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RXR Rexinoids for Cancer Chemoprevention

RXR Rexinoids 用于癌症化学预防

基本信息

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
项目类别：
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

项目摘要

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，因此 NMSC 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针对肾移植受者 NMSC 化学预防的新型 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，但在关键区域没有空间体积，据信可以刺激信号传导从而诱导脂质合成。 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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.

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