Phase II trial of 17-AAG in melanoma patients

17-AAG 在黑色素瘤患者中的 II 期试验

• 批准号: 7111952
• 负责人: PAUL B CHAPMAN
• 金额: $ 37.98万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-19 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111952
• 关键词: antineoplastics; biological signal transduction; clinical research; clinical trial phase II; cyclin dependent kinase; gene mutation; heat shock proteins; human subject; human therapy evaluation; melanoma; mitogen activated protein kinase; neoplasm /cancer chemotherapy; neoplastic growth; neoplastic process; patient oriented research; protein tyrosine phosphatase; protooncogene; rifabutin

DESCRIPTION (provided by applicant): Between 40-67% of melanoma tumors contain and activating BRAF mutations (almost always V599E). Upstream of BRAF, activating mutations in N-RAS are seen in another 5-36% of melanomas. Thus, activating mutations in the MARK pathway are seen in most melanomas. These observations along with many in vitro and animal studies indicate that the MARK pathway is critical for melanoma growth. Our overall objective is to interfere with the MARK pathway in melanoma as a treatment strategy. BRAF depends on HSP90 for proper folding and there is evidence that mutated BRAF is even more dependent on HSP90. Inhibition of HSP90 by 17-AAG results in depletion of BRAF in cell lines and in xenograft models and inhibition of cell growth. Other HSP90 client proteins of interest in melanoma depleted by 17-AAG are CDK4 and AKT. Phase I studies using 17-AAG in a variety of cancer types have defined a weekly dose of 450 mg/m2 as the most promising phase II dose. Although few melanoma patients have been included in these phase I trials, some clinical responses have been reported. We propose a phase II trial of 17-AAG in patients with metastatic melanoma at a dose of 450 mg/m2/week x 6 every 8 weeks. Two cohorts of 25 patients each - one cohort with wild-type BRAF and one cohort with mutant BRAF - will be treated. The trial will be conducted at MSKCC (lead institution), Cancer Inst. of New Jersey, and H.Lee Moffitt Cancer Center. Specific aim #1: Determine the clinical response rate in each cohort and test the hypothesis that tumors with mutant BRAF will be more sensitive to 17-AAG. Specific aim #2: Test the hypothesis that treatment with 17-AAG can disrupt the MAPK pathway by depleting intra-tumor stores of BRAF and/or downstream proteins such as phospho-ERK, CDK4 and cyclin D1. To address this, we will obtain tumor biopsies in the first 10 patients pre-treatment and 18-48 hr following the first 17-AAG treatment. Tumors will be analyzed by Western blot and immunohistochemistry. A secondary aim is to determine if effects on the MAPK pathway correlate with clinical responses or with the presence of mutated BRAF in the tumor. We also intend to analyze the biopsies by expression array profiling. As an exploratory analysis, we will compare expression patterns in pre-treatment vs. post-treatment specimens, clinically responding tumors vs. non-responding tumors, and mutant BRAF vs. wild-type BRAF tumors.

描述（由申请人提供）：40-67%的黑色素瘤肿瘤含有并激活BRAF突变（几乎总是V599 E）。在BRAF上游，在另外5-36%的黑色素瘤中观察到N-RAS的激活突变。因此，在大多数黑色素瘤中可以看到MARK通路的激活突变。这些观察结果沿着许多体外和动物研究表明MARK途径对黑色素瘤生长至关重要。我们的总体目标是干扰黑色素瘤中的MARK通路作为治疗策略。BRAF依赖于HSP 90进行正确的折叠，有证据表明突变的BRAF甚至更依赖于HSP 90。17-AAG对HSP 90的抑制导致细胞系和异种移植模型中BRAF的耗竭以及细胞生长的抑制。在被17-AAG耗尽的黑素瘤中感兴趣的其他HSP 90客户蛋白是CDK 4和AKT。在各种癌症类型中使用17-AAG的I期研究已经将450 mg/m2的每周剂量定义为最有希望的II期剂量。虽然这些I期试验中纳入的黑色素瘤患者很少，但已报告了一些临床反应。我们建议在转移性黑色素瘤患者中进行17-AAG的II期试验，剂量为450 mg/m2/周x 6，每8周一次。将治疗各25名患者的两个队列-一个具有野生型BRAF的队列和一个具有突变型BRAF的队列。本试验将在MSKCC（牵头机构）、新泽西癌症研究所和H.Lee Moffitt癌症中心进行。具体目标1：确定每个队列的临床缓解率，并检验BRAF突变肿瘤对17-AAG更敏感的假设。具体目标2：检验17-AAG治疗可通过消耗肿瘤内储存的BRAF和/或下游蛋白（如磷酸化ERK、CDK 4和细胞周期蛋白D1）破坏MAPK通路的假设。为了解决这个问题，我们将在治疗前和第一次17-AAG治疗后18-48小时获得前10名患者的肿瘤活检。将通过蛋白质印迹和免疫组织化学分析肿瘤。第二个目的是确定对MAPK通路的影响是否与临床反应或肿瘤中突变的BRAF的存在相关。我们还打算通过表达阵列分析来分析活检。作为探索性分析，我们将比较治疗前与治疗后标本、临床应答肿瘤与无应答肿瘤以及突变型BRAF与野生型BRAF肿瘤的表达模式。