RXR Rexinoids for Cancer Chemoprevention

RXR Rexinoids 用于癌症化学预防

• 批准号: 10263919
• 负责人: Craig A Elmets
• 金额: $ 90.04万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263919
• 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]）是肾移植长期存活者发病的主要来源。 由于这些患者必须服用药物以防止移植排斥反应，NMSC发生更多 通常（SCC为一般人群的65- 250倍; BCC为10倍），表现得更积极， 并且比一般人群更容易转移。口服维甲酸有效保护 针对这些患者的NMSC，但剂量具有不可接受的毒性。我们的团队已被 设计了对类维生素A X受体（RXR）具有高度特异性的rexinoids， RXR：肝脏中的LXR（肝脏X受体）（或其他RXR异二聚体）。这就排除了被标记者 高甘油三酯血症是贝沙罗汀的限速毒性，贝沙罗汀是FDA批准的唯一RXR 结合rexinoid。我们的先导化合物UAB 30可在动物模型中预防UV诱导的NMSC。 UAB 30已进入正常个体的临床试验，并没有显示出明显的毒性。我们 假设UAB 30和其他基于UAB 30结构类Rexinoids可用作 高效、低毒化学预防剂限制肾移植中NMSC 受惠人士该计划汇集了7名研究人员，仔细研究 rexinoid化学预防NMSC，并开发一种系统的方法来翻译 新rexinoids用于肾移植受者NMSC化学预防的科学发现。 该项目由三个互动项目组成。Elmets博士（项目）1)将进行一次随机， 一项双盲、安慰剂对照研究，以确定可用作短期治疗的生物标志物 器官移植受者中NMSC预防的有效性预测因子。Muccio博士（项目）（二） 计划设计新的rexinoid，在rexinoid的环区域具有所需的空间体积， 作为激动剂，但在关键区域没有被认为刺激信号传导的空间体积 诱导脂质合成Kedishvili博士（项目）3)将研究rexinoids是否能增强 转录活性的现有内源性全反式维甲酸（ATRA）介导的 RXR/RAR异二聚体，这反过来又导致ATRA水平的进一步上调。的项目 将由3个核心（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， 在rexinoid化学，生物化学，癌症化学预防和翻译方面有共同的兴趣 科学