Dissecting the Role of Proteostasis in Anti-Androgen Resistant Prostate Cancer

剖析蛋白质稳态在抗雄激素抵抗性前列腺癌中的作用

基本信息

批准号：
10211202
负责人：
Chengfei Liu
金额：
$ 35.91万
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：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211202
关键词：
Acetates Androgen Antagonists Androgen Receptor Antiandrogen Therapy Antibodies Automobile Driving Binding Sites Biochemical Biological Assay Bone marrow biopsy Calorimetry Cancer Etiology Cancer Patient Cell Culture Techniques Cell Survival Cells Cessation of life Chronic Co-Immunoprecipitations Complex Data Deposition Diagnosis Disease Drug resistance Evolution Flow Cytometry Genes Gleason Grade for Prostate Cancer Glucocorticoid Receptor Goals Human Immunofluorescence Immunologic Impairment In Vitro Label Length Ligation Longevity Lysine Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Mediating Molecular Chaperones Neoadjuvant Therapy Oncogenic Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Play Population Precipitation Primary Neoplasm Prostate Cancer therapy Prostatic Neoplasms Proteins Radiation Radical Prostatectomy Reporting Resistance Resistance development Role Specimen Stains System Technology Testing Therapeutic Time Tissue Microarray Titrations Treatment outcome Ubiquitin Ubiquitin-mediated Proteolysis Pathway Ubiquitination United States Variant abiraterone advanced prostate cancer androgen deprivation therapy base cancer cell cancer drug resistance castration resistant prostate cancer clinically relevant effective therapy effectiveness testing efficacy testing improved in vivo inhibitor/antagonist insight men multicatalytic endopeptidase complex next generation novel novel strategies patient derived xenograft model programs prostate cancer cell prostate cancer progression protein aggregation proteostasis receptor expression resistance mechanism small molecule small molecule inhibitor success targeted treatment therapy resistant tumor tumor growth tumor progression tumorigenesis ubiquitin-protein ligase

项目摘要

PROJECT ABSTRACT In the United States, prostate cancer (PCa) is predicted to be the second leading cause of cancer related death in men in the United States in 2020. After initial diagnosis of PCa, radical prostatectomy, radiation and androgen deprivation therapy (ADT) are used to treat the primary tumors. When cancer recurs, castrate- resistant prostate cancer (CRPC) is treated by anti-androgen drugs, such as enzalutamide (XTANDI®), abiraterone acetate (ZYTIGA®) or apalutamide (ERLEADA™). Although these drugs are highly effective initially, patients quickly develop resistance through mechanisms that are not completely understood. Therefore, there is an urgent need to identify resistant mechanisms to improve the treatment outcome of CRPC. Protein homeostasis (proteostasis) deficiency and oncogenic activation plays important roles during tumorigenesis; however, proteostasis modulation involved in anti-androgen resistant PCa is still rudimentarily understood. We have reported that ubiquitin mediated proteolysis pathway and proteasome activity are suppressed in enzalutamide and abiraterone resistant PCa cells. As a result, androgen receptor (AR) and its variant form AR- V7 protein are stabilized and accumulated in these resistant cells through chaperone-ubiquitin-proteasome- system alteration. The chaperone (Hsp70)/E3 ubiquitin ligase (Stub1) machinery regulates full length AR and AR variant proteostasis. Hsp70 inhibition by small molecules promotes Hsp70, AR-V7 and Stub1 proximity which significantly disrupts AR/AR-V7 gene programs and suppresses prostate tumor growth. This proposal initiates a new paradigm to explore the underlying mechanisms driving next generation anti-androgen resistance in CRPC. The ultimate goal of this program is to dissect the roles of chaperone-ubiquitin- proteasome-system in anti-androgen resistance and develop new pharmaceutical approaches to provide co- targeting neoadjuvant with anti-AR agents to personalized CRPC patients’ treatment. We will provide a novel mechanism of next generation anti-androgen resistance via proteostasis impairment and uncover that Hsp70/Stub1 machinery in anti-androgen resistant CRPC may trigger accumulation of oncogenic proteins such as AR variants and glucocorticoid receptor (GR) due to inability of protein clearance. We will functionally interrogate the Hsp70/Stub1/AR-V7 ternary complex through biochemical assays, and uncover the mechanisms of inhibition of Hsp70 activity in inducing AR-V7 degradation through the proximity of Stub1. We will unveil the underlying mechanisms of AR and AR-V7 ubiquitination through the ubiquitination binding sites identification and large-scale ubiquitin remnants sequencing. Importantly, we will provide the rationale to correct proteostasis imbalance through modulation of Hsp70/Stub1 as a potential therapeutic strategy to overcome resistance to AR-targeted therapies in CRPC patients and develop conditional reprogramed cell cultures (CRCs) and patient derived xenograft (PDX) models to dissect the mechanisms in vivo. This proposal will fill the gap in overcoming next generation anti-androgen resistance in CRPC patients and point the way to future research by improving current AR-targeted therapies.

项目摘要在美国，预测前列腺癌（PCA）是与癌症相关的第二大原因在2020年，美国男性死亡。在最初诊断PCA后，前列腺切除术，辐射和雄激素剥夺疗法（ADT）用于治疗原发性肿瘤。当癌症复发时，耐药性前列腺癌（CRPC）由抗雄激素药物（例如enzalutamide（XTANDI®））治疗乙酸酯（Zytiga®）或Apalutamide（Erleada™）。尽管这些药物最初是非常有效的，但患者通过未完全理解的机制迅速发展出抵抗力。因此，那里迫切需要确定耐药机制以改善CRPC的治疗结果。蛋白质稳态（蛋白抑制）缺乏症和致癌激活在肿瘤发生过程中起着重要作用。然而，抗抗雄激素耐药PCA涉及的蛋白抑制剂仍然是一定理解的。我们据报道，泛素介导的蛋白水解途径和蛋白酶体活性在恩扎拉胺和阿比罗酮耐药PCA细胞。结果，雄激素受体（AR）及其变体形成ar- V7蛋白通过伴侣 - 泛素 - 蛋白酶体 - 稳定并积聚在这些抗性细胞中系统更改。伴侣（HSP70）/E3泛素连接酶（Stub1）机械调节全长AR和 AR变体蛋白质量。小分子抑制HSP70可促进HSP70，AR-V7和Stub1接近度这显着破坏了AR/AR-V7基因程序并抑制前列腺肿瘤的生长。这个建议启动一个新的范式来探索驱动下一代抗雄激素的基本机制 CRPC的阻力。该计划的最终目标是剖析伴侣 - 泛素 - 泛素 - 抗雄激素耐药性中的蛋白酶体系统，并开发出新的药物方法以提供共同针对个性化CRPC患者治疗的新辅助药物新辅助药物。我们将提供小说下一代抗雄激素耐药性的机理，通过蛋白质抑制作用，并发现该机制抗雄激素耐药性CRPC中的HSP70/Stub1机械可能会触发致癌蛋白的积累。由于蛋白质清除率无能为力，作为AR变体和糖皮质激素受体（GR）。我们将在功能上通过生化测定法询问HSP70/Stub1/AR-V7三元复合物，并发现通过Stub1的接近性，HSP70活性抑制HSP70活性的机制。我们将通过泛素化位点揭示AR和AR-V7泛素化的基本机制识别和大规模的泛素残余测序。重要的是，我们将提供理由通过调节Hsp70/ub1作为一种潜在的治疗策略来纠正蛋白质的失衡克服CRPC患者中对AR靶向疗法的耐药性并发展为有条件的重编程细胞培养物（CRC）和患者衍生的异种移植（PDX）模型，以在体内剖析机制。这个建议将填补CRPC患者中的下一代抗雄激素耐药性的空白，并指向通过改善当前的AR靶向疗法，未来的研究。