Modulating HSP70/STUB1 machinery in therapy-resistant prostate cancer

调节 HSP70/STUB1 机制治疗耐药性前列腺癌

• 批准号: 10442601
• 负责人: Chengfei Liu
• 金额: $ 36.24万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442601
• 关键词: Acetates; Address; American; Androgen Antagonists; Androgen Receptor; Androgens; Animal Model; Anthelmintics; Antiandrogen Therapy; Antibodies; Binding Sites; Biodistribution; Biological Assay; Biological Availability; Blood; Bypass; Calorimetry; Cancer Patient; Cell Culture Techniques; Cell Survival; Cell model; Cells; Characteristics; Chronic; Clinic; Clinical; Clinical Trials; Co-Immunoprecipitations; Complex; Data; Deposition; Development; Diagnosis; Disease; Disease Resistance; Drug Kinetics; Drug resistance; Drug usage; Enzymes; Flow Cytometry; Future; Goals; Half-Life; Heat-Shock Proteins 70; Immunocompetent; Immunofluorescence Immunologic; In Vitro; Label; Ligation; Longevity; Luciferases; Lysine; MYC Family Protein; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular Chaperones; Molecular Target; Oncogenic; Oral; Organoids; Outcome; Parasitic infection; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Post-Translational Protein Processing; Precipitation; Primary Neoplasm; Property; Prostatic Neoplasms; Proteins; Quality of life; Reagent; Receptor Signaling; Regulation; Reporter; Research Personnel; Resistance; Sprague-Dawley Rats; Stains; Surface Plasmon Resonance; System; Technology; Testing; Testosterone; Therapeutic; Time; Titrations; Toxic effect; Translating; Translations; Tumor-Derived; Ubiquitin; Ubiquitin-mediated Proteolysis Pathway; Ubiquitination; United States Food and Drug Administration; Variant; abiraterone; analog; base; cancer cell; cancer therapy; castration resistant prostate cancer; clinically relevant; effective therapy; enzalutamide; improved; in vivo; liquid chromatography mass spectrometry; male; men; mouse model; multicatalytic endopeptidase complex; next generation; novel; patient derived xenograft model; prostate cancer cell; protein aggregation; protein degradation; proteostasis; receptor; resistance mechanism; small molecule; success; therapy resistant; tumor; tumor progression; ubiquitin-protein ligase

PROJECT ABSTRACT Prostate cancer will claim lives of over 30,000 American men in 2020 alone. The disease evolves from primary tumors to castrate-resistant prostate cancer (CRPC), which only takes around 2-3 years. CRPC is still driven by androgens such as testosterone which is why anti-androgen drugs are widely used to treat the disease. These drugs include enzalutamide (XTANDI®), abiraterone acetate (ZYTIGA®) and apalutamide (ERLEADA™). Although these drugs are highly effective initially, patients often quickly develop resistant disease to these drugs. Therefore, there is an urgent need to find strategies that control the emergence of anti- androgen resistant prostate cancer. Researchers have shown that drug resistant CRPC often occurs due to expression of a variant form of receptor called androgen receptor variant-7 (AR-V7). This receptor can be activated independent of androgen. Data from my group shows that protein degrading enzyme (STUB1) and its chaperone protein (HSP70) are altered in resistant CRPC cells. This HSP70/STUB1 complex is a critical regulator of protein stability/half-life. We found that HSP70/STUB1 is responsible for AR/AR-V7 proteins homeostasis (proteostasis) and remaining active for long periods. We have shown that modulating the HSP70/STUB1 complex with a Food and Drug Administration (FDA) approved drug used for parasite infection namely, niclosamide, reduces the levels of AR-V7 and importantly resensitizes resistant prostate cancer to anti-androgen therapy. However, niclosamide has a poor characteristic that is hard to reach satisfied concentration in blood as a cancer therapeutic. To address this, we modified niclosamide to yield a range of potent HSP70/STUB1 modulators (HSMs) and one of the small molecule compounds known as HSM-7, which has a better bio-distribution profile and superior effects on killing drug resistant prostate tumors. The overarching goal of this application is to develop HSMs and build a strong rationale for translating the drug to the clinic to treat patients with lethal CRPC disease. In this project, we will study HSM-7 on its regulation of HSP70/STUB1/AR-V7 ternary complex which will be critical to strategize to overcome anti-androgen resistance. We will discover the multiplicity targets regulated by HSMs through HSP70/STUB1 machinery and dissect how ubiquitination alteration by HSMs treatment controls oncogenic protein turnover. Additionally, we will evaluate the drug properties of HSM-7 and test its efficacy in novel patient tumor derived animal and cell models of CRPC for future clinical trial initiation. The outcomes of the proposed studies will provide a strong rationale for translating HSM-7 into the clinical setting and in addressing the major unmet need of overcoming next generation anti-androgen resistance in CRPC patients. We believe that HSM-7 will ultimately increase the overall survival and improve the quality of life men diagnosed with CRPC.

项目摘要