Novel Androgen Receptor Degraders to Treat Castration-Resistant Prostate Cancer

新型雄激素受体降解剂治疗去势抵抗性前列腺癌

• 批准号: 9047498
• 负责人: Ian Taylor
• 金额: $ 64.84万
• 依托单位: ARVINAS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047498
• 关键词: Androgen Antagonists; Androgen Receptor; Androgens; Animals; Area; Awareness; Bicalutamide; Binding; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Chemicals; Chemistry; Chimera organism; Clinical; Clinical Chemistry; Clinical Trials; Data; Development; Disease; Disease Progression; Dose; Drug Design; Early Diagnosis; Flutamide; Formulation; Gene Targeting; Generations; Goals; Grant; Growth; Hematology; Hormones; In Vitro; Investigational Drugs; Knowledge; LNCaP; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Metastatic to; Mus; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacodynamics; Process; Property; Prostate-Specific Antigen; Proteins; Proteolysis; Receptor Signaling; Recovery; Resistance; Resistance development; Rodent; Role; Route; SCID Mice; Safety; Schedule; Sequential Treatment; Serum; Solubility; Subcutaneous Injections; Therapeutic; Time; Toxicology; VCaP; Xenograft Model; abiraterone; castration resistant prostate cancer; cellular engineering; deprivation; effective therapy; fight against; head-to-head comparison; improved; innovation; intravenous injection; men; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; prostate cancer cell; public health relevance; receptor; response; safety study; small molecule; standard of care; targeted agent; treatment strategy; tumor; tumor growth; tumor progression; tumor xenograft

 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.

 描述（由申请人提供）：该资助的总体目标是生成数据，以了解并开发一种治疗去势抵抗性前列腺癌患者的新型治疗方法。前列腺癌是第三大致命癌症 在美国，预计2015年将出现220，000例新病例和27，000例死亡。虽然早期发现，手术和激素剥夺疗法是有效的，但约10-20%的局限性前列腺癌最终成为转移性去势抵抗性前列腺癌（mCRPC）。mCRPC的主要驱动因素是雄激素受体（AR），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（氟氯普胺和比卡鲁胺）以及第二代抗雄激素药物（enzalutamide和阿比特龙）治疗的这些癌症患者的生存期延长，但大多数mCRPC也对这些药物产生耐药性。鉴于AR在前列腺癌中的核心作用，迫切需要以独特的作用模式靶向AR的药物。一种方法是使用小分子降解AR。我们使用了一种新颖的创新方法，该方法采用双功能小分子来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的分子已被证明在细胞和动物研究中是有效的、选择性的和有效的。已经选择了临床候选分子以推进临床试验。该资助的目标以几种方式支持这一过程：他们旨在建立临床候选药物的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，并对临床候选药物进行研究性新药（IND）研究。总之，这些研究将使一种新型药物能够进入mCRPC患者的临床试验，并对其生产和安全性有良好的认识，清楚地了解如何使用这种新型疗法，最重要的是，了解哪些患者可能从这种新疗法中获益。