权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

A novel AR degrader in castrate-resistant prostate cancer

一种治疗去势抵抗性前列腺癌的新型 AR 降解剂

基本信息

批准号：
10714811
负责人：
Hyeong-Reh Choi Kim
金额：
$ 59.42万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714811
关键词：
Agonist Anabolism Androgen Antagonists Androgen Receptor Androgens Animal Model Antiandrogen Therapy Autophagocytosis Autophagosome Biochemical Pathway Biogenesis Biology Cell Line Cell model Cells Chimera organism Clinical Research Complex Cytoplasm DNA Binding Domain DNA Sequence Alteration Data Development Disease Disease Progression Excision Gene Expression Profile Goals Histopathology Human In Vitro Knock-out Knockout Mice Length Ligand Binding Ligand Binding Domain Ligands Link Literature Lysosomes Malignant neoplasm of prostate Mediating Membrane Modeling Molecular Nuclear Oncogenic PTEN gene Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Play Production Prostate Protac Proteins RNA Splicing Receptor Inhibition Receptor Signaling Resistance Role Stanolone Technology Testing Testosterone Therapeutic Therapeutic Agents Tissues Treatment Efficacy Ubiquitination Variant androgen deprivation therapy androgen sensitive antagonist cancer cell castration resistant prostate cancer clinically relevant deprivation dimer enzalutamide gain of function high risk in vivo inhibitor innovation malignant phenotype men mortality risk mouse model mutant neoplastic cell novel novel therapeutics patient derived xenograft model programs prostate cancer cell prostate cancer model prostate cancer progression protein complex protein degradation receptor receptor binding receptor function response single-cell RNA sequencing small molecule standard of care therapeutic evaluation therapeutic target therapeutically effective therapy resistant transcription factor transcriptome treatment response tumor tumor heterogeneity tumor microenvironment

项目摘要

Androgen receptor (AR) plays a critical role in prostate cancer (PCa) in all stages. While a majority of patients with PCa initially respond to androgen deprivation and/or anti-androgen therapies, a significant portion of patients develop castrate-resistant prostate cancer (CRPC). Clinical studies showed that CRPC is often enriched with AR splice variants lacking the ligand binding domain (LBD), thereby being constitutively active in an androgen-independent manner and escaping from the antiandrogen enzalutamide-mediated AR inhibition. The goal of this RO1 application is to develop and characterize novel therapeutics that effectively degrade (remove) AR proteins in PCa. Technical innovations include the development of a novel therapeutic platform for AR protein degradation using autophagy-targeting chimera (AUTOTAC). We successfully generated AR- targeted AUTOTACs, which are bifunctional molecules, composed of enzalutamide (an AR ligand binding domain inhibitor) or VPC-14449 (an AR DNA binding domain inhibitor) as a target binding ligand, linked to YTK-6-2 as a ligand of the autophagic cargo receptor p62/Sequestosome-1/SQSTM1. AR-targeted AUTOTAC brings the target protein AR to p62, forming a ternary complex. YTK-6-2 induces p62 self-oligomerization, resulting in AR-p62 oligomeric complexes. YTK-6-2-activated p62 facilitates AR-p62-LC3 interaction on autophagic membranes and promotes autophagosome biogenesis and degradation of AR proteins. Using clinically relevant animal models that reflect the relevant tumor microenvironment and tumor heterogeneity, we will test our novel hypothesis that AUTOTAC-mediated degradation (removal) of AR and its variants is a more effective approach than the currently available therapeutics including anti-androgen therapy. We also hypothesize that unlike anti-androgens which result in therapy-resistant PCa cells involving activation of noncanonical AR signaling programs, the AR-targeted AUTOTAC platform is unlikely to result in noncanonical AR signaling-associated malignant phenotypes. Aim 1 will characterize the molecular actions of AR LBD- targeted AUTOTAC (Enz-AUTOTAC) and AR DBD-targeted AUTOTAC (VPC-AUTOTAC), and evaluate their therapeutic efficacies in prostate cancer cell models. Aim 2 will evaluate the therapeutic efficacies of Enz- AUTOTAC and VPC-AUTOTAC in vivo using PTEN knockout and patient-derived xenograft (PDX) mouse models of prostate cancer. Activation of potential oncogenic pathways in therapy-resistant tumors will be examined in relation to the expression levels of AR and the status of AR variants. In addition to the transcriptome analysis of tumor cells, tumor heterogeneity, cancer cell plasticity and tumor microenvironments will also be assessed by single cell RNA-seq analysis before and after drug treatments. These data may lead to the identification of additional therapeutic target(s) in castrate-resistant PCa. Successful completion of the proposed study will develop a revolutionary drug platform of AR degraders for patients with CRPC.

雄激素受体（AR）在前列腺癌（PCa）的各个阶段都起着关键作用。虽然大多数患者对于最初对雄激素剥夺和/或抗雄激素治疗有反应的PCa，患者发生去势抵抗性前列腺癌（CRPC）。临床研究表明，CRPC通常富含缺乏配体结合结构域（LBD）的AR剪接变体，从而在以下方面具有组成性活性：雄激素非依赖性方式和逃避抗雄激素Enzalutamide介导的AR抑制。该RO 1应用的目标是开发和表征能够有效降解（去除）PCa中的AR蛋白。技术创新包括开发新型治疗平台用于使用自噬靶向嵌合体（AUTOTAC）的AR蛋白降解。我们成功地生成了AR- 靶向AUTOTAC是双功能分子，由Enzalutamide（AR配体结合蛋白）组成，结构域抑制剂）或VPC-14449（AR DNA结合结构域抑制剂）作为靶结合配体，连接至 YTK-6-2作为自噬货物受体p62/Sequestosome-1/SQSTM 1的配体。AR靶向AUTOTAC 将靶蛋白AR带到p62，形成三元复合物。YTK-6-2诱导p62自身寡聚化，产生AR-p62寡聚复合物。YTK-6-2激活的p62促进AR-p62-LC 3相互作用，自噬体是自噬膜的一部分，并促进自噬体的生物发生和AR蛋白的降解。使用反映相关肿瘤微环境和肿瘤异质性的临床相关动物模型，我们将测试我们的新假设，即AUTOTAC介导的AR及其变体的降解（去除）是一种更有效的方法。比目前可用的治疗方法，包括抗雄激素治疗更有效的方法。我们也假设与导致治疗抗性PCa细胞的抗雄激素不同，对于非经典AR信号程序，AR靶向AUTOTAC平台不太可能导致非经典AR信号程序。 AR信号相关恶性表型。目的1将表征AR LBD的分子作用- 靶向AUTOTAC（Enz-AUTOTAC）和AR DBD靶向AUTOTAC（VPC-AUTOTAC），并评估其前列腺癌细胞模型中的治疗功效。目的2：评价酶制剂治疗慢性乙型肝炎的疗效。使用PTEN敲除和患者来源的异种移植（PDX）小鼠的体内AUTOTAC和VPC-AUTOTAC 前列腺癌的模型。治疗抗性肿瘤中潜在致癌途径的激活将是检查与AR的表达水平和AR变体的状态的关系。除了有肿瘤细胞的转录组分析、肿瘤异质性、癌细胞可塑性和肿瘤微环境还将在药物治疗前后通过单细胞RNA-seq分析进行评估。这些数据可能会导致鉴定去势抵抗性前列腺癌中的其他治疗靶点。成功完成拟议的研究将开发革命性的AR药物平台 CRPC患者的降解产物。