Modulating HSP70/STUB1 machinery in therapy-resistant prostate cancer

调节 HSP70/STUB1 机制治疗耐药性前列腺癌

基本信息

批准号：
10298903
负责人：
Chengfei Liu
金额：
$ 36.23万
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：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298903
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 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

项目摘要

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，前列腺癌将夺取30,000多名美国男性的生命。该疾病是从初级演变的肿瘤到耐Castrate的前列腺癌（CRPC），仅需2 - 3年。 CRPC仍然被驱动由雄激素（例如睾丸激素），这就是为什么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enzalutamide（XTANDI®），乙酸阿比罗酮（Zytiga®）和Apalutamide （ERLEADA™）。尽管这些药物最初是非常有效的，但患者通常会迅速发展抗性这些药物的疾病。因此，迫切需要寻找控制反 - 出现的策略抗雄激素的前列腺癌。研究人员表明，耐药性CRPC通常是由于称为雄激素受体变体7（AR-V7）的变体形式的表达。这个受体可以是激活独立于雄激素。来自我组的数据表明蛋白质降解酶（ub1）及其在抗性CRPC细胞中改变了伴侣蛋白（HSP70）。此HSP70/Stub1复合物是关键蛋白质稳定性/半衰期的调节剂。我们发现HSP70/Stub1负责AR/AR-V7蛋白体内平衡（蛋白抑制），长期保持活跃。我们已经表明，调整 HSP70/Stub1复合物，配备食品药物管理局（FDA）批准用于寄生虫感染的药物也就是说，烟酰胺降低了AR-V7的水平，并重要地使耐药性前列腺癌对抗雄激素治疗。但是，烟酰胺的特征很差，难以满足血液中的浓度作为癌症疗法。为了解决这个问题，我们修改了烟酰胺，以产生一系列潜在的HSP70/Stub1调节剂（HSM）和一种称为HSM-7的小分子化合物之一对杀死耐药性前列腺肿瘤的生物分布概况更好，并且具有出色的影响。该应用程序的总体目标是开发HSM并建立一个有力的理由，以将药物转化为治疗致命CRPC疾病患者的诊所。在这个项目中，我们将研究HSM-7的调节 HSP70/Stub1/AR-V7三元复合物对于克服抗雄激素耐药性至关重要。我们将通过HSP70/Stub1机械发现HSM调节的多重目标，并剖析如何 HSMS治疗控制的泛素化改变了致癌蛋白更新。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衍生的动物和细胞模型中的有效性 CRPC未来的临床试验计划。拟议研究的结果将为将HSM-7转换为临床环境，并在满足下一步的主要未满足需求时 CRPC患者的产生抗雄激素耐药性。我们相信HSM-7最终将增加总体生存和提高被诊断为CRPC的男性的生活质量。