Modulating HSP70/STUB1 machinery in therapy-resistant prostate cancer

项目摘要 仅在2020年，前列腺癌就将夺走3万多名美国男性的生命。该病由原发疾病演变而来 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仍在推动 通过雄激素，如睾酮，这就是为什么抗雄激素药物被广泛用于治疗这种疾病。 这些药物包括苯扎鲁胺(XTANDI®)、醋酸阿比特龙(ZYTIGA®)和阿帕鲁胺 (ERLEADA™)。虽然这些药物最初非常有效，但患者往往很快就会产生抗药性。 对这些药物的抗病作用。因此，迫切需要找到控制反腐败现象出现的策略。 雄激素抵抗前列腺癌。研究人员表明，耐药CRPC通常是由于 表达一种称为雄激素受体变体-7(AR-V7)的变异型受体。这种受体可以是 不依赖雄激素而激活。来自我的小组的数据显示，蛋白质降解酶(STUB1)及其 伴侣蛋白(HSP70)在耐药的CRPC细胞中发生改变。这种HSP70/STUB1复合体是一个关键的 蛋白质稳定性/半衰期的调节剂。我们发现HSP70/STUB1与AR/AR-V7蛋白有关 动态平衡(蛋白质平衡)并长时间保持活跃。我们已经证明，调制 HSP70/STUB1复合体与食品和药物管理局(FDA)批准的治疗寄生虫感染的药物 也就是说，氯硝柳胺降低AR-V7水平，重要的是使耐药前列腺癌对 抗雄激素治疗。然而，氯硝柳胺有一个很难令人满意的不良特性。 血液中的浓缩物可作为癌症治疗药物。为了解决这个问题，我们对氯硝柳胺进行了修改，以产生一系列 有效的HSP70/STUB1调节剂(HSM)和一种名为HSM-7的小分子化合物，它 具有更好的生物分布特征和更好的杀灭耐药前列腺癌的效果。这个 该应用程序的总体目标是开发HSM，并为将药物转换为 治疗致命性慢性前列腺癌患者的诊所。在本项目中，我们将研究HSM-7对 HSP70/STUB1/AR-V7三元复合体是克服抗雄激素耐药策略的关键。 我们将通过HSP70/STUB1机制发现HSM调控的多样性靶点，并剖析如何 HSMS治疗引起的泛素化改变控制致癌蛋白的周转。此外，我们还将评估 HSM-7的药物性质及其在新的人肿瘤动物和细胞模型中的作用 CRPC用于未来的临床试验启动。拟议研究的结果将提供一个强有力的理由 将HSM-7转化为临床环境，并解决下一步尚未满足的主要需求 慢性前列腺癌患者产生抗雄激素耐药。我们相信，HSM-7最终将增加 诊断为CRPC的男性总体生存和改善生活质量。

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.