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 仅在2020年，前列腺癌就将夺去3万多名美国男性的生命。这种疾病从原发性 从肿瘤到去势抵抗性前列腺癌（CRPC），只需2-3年。CRPC仍在推动 这就是为什么抗雄激素药物被广泛用于治疗这种疾病。 这些药物包括恩杂鲁胺（XTANDI®）、醋酸阿比特龙（ZYTIGA®）和阿帕鲁胺（apalutamide）。 （ERLEADA™）。虽然这些药物最初非常有效，但患者通常很快产生耐药性 这些疾病的药物。因此，迫切需要找到控制反政府武装出现的战略， 雄激素抵抗性前列腺癌研究人员已经表明，耐药CRPC经常发生， 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 不依赖于雄激素激活。来自我的小组的数据表明，蛋白质降解酶（STUB 1）及其 伴侣蛋白（HSP 70）在耐药CRPC细胞中发生改变。这种HSP 70/STUB 1复合物是一种关键的 蛋白质稳定性/半衰期的调节剂。我们发现HSP 70/STUB 1与AR/AR-V7蛋白有关 体内平衡（蛋白质平衡）和长期保持活性。我们已经证明， HSP 70/STUB 1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，降低AR-V7的水平，重要的是使耐药前列腺癌对 抗雄激素治疗然而，氯硝柳胺具有较差的特性，难以达到满意 血液中的浓度作为癌症治疗剂。为了解决这个问题，我们修改了氯硝柳胺， 有效的HSP 70/STUB 1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和对抗药性前列腺肿瘤的上级杀伤作用。的 本申请的首要目标是开发HSM，并为将药物转化为 临床治疗致命性CRPC疾病的患者。在本项目中，我们将研究HSM-7对细胞凋亡的调控作用。 HSP 70/STUB 1/AR-V7三元复合物，这对于制定克服抗雄激素抗性的策略至关重要。 我们将通过HSP 70/STUB 1机制发现HSMs调控的多重靶点，并分析其如何调控HSP 70/STUB 1的表达。 HSMs处理引起的泛素化改变控制致癌蛋白质周转。此外，我们将评估 本文描述了HSM-7的药物性质，并测试了其在新的患者肿瘤衍生的动物和细胞模型中的功效。 CRPC用于未来临床试验启动。拟议研究的结果将为以下方面提供强有力的依据： 将HSM-7转化为临床环境并解决克服下一个问题的主要未满足需求 CRPC患者产生抗雄激素抵抗。我们相信，HSM-7将最终提高 总生存期和改善生活质量的男性诊断为CRPC。