMSCs in animal models. UAB30 has entered clinical trials in normal individuals and has shown no significant toxicity. We hypothesize that UAB30 and other rexinoids that are based on UAB30's structure can be used as highly effective, low toxicity chemopreventive agents limiting NMSCs in renal transplant recipients. This Program brings together 7 researchers to carefully investigate mechanisms of rexinoid chemoprevention of NMSCs, and to develop a systemic approach to translating the scientific findings into new rexinoids for NMSC chemoprevention in renal transplant recipients. The Program consists of 3 interactive Projects. Dr. Elmets (Proj. 1) will conduct a randomized, double-blind, placebo-controlled study to identify biomarkers that can be employed as short term predictors of efficacy for NMSC prevention in organ transplant recipients. Dr. Muccio (Proj. 2) plans to design new rexinoids with the needed steric bulk in the ring region of the rexinoid to act as an agonist, but without the steric bulk in critical regions that are believed to stimulate signaling that induces lipid synthesis. Dr. Kedishvili (Proj. 3) will examine whether rexinoids potentiate the transcriptional activity of existing endogenous all-trans-retinoic acid (ATRA) mediated by RXR/RAR heterodimers, which, in turn, leads to further upregulation of ATRA levels. The Projects will be supported by 3 Cores (Administrative; Design and Synthesis; Rexinoid Screening and Animal). Scientists involved in the Program have a long history of collaboration and are joined by shared interests in rexinoid chemistry, biochemistry, cancer chemoprevention and translational science.


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: 2024 ( Subtotal = -$333,705 )
2024	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	000	5	2/12/2024	NON-COMPETING CONTINUATION	-$312,884
2024	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	001	5	2/12/2024	SUPPLEMENT FOR EXPANSION	-$20,821
														Subtotal = -$333,705

Issue Date FY: 2021 ( Subtotal = $960,356 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	001	5	8/18/2021	SUPPLEMENT FOR EXPANSION	$59,920
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	000	5	8/17/2021	NON-COMPETING CONTINUATION	$900,436
														Subtotal = $960,356

Issue Date FY: 2020 ( Subtotal = $1,516,989 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	000	4	9/14/2020	NON-COMPETING CONTINUATION	$1,516,989
														Subtotal = $1,516,989

Issue Date FY: 2019 ( Subtotal = $1,546,718 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	001	3	9/11/2019	SUPPLEMENT FOR EXPANSION	$59,920
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	002	3	9/12/2019	SUPPLEMENT FOR EXPANSION	$60,295
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	000	3	9/3/2019	NON-COMPETING CONTINUATION	$1,426,503
														Subtotal = $1,546,718

Issue Date FY: 2018 ( Subtotal = $1,481,363 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	000	2	8/9/2018	NON-COMPETING CONTINUATION	$1,481,363
														Subtotal = $1,481,363

Issue Date FY: 2017 ( Subtotal = $1,770,718 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	000	1	9/1/2017	NEW	$1,770,718
														Subtotal = $1,770,718

Grand Total All Awards = $6,942,439

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RXR Rexinoids for Cancer Chemoprevention

Award Number: P01CA210946

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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