Targeting AR variants in advanced prostate cancer

靶向晚期前列腺癌中的 AR 变异

基本信息

批准号：
10318581
负责人：
Allen C Gao
金额：
$ 35.18万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318581
关键词：
Androgen Antagonists Androgen Receptor Anthelmintics Antineoplastic Agents Biological Availability Cells Cestode Infections ChIP-seq Clinical Data Clinical Research Complex Drug resistance FDA approved Generations Genetic Transcription Genomic approach Heat-Shock Proteins 70 In Vitro Length Libraries Mediating Metabolic Oral Pathway interactions Penetration Pharmaceutical Preparations Play RNA Splicing Resistance Resistance development Role Safety Signal Transduction Therapeutic Toxic effect Ubiquitin Variant abiraterone advanced prostate cancer analog carcinogenesis castration resistant prostate cancer cell growth clinical efficacy efficacy evaluation enzalutamide experimental study functional genomics improved in vitro Model in vivo in vivo Model inhibitor multicatalytic endopeptidase complex next generation novel novel marker novel therapeutics patient derived xenograft model pre-clinical prevent prostate cancer cell prostate cancer model prostate cancer progression protein degradation protein expression small molecule inhibitor targeted agent therapy resistant transcriptome transcriptome sequencing treatment response treatment strategy tumor tumor growth

项目摘要

Although enzalutamide and abiraterone are effective initially for the treatment of castration-resistant prostate cancer (CRPC), resistance to both drugs occurs frequently through the mechanisms which are incompletely understood. Considerable evidence from both clinical and experimental studies demonstrated that androgen receptor splice variant AR-V7 plays vital roles in promoting CRPC progression and induction of resistance to enzalutamide and abiraterone. AR-V7 is not targeted by either enzalutamide or abiraterone and therefore, there is an urgent need to develop novel treatment strategies that target AR-V7 to overcome resistance. Currently, no AR-V7 targeting agents have shown clinical efficacy for CRPC despite convincing experimental and clinical data supporting a clear role for AR-V7 in resistant CRPC. We previously identified that niclosamide, an anthelmintic agent approved by the FDA for the treatment of tapeworm infections, inhibits expression of AR variants such as AR-V7 and overcomes resistance to enzalutamide and abiraterone in preclinical CRPC models. To improve the bioavailability and potency of niclosamide, we synthesized a library of niclosamide analogs according to predicted bioavailability. We have identified several novel small molecule inhibitors of AR-V7 (ARVib). We showed that ARVib has better efficacy in inhibition of AR-V7 expression, AR- V7 mediated transcriptional activity, and anti-CRPC tumor growth than niclosamide. Furthermore, we demonstrated that ARVib synergizes with enzalutamide/abiraterone. This proposal is aimed to functionally characterize and validate the most promising AR variant inhibitors (ARVib) and develop next generation treatment strategies for resistant CRPC by targeting AR-V7 using ARVib. The overall hypothesis is that inhibition of AR variants by ARVib suppresses CRPC tumor growth and overcomes resistance to improve enzalutamide/abiraterone therapy. In Aims 1 and 2, we will characterize and optimize the identified selective inhibitors of AR variants (ARVib), and evaluate the efficacy of these ARVib for their anti-tumor activity and their ability to sensitize resistant cells to enzalutamide/abiraterone treatment in resistant CRPC and PDX models in vitro and in vivo. Aim 3 will determine the mechanisms of action (MOA) of the ARVib in anti-tumor activity and resensitization to enzalutamide/abiraterone.

尽管恩扎拉胺和阿比罗酮最初是有效的，可用于治疗castration抗性前列腺癌症（CRPC），两种药物的抗性经常通过不完全的机制发生理解。来自临床和实验研究的大量证据表明雄激素受体剪接变体AR-V7在促进CRPC进展和抗药性中起着至关重要的作用恩扎拉胺和阿比拉酮。 AR-V7均不针对Enzalutamide或abiraterone，因此迫切需要制定针对AR-V7以克服抵抗力的新型治疗策略。目前，尽管令人信服的实验性以及支持AR-V7在耐药性CRPC中的明确作用的临床数据。我们以前确定烟酰胺是FDA批准用于治疗tape虫感染的驱虫药物，抑制 AR-V7等AR变体的表达和克服对恩扎拉胺和阿比罗酮的抗性临床前CRPC模型。为了提高烟酰胺的生物利用度和效力，我们合成了一个库根据预测的生物利用度。我们已经确定了几个新型的小分子 AR-V7（ARVIB）的抑制剂。我们表明，Arvib在抑制AR-V7表达，AR-具有更好的疗效 V7介导的转录活性和抗CRPC肿瘤的生长比烟酰胺。此外，我们证明Arvib与Enzalutamide/Abiraterone协同作用。该建议的目的是在功能上表征和验证最有希望的AR变体抑制剂（ARVIB）并发展下一代通过使用ARVIB靶向AR-V7的抗性CRPC的治疗策略。总体假设是通过ARVIB抑制AR变体可抑制CRPC肿瘤的生长并克服抗药性恩扎拉胺/阿比罗酮治疗。在目标1和2中，我们将表征和优化已确定的选择性 AR变体抑制剂（ARVIB），并评估这些Arvib的抗肿瘤活性及其疗效能够使耐药细胞在耐药性CRPC和PDX模型中敏感性细胞对enzalutamide/abiraterone处理体内和体内。 AIM 3将确定Arvib在抗肿瘤活性中的作用机理（MOA）和对Enzalutamide/abiraterone的敏感性。