RXR Rexinoids for Cancer Chemoprevention

RXR Rexinoids 用于癌症化学预防

• 批准号: 10007585
• 负责人: Craig A Elmets
• 金额: $ 151.7万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10007585
• 关键词: Agonist; Animal Model; Animals; Basal cell carcinoma; Bexarotene; Binding; Biochemistry; Biological Markers; Biological Models; Biometry; Cell Line; Chemistry; Chemoprevention; Chemopreventive Agent; Clinical Trials; Collaborations; Data; Development; Double-Blind Method; Drug Design; FDA approved; General Population; Generations; Genetic Transcription; Goals; Graft Rejection; Human; Hypertriglyceridemia; In Vitro; Individual; Kidney Transplantation; Lead; Lipids; Liver; Liver X Receptor; Long-Term Survivors; Malignant Neoplasms; Mediating; Morbidity - disease rate; Neoplasm Metastasis; Nuclear Receptors; Oral; Organ Transplantation; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Poison; Prevention; Prevention Research; Prevention therapy; Process; Program Research Project Grants; RXR; Randomized; Recording of previous events; Research Personnel; Retinoids; Risk; Scientist; Services; Signal Transduction; Skin; Skin Carcinogenesis; Skin Carcinoma; Source; Specificity; Squamous cell carcinoma; Structure; Toxic effect; Translating; Translational Research; Transplant Recipients; Tretinoin; UV induced; University of Alabama at Birmingham Cancer Center; Up-Regulation; Vitamin A; base; cancer chemoprevention; cancer prevention; cohesion; cost; design; dosage; efficacy study; experimental study; high risk; in vivo; interest; keratinocyte; mouse model; novel; placebo controlled study; prevent; programs; receptor binding; safety study; screening; skin cancer prevention; structural biology; success; translational scientist

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.

非黑色素瘤皮肤癌（NMSCs），鳞状细胞癌（SCC）和基底细胞癌