Clinical Development of Next-Generation Antiandrogens and the Impact of PTEN Status

下一代抗雄激素的临床开发和 PTEN 状态的影响

• 批准号: 8730087
• 负责人: NEAL ROSEN
• 金额: $ 24.73万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730087
• 关键词: Acetates; Address; Androgen Antagonists; Androgen Receptor; Antineoplastic Agents; Apoptosis; Biological Markers; Biology; Biopsy; Canis familiaris; Castration; Cleaved cell; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Conduct Clinical Trials; Cytotoxic agent; Data; Development; Diagnosis; Diagnostic; Disease; Dose; Drug Approval; Drug resistance; Eligibility Determination; Enrollment; Evaluation; Funding; Hormones; Instruction; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Lesion; Molecular Profiling; Neoadjuvant Therapy; Oncogenic; PTEN gene; Pathologic; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Pilot Projects; Prostate; Radical Prostatectomy; Randomized; Receptor Inhibition; Receptor Signaling; Reporting; Resistance; Role; Sampling; Side; Time Study; Work; abiraterone; base; caspase-3; castration resistant prostate cancer; cohort; drug development; inhibitor/antagonist; mTOR Inhibitor; men; next generation; novel; phase 1 study; pre-clinical; prostate cancer model; response; tumor

Growing evidence from clinical trials of the next-generation androgen receptor (AR) pathway inhibitors abiraterone acetate (AA) and MDV3100 suggests that both compounds are likely to transform the care of patients with castration-resistant prostate cancer (CRPC), and drug approvals are anticipated in the next 1 to 2 years. However, not all patients benefit from these drugs, and the durability of response in those who do respond can be short. We are focusing on two parallel strategies to achieve better clinical results: 1) developing more potent AR inhibitors, and 2) defining mechanisms of drug resistance that will guide the rational selection of combination therapies. During the current funding cycle of this project (formerly RP-6, 2008-2010), we discovered the novel antiandrogen A52, which has superior activity to MDV3100 in side-by-side comparison. We then advanced the compound (now called ARN-509) to a phase 1 clinical trial in patients with CRPC, in collaboration with a corporate partner (Aragon Pharmaceuticals). In other work, we discovered that PTEN loss (found in -40% of primary prostate cancers) confers resistance to both MDV3100 and ARN-509 in preclinical prostate cancer models, but that this resistance can be overcome by combination therapy with a dual P13K/mTOR inhibitor, BEZ235. In the proposed funding period we will conduct clinical trials that directly address 1) the role of PTEN loss as a biomarker of resistance, and 2) whether combined PI3K + next-generation AR inhibition is more active than next-generation AR inhibition alone. We will also conduct pilot studies to evaluate ARN-509 in presurgical (ie, noncastrate) patients with prostate cancer. Aim 1: To determine if PTEN loss confers resistance to the next-generation AR antagonist ARN-509 in an expansion cohort of patients with metastatic CRPC treated in an ongoing phase 1 clinical trial. Aim 2: To evaluate the activity of the dual PI3K/mT0R inhibitor BEZ235 in patients with CRPC, first alone, then in combination with abiraterone. Aim 3: To evaluate the effects of ARN-509 in localized, hormone-naïve disease in presurgical trials

下一代雄激素受体 (AR) 通路抑制剂的临床试验提供了越来越多的证据 醋酸阿比特龙 (AA) 和 MDV3100 表明这两种化合物可能会改变对患者的护理 去势抵抗性前列腺癌 (CRPC) 患者的药物预计将在未来 1 到 1 年内获得批准 2年。然而，并非所有患者都能从这些药物中受益，而且受益者的反应持久性 响应可以很短。我们专注于两种并行策略以取得更好的临床结果：1) 开发更有效的 AR 抑制剂，以及 2）定义耐药机制，以指导 合理选择联合治疗。在该项目（以前称为 RP-6、 2008-2010），我们发现了新型抗雄激素A52，其并列活性优于MDV3100 比较。然后，我们将该化合物（现在称为 ARN-509）推进到 1 期临床试验 CRPC 患者，与企业合作伙伴（Aragon Pharmaceuticals）合作。在其他工作中，我们 发现 PTEN 缺失（在 -40% 的原发性前列腺癌中发现）赋予对 MDV3100 的抵抗力 和 ARN-509 在临床前前列腺癌模型中的应用，但这种耐药性可以通过组合克服 使用 P13K/mTOR 双重抑制剂 BEZ235 进行治疗。在拟议的资助期内，我们将进行临床 直接解决 1) PTEN 缺失作为耐药生物标志物的作用的试验，以及 2) 是否结合 PI3K + 下一代 AR 抑制比单独的下一代 AR 抑制更活跃。我们还将 开展试点研究以评估 ARN-509 在术前（即未去势）前列腺癌患者中的作用。 目标 1：确定 PTEN 缺失是否会导致对下一代 AR 拮抗剂 ARN-509 的耐药性 在一项正在进行的 1 期临床试验中接受治疗的转移性 CRPC 患者的扩展队列。 目标 2：首先单独评估 PI3K/mT0R 双重抑制剂 BEZ235 在 CRPC 患者中的活性， 然后与阿比特龙联合使用。 目标 3：在术前试验中评估 ARN-509 对局限性、未接受激素治疗的疾病的影响