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（NMSC），（鳞状细胞癌[SCC]和基底细胞 癌[BCC]）是肾移植长期幸存者发病率的主要来源。 由于药物这些患者必须采取的防止移植排斥，NMSC发生了更多 经常（65-250x SCC的一般人群； BCC的10倍），表现更积极， 并且比普通人群更有可能转移。口服性类维生素有效保护 针对这些患者的NMSC，但剂量为不可接受的毒性。我们的团队有 设计了具有高特异性的类维生素X受体（RXR）的逆逆红色毒素，而无需通过信号传导 RXR：肝脏（或其他RXR异二聚体）中的LXR（肝X受体）。这消除了标记的 高甘油三酯血症是限制贝沙洛烯的毒性的速率，这是唯一获得FDA批准的RXR的毒性 结合雷克内氏菌。我们的铅化合物UAB30可防止动物模型中紫外线诱导的NMSC。 UAB30已在正常个体中进行了临床试验，但没有明显的毒性。我们 假设UAB30和其他基于UAB30结构的Rexinoids可以用作 高效，低毒性化学预防剂限制肾移植中NMSC 收件人。该计划汇集了7位研究人员，以仔细研究 NMSC的Rexinoid化学预防，并开发一种系统性的方法来翻译 在肾移植受者中，用于NMSC化学预防的新雷类动物的科学发现。 该计划由3个互动项目组成。 Elmets博士（Proj。1）将进行随机的， 双盲，安慰剂对照研究，以识别可以用作短期的生物标志物 预测器官移植受体中NMSC预防功效的预测指标。 Muccio博士（Proj。2） 计划在Rexinoid的环区域中设计新的雷克内类动物，以行动 作为激动剂，但在临界区域中没有空间散装，据信刺激信号传导 这会诱导脂质合成。 Kedishvili博士（Proj。3）将检查Rexinoids是否会增强 由现有内源性全反式反激酸（ATRA）的转录活性由 RXR/RAR异二聚体，这又导致ATRA水平的进一步上调。项目 将得到3个核心（行政；设计和合成；雷克尼筛查和 动物）。参与该计划的科学家有悠久的协作历史，并加入了 共同对雷毒素化学，生物化学，癌症化学预防和翻译的兴趣 科学。