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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