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 V599E）。 BRAF 上游的 N-RAS 激活突变见于另外 5-36% 的黑色素瘤中。因此，在大多数黑色素瘤中都可以看到 MARK 通路的激活突变。这些观察结果以及许多体外和动物研究表明 MARK 通路对于黑色素瘤的生长至关重要。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 HSP90 才能正确折叠，并且有证据表明突变的 BRAF 更加依赖于 HSP90。 17-AAG 对 HSP90 的抑制导致细胞系和异种移植模型中 BRAF 的消耗以及细胞生长的抑制。 17-AAG 耗尽的黑色素瘤中其他感兴趣的 HSP90 客户蛋白是 CDK4 和 AKT。在多种癌症类型中使用 17-AAG 的 I 期研究已将 450 mg/m2 的每周剂量定义为最有希望的 II 期剂量。尽管很少有黑色素瘤患者参与这些 I 期试验，但已经报告了一些临床反应。我们建议对转移性黑色素瘤患者进行 17-AAG 的 II 期试验，剂量为 450 mg/m2/周，每 8 周 6 次。将治疗两组，每组 25 名患者，一组为野生型 BRAF，一组为突变型 BRAF。该试验将在癌症研究所 MSKCC（牵头机构）进行。新泽西州和 H.Lee Moffitt 癌症中心。具体目标#1：确定每个队列的临床缓解率，并测试具有突变 BRAF 的肿瘤对 17-AAG 更敏感的假设。具体目标#2：测试以下假设：17-AAG 治疗可以通过消耗肿瘤内 BRAF 和/或下游蛋白（如磷酸-ERK、CDK4 和细胞周期蛋白 D1）的储存来破坏 MAPK 通路。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 小时内对前 10 名患者进行肿瘤活检。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 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样本、临床有反应肿瘤与无反应肿瘤以及突变型 BRAF 与野生型 BRAF 肿瘤中的表达模式。