RXR Rexinoids for Cancer Chemoprevention

RXR Rexinoids 用于癌症化学预防

• 批准号: 10411342
• 负责人: Craig A Elmets
• 金额: $ 5.99万
• 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/10411342
• 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)、(鳞状细胞癌和基底细胞癌 癌症[BCC])是肾移植长期存活者的主要发病率来源。 由于这些患者必须服用药物来防止移植排斥反应，NMSCs的发生率更高 通常(鳞癌人口的65-250倍；密件抄送人口的10倍)，表现得更加咄咄逼人， 而且比普通人群更有可能转移。口服维甲酸有效保护 针对这些患者的NMSCs，但剂量具有不可接受的毒性。我们队有 设计了对维甲酸X受体(RXR)具有高度特异性的Rexinoid，而不通过 RXR：肝脏(或其他RXR杂二聚体)中的LXR(肝X受体)。这将消除标记的 高甘油三酯血症是贝沙罗汀的限速毒性，FDA唯一批准的RXR 结合型雷克素。我们的先导化合物UAB30可以在动物模型中防止紫外线诱导的NMSCs。 UAB30已经进入了正常人的临床试验，没有显示出明显的毒性。我们 假设UAB30和其他基于UAB30的S结构的Rexinoid可以用作 限制NMSCs在肾移植中应用的高效低毒化学预防药物 收件人。这个项目汇集了7名研究人员，仔细研究了 Rexin对NMSCs的化学预防，并开发一种系统的方法来翻译 用于肾移植受者NMSC化学预防的新的Rexinoid的科学发现。 该计划由3个互动项目组成。Elmets博士(项目。1)将进行随机、 双盲、安慰剂对照研究以确定可作为短期使用的生物标记物 器官移植受者预防NMSC疗效的预测因素。Muccio博士(项目。2) 计划设计新的rexinoid，在rexinid的环状区域具有所需的立体结构以起作用 作为一种激动剂，但在关键区域没有立体物质，据信刺激信号 这会导致脂肪合成。凯迪什维利博士(项目。3)将检查rexinoid是否会增强 内源性全反式维甲酸(ATRA)的转录活性 RXR/RAR异二聚体，这反过来又导致ATRA水平的进一步上调。这些项目 将由3个核心提供支持(行政；设计和合成；Rexinid筛选和 动物)。参与该计划的科学家有很长的合作历史，并有 在类脂化学、生物化学、癌症化学预防和翻译方面的共同兴趣 科学。

项目成果

Next-generation retinoid X receptor agonists increase ATRA signaling in organotypic epithelium cultures and have distinct effects on receptor dynamics.

• DOI: 10.1016/j.jbc.2022.102746
• 发表时间: 2023-01
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Melo, Nathalia;Belyaeva, Olga V.;Berger, Wilhelm K.;Halasz, Laszlo;Yu, Jianshi;Pilli, Nagesh;Yang, Zhengrong;Klyuyeva, Alla V.;Elmets, Craig A.;Atigadda, Venkatram;Muccio, Donald D.;Kane, Maureen A.;Nagy, Laszlo;Kedishvili, Natalia Y.;Renfrow, Matthew B.
• 通讯作者: Renfrow, Matthew B.

Combined inhibition of BET bromodomain and mTORC1/2 provides therapeutic advantage for rhabdomyosarcoma by switching cell death mechanism.

• DOI: 10.1002/mc.23414
• 发表时间: 2022-08
• 期刊: Molecular carcinogenesis
• 影响因子: 4.6

Ex Vivo Culture Models of Hidradenitis Suppurativa for Defining Molecular Pathogenesis and Treatment Efficacy of Novel Drugs.

• DOI: 10.1007/s10753-022-01629-w
• 发表时间: 2022-06
• 期刊: Inflammation
• 影响因子: 5.1