Novel Androgen Receptor Degraders to Treat Castration-Resistant Prostate Cancer

 描述(由申请者提供)：这笔赠款的总体目标是产生数据，以了解并使开发一种新的治疗方法来治疗去势抵抗前列腺癌患者。前列腺癌是第三大致命癌症。 在美国，预计2015年将出现22万新病例和2.7万人死亡。虽然早期发现、手术和激素剥夺治疗是有效的，但大约10%-20%的局限性前列腺癌最终变成转移性去势抵抗型前列腺癌(MCRPC)。雄激素受体(AR)是mCRPC的主要驱动力，AR靶基因前列腺特异性抗原(PSA)循环水平的升高证明了这一点。接受第一代抗雄激素药物(氟他胺和比卡鲁胺)以及第二代抗雄激素药物(苯扎鲁胺和阿比特龙)治疗的这些癌症患者的存活率有所提高，但大多数mCRPC也对这些药物产生了耐药性。鉴于AR在前列腺癌中的核心作用，迫切需要具有独特作用模式的针对AR的药物。一种方法是使用小分子来降解AR。我们使用了一种新颖的创新方法，使用双功能小分子结合并主动泛素化和降解AR蛋白。在初步研究中，这些被称为AR PROTAC的分子在细胞和动物研究中都被证明是有效的、选择性的和有效的。一种临床候选分子已经被选中，以推进临床试验。这笔赠款的目标以几种方式支持这一过程：它们旨在为临床候选人建立PK/PD/疗效关系，证明这种AR PROTAC抑制对当前治疗耐药的mCRPC肿瘤的生长，以及对临床候选人进行使能新药(IND)的研究。综上所述，这些研究将使一种新型药物能够进入mCRPC患者的临床试验，对其制造和安全性有很好的了解，对如何使用这种新疗法有明确的了解，最重要的是，知道哪些患者可能从这种新疗法中受益。

 DESCRIPTION (provided by applicant): The overall aim of this grant is to generate data to understand and enable the development of a novel therapeutic approach for the treatment of patients with castration-resistant prostate cancer. Prostate cancer is the third most lethal cancer in the US, with 220,000 new cases and 27,000 deaths projected to occur in 2015. While early detection, surgery and hormone deprivation therapies are effective, about 10-20% of localized prostate cancer eventually becomes metastatic castrate-resistant prostate cancer (mCRPC). The major driver of mCRPC is the androgen receptor (AR), as evidenced by the rise in the circulating levels of the AR target gene prostate specific antigen (PSA). Patients with these cancers treated with first-generation anti-androgens (flutamide and bicalutamide) as well as the second-generation anti-androgen agents (enzalutamide and abiraterone) have increased survival, but the majority of mCRPCs also develop resistance to these agents. Given the central role of AR in prostate cancer, agents that target AR with a unique mode of action are urgently needed. One approach is to use small molecules to degrade AR. We used a novel and innovative approach that employs bi-functional small molecules to bind and actively ubiquitinate and degrade AR proteins. In preliminary studies, these molecules, called AR PROTACs, have been shown to be potent, selective, and efficacious in both cell and animals studies. A clinical candidate molecule has been chosen to advance towards clinical trials. The goals of this grant support that process in several ways: they aim to establish the PK/PD/efficacy relationship for the clinical candidate, to demonstrate that this AR PROTAC inhibits the growth of mCRPC tumors that are resistant to current therapy, and to conduct Investigational New Drug (IND)-enabling studies on the clinical candidate. Taken together, these studies will enable a novel agent to move into clinical trials for patients with mCRPC with a good awareness about its manufacture and safety, with a clear understanding of how to use this novel therapy, and, mostly importantly, with knowledge of which patients are likely to derive benefit from this new therapy.