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: 10678891
• 负责人: Chengfei Liu
• 金额: $ 35.52万
• 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/10678891
• 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; 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 仅 2020 年，前列腺癌就会夺去 30,000 多名美国男性的生命。本病由原发发展而来 肿瘤到去势抵抗性前列腺癌（CRPC）只需要大约2-3年的时间。 CRPC仍受驱动 由睾酮等雄激素引起，这就是抗雄激素药物被广泛用于治疗该疾病的原因。 这些药物包括恩杂鲁胺 (XTANDI®)、醋酸阿比特龙 (ZYTIGA®) 和阿帕鲁胺 （ERLEADA™）。尽管这些药物最初非常有效，但患者往往很快就会产生耐药性 这些药物引起的疾病。因此，迫切需要寻找控制反病毒出现的策略。 雄激素抵抗性前列腺癌。研究人员表明，耐药 CRPC 的发生通常是由于 表达一种称为雄激素受体变体 7 (AR-V7) 的受体变体形式。该受体可以是 不依赖雄激素而激活。我小组的数据显示蛋白质降解酶（STUB1）及其 伴侣蛋白 (HSP70) 在耐药 CRPC 细胞中发生改变。 HSP70/STUB1 复合物是一个关键的 蛋白质稳定性/半衰期的调节剂。我们发现 HSP70/STUB1 负责 AR/AR-V7 蛋白 稳态（蛋白质稳态）并长期保持活跃。我们已经证明，调节 HSP70/STUB1 复合物与食品和药物管理局 (FDA) 批准的用于寄生虫感染的药物 即氯硝柳胺，可降低 AR-V7 的水平，重要的是使耐药性前列腺癌重新敏感。 抗雄激素治疗。但氯硝柳胺的特性较差，难以达到满意的效果。 作为癌症治疗剂在血液中的浓度。为了解决这个问题，我们修改了氯硝柳胺以产生一系列 有效的 HSP70/STUB1 调节剂 (HSM) 和一种称为 HSM-7 的小分子化合物， 具有更好的生物分布特征，对耐药性前列腺肿瘤的杀灭效果更佳。这 该应用的总体目标是开发 HSM 并为将该药物转化为 该诊所治疗致命的 CRPC 疾病患者。在这个项目中，我们将研究HSM-7的调节作用 HSP70/STUB1/AR-V7 三元复合物对于制定克服抗雄激素耐药性的策略至关重要。 我们将通过 HSP70/STUB1 机制发现 HSM 调节的多重目标，并剖析如何 HSM 处理引起的泛素化改变控制着致癌蛋白的周转。此外，我们将评估 HSM-7 的药物特性并测试其在新型患者肿瘤来源的动物和细胞模型中的功效 CRPC 用于未来临床试验的启动。拟议研究的结果将为 将 HSM-7 转化为临床环境并解决克服下一步主要未满足的需求 CRPC 患者产生抗雄激素抵抗。我们相信 HSM-7 最终将提高 诊断患有 CRPC 的男性的总体生存率并提高生活质量。