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

下一代雄激素受体（AR）通路抑制剂临床试验的证据越来越多 醋酸阿比特龙（AA）和MDV 3100表明，这两种化合物都可能改变 去势抵抗性前列腺癌（CRPC）患者，预计药物批准将在未来1至 2年然而，并不是所有的患者都能从这些药物中受益，而且那些受益的患者的反应的持久性 回答可以很短。我们专注于两个并行的策略，以实现更好的临床效果：1） 开发更有效的AR抑制剂，以及2）定义将指导治疗的耐药机制。 合理选择联合治疗。在本项目（原RP-6， 2008-2010），我们发现了新的抗雄激素A52，其在与MDV 3100的并行治疗中具有上级活性。 对比然后，我们将这种化合物（现在称为ARN-509）推进到了第一阶段的临床试验。 CRPC患者，与企业合作伙伴（阿拉贡制药）合作。在其他工作中，我们 发现PTEN缺失（在约40%的原发性前列腺癌中发现）赋予对MDV 3100和MDV 3100的抗性。 和ARN-509在临床前前列腺癌模型中的耐药性，但这种耐药性可以通过联合治疗来克服。 使用双重P13 K/mTOR抑制剂BEZ 235进行治疗。在拟议的资助期内，我们将进行临床 试验直接解决1）PTEN缺失作为耐药生物标志物的作用，以及2）是否结合 PI 3 K+下一代AR抑制比单独的下一代AR抑制更有效。我们还将 进行试点研究，以评估ARN-509在术前（即，非去势）前列腺癌患者。 目的1：确定在一个受试者中，PTEN缺失是否赋予对下一代AR拮抗剂ARN-509的抗性。 正在进行的I期临床试验中接受治疗的转移性CRPC患者扩展队列。 目的2：评估双重PI 3 K/mT 0 R抑制剂BEZ 235在CRPC患者中的活性，首先单独使用， 然后与阿比特龙组合。 目的3：在术前试验中评价ARN-509在局部、初治性疾病中的作用

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