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) 在各个阶段的前列腺癌 (PCa) 中都发挥着关键作用。虽然大多数患者 PCa 最初对雄激素剥夺和/或抗雄激素治疗有反应，其中很大一部分患者发展为去势抵抗性前列腺癌（CRPC）。临床研究表明，CRPC 常富含缺乏配体结合域（LBD）的 AR 剪接变体，因此在一种不依赖雄激素的方式并逃避抗雄激素恩杂鲁胺介导的 AR 抑制。 RO1 应用的目标是开发和表征可有效降解的新型疗法（去除）PCa 中的 AR 蛋白。技术创新包括开发新型治疗平台使用自噬靶向嵌合体 (AUTOTAC) 降解 AR 蛋白。我们成功生成了AR- 靶向 AUTOTAC 是双功能分子，由恩杂鲁胺（一种 AR 配体结合结构域抑制剂）或 VPC-14449（一种 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/SQSTM1 的配体。针对 AR 的 AUTOTAC 将靶蛋白 AR 带到 p62 上，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-LC3相互作用自噬膜并促进自噬体生物发生和 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，我们将检验我们的新假设，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。我们也假设与抗雄激素不同的是，抗雄激素会导致 PCa 细胞出现治疗耐药，涉及激活非规范的 AR 信号程序，针对 AR 的 AUTOTAC 平台不太可能导致非规范的结果 AR信号传导相关的恶性表型。目标 1 将描述 AR LBD- 的分子作用目标 AUTOTAC (Enz-AUTOTAC) 和 AR DBD 目标 AUTOTAC (VPC-AUTOTAC)，并评估它们前列腺癌细胞模型中的治疗效果。目标 2 将评估 Enz-的治疗效果使用 PTEN 敲除和患者来源的异种移植 (PDX) 小鼠进行体内 AUTOTAC 和 VPC-AUTOTAC 前列腺癌模型。治疗抵抗性肿瘤中潜在致癌途径的激活将是检查 AR 表达水平和 AR 变体状态的关系。除了肿瘤细胞转录组分析、肿瘤异质性、癌细胞可塑性和肿瘤微环境还将通过药物治疗前后的单细胞 RNA-seq 分析进行评估。这些数据可能会导致确定去势抵抗性前列腺癌的其他治疗靶点。成功完成拟议研究将开发革命性的 AR 药物平台 CRPC 患者的降解剂。