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

基本信息

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
项目类别：
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

项目摘要

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

越来越多的证据来自下一代雄激素受体（AR）途径抑制剂的临床试验乙酸阿比罗酮（AA）和MDV3100表明，两种化合物都可能改变了护理预计将在接下来的1点前1例 2年。但是，并非所有患者都从这些药物中受益，以及那些患者的持久性响应可能很短。我们专注于两种平行策略，以获得更好的临床结果：1）开发更多潜在的AR抑制剂，以及2）定义耐药性机制，以指导合理选择组合疗法。在该项目的当前资金周期中（以前是RP-6， 2008-2010），我们发现了新型的抗雄激素A52，它的活性优于MDV3100 比较。然后，我们将化合物（现在称为ARN-509）提高到1期临床试验患有CRPC的患者与公司合作伙伴（Aragon Pharmaceuticals）合作。在其他工作中，我们发现PTEN损失（在-40％的主要前列腺癌中发现）赋予了对MDV3100的抵抗力临床前前列腺癌模型中的ARN-509，但可以通过组合克服这种抗性用双P13K/mTOR抑制剂BEZ235治疗。在拟议的资金期间，我们将进行临床直接解决的试验1）PTEN损失作为电阻的生物标志物的作用，以及2）是否合并 PI3K +下一代AR抑制比仅下一代AR抑制更为活跃。我们也会进行试点研究以评估前术（IE，非腹侧）患有前列腺癌的ARN-509。目标1：确定PTEN损失是否同意对下一代AR拮抗剂ARN-509的抵抗力在正在进行的1期临床试验中治疗转移性CRPC患者的扩张队列。目标2：评估双PI3K/MT0R抑制剂BEZ235对CRPC患者的活性，首先是单独的然后与阿比罗酮结合使用。目标3：评估ARN-509在局部激素疾病中的影响