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 癌[BCC]）是肾移植长期幸存者发病的主要来源。 由于这些患者必须服用药物来预防移植排斥，NMSCs 的发生率更高 频繁（SCC 是一般人群的 65-250 倍；BCC 是一般人群的 10 倍），行为更加激进， 并且比一般人群更容易发生转移。口服维A酸有效保护 对抗这些患者中的 NMSC，但剂量具有不可接受的毒性。我们的团队有 设计了对视黄醇 X 受体 (RXR) 具有高度特异性的 rexinoid，无需通过信号传递 RXR：肝脏中的LXR（肝脏X受体）（或其他RXR异二聚体）。这消除了标记的 高甘油三酯血症是贝沙罗汀的限速毒性，贝沙罗汀是 FDA 唯一批准的 RXR 结合类胡萝卜素。我们的先导化合物 UAB30 可预防动物模型中紫外线诱导的 NMSCs。 UAB30已进入正常个体的临床试验，未表现出明显的毒性。我们 假设UAB30和基于UAB30结构的其他rexinoids可以用作 高效、低毒的化学预防剂限制肾移植中的 NMSCs 收件人。该计划汇集了 7 位研究人员，仔细研究 NMSCs 的 rexinoid 化学预防，并开发一种系统方法来转化 新类rexinoids用于肾移植受者NMSC化学预防的科学发现。 该计划由 3 个互动项目组成。 Elmets 博士（项目 1）将进行一项随机、 双盲、安慰剂对照研究，以确定可用作短期的生物标志物 器官移植受者 NMSC 预防效果的预测因子。 Muccio 博士（项目 2） 计划设计新的rexinoids，在rexinoid环区域具有所需的空间体积以发挥作用 作为激动剂，但在被认为可以刺激信号传导的关键区域中没有空间体积 从而诱导脂质合成。 Kedishvili 博士（项目 3）将检查 rexinoids 是否会增强 现有内源性全反式视黄酸（ATRA）的转录活性由 RXR/RAR 异二聚体，进而导致 ATRA 水平进一步上调。项目 将由 3 个核心支持（管理；设计和合成；Rexinoid 筛选和 动物）。参与该计划的科学家有着悠久的合作历史，并加入了 在类胡萝卜素化学、生物化学、癌症化学预防和转化方面有共同的兴趣 科学。