Somatic genetic predictors of response to therapy in metastatic melanoma

目前可用于晚期黑色素瘤的治疗方法是不够的。目前还没有治疗方法被证明 延长生存时间。由于在大多数黑色素瘤病例中发现了BRAF突变，靶向 MAP激酶通路已成为黑色素瘤新的治疗策略的核心。索拉非尼，一种 新型丝氨酸苏氨酸激酶抑制剂具有抗BRAF的效力，是唯一的小分子抑制剂 目标是在第一阶段试验之后取得进展。根据#年索拉非尼的II期试验结果 与黑色素瘤化疗相结合，一项随机、安慰剂对照的III期试验(E2603)是 通过ECOG进行索拉非尼、卡铂和紫杉醇的疗效比较 (试验组)卡铂和紫杉醇(对照组)在不能切除的III期或 静脉注射黑色素瘤。E2603的参与者必须提交肿瘤块，并将构成 无价的资源。为了识别最有可能有反应的患者子集和对其有反应的患者子集 其他研究疗法可能具有更高的优先级，在大规模研究背景下进行生物标记物分析 临床试验是必不可少的。黑色素瘤基因变化的复杂性是一个活跃的研究领域。 而最近的数据表明，三条相互作用的途径(RAS信号转导[MAPK， PI3K/Akt]、p16-CDK4-Rb和P53)在黑色素瘤中起重要作用。这些基因的变化 路径不是独立的，通常表现为路径的“排他性”。因此，要理解 治疗E2603的患者的应答决定因素我们需要建立一个完整的突变图谱，服用 考虑到不同水平的单个通路以及多个同时受影响的通路。我们 提出三种方法来识别与反应相关的基因变化。具体目标1侧重于 已知在黑色素瘤发生中起重要作用的基因的遗传变化；分子研究将在550完成 参赛者被分在两个手臂上。《特定目标2》使用基于阵列的比较基因组学 杂交(ACGH)以充分表征基因组变化与E2603的反应相关 在200例黑色素瘤中(每只手臂50名应答者和50名无应答者)。具体目标3侧重于 确定无反应者的扩增基因作为下一组临床试验的潜在靶点 表达谱和aCGH，并在功能研究中进行验证。这些目标将提供有价值的 关于选择黑色素瘤患者进行靶向治疗的信息，并为进一步 治疗方面的发展。

Currently available therapies for advanced melanoma are inadequate. No therapy has been shown to prolong survival. Since the identification of BRAF mutations in the majority "ofcases of melanoma, targeting the MAP kinase pathway has become central to novel therapeutic strategies in melanoma. Sorafenib, a novel serine threonine kinase inhibitor with potency against BRAF, is the only small molecule inhibitor of this target to have advanced beyond phase I trials. Based on the results of phase II trials of sorafenib in combination with chemotherapy in melanoma, a randomized, placebo-controlled phase III trial (E2603) is being conducted through ECOG to compare the efficacy of sorafenib, carboplatin and paclitaxel (experimental arm) to carboplatin and paclitaxel (control arm) among patients with unresectable stage III or IV melanoma. The submission of tumor blocks for participants in E2603 is required and will constitute an invaluable resource. In order to identify patient subsets that are most likely to respond and those for which other investigational therapies may be of higher priority, biomarker analyses in the context of large-scale clinical trials are essential. The complexity of genetic changes in melanoma is an area of active research and recent data suggest that genetic changes in three interacting pathways (RAS signaling [MAPK, PI3K/Akt], p16-CDK4-Rb and p53) play important roles in melanoma. The genetic changes in these pathways are not independent and generally display pathway 'exclusivity'. Thus, to understand the determinants of response for patients treated in E2603 we need to build a complete mutational profile, taking into account, different levels of a single pathway as well as multiple simultaneously affected pathways. We propose three approaches to identify genetic changes as they relate to response. Specific Aim 1 focuses on genetic changes in genes known to be important in melanomagenesis; molecular studies will be done in 550 participants divided between the two arms. Specific Aim 2 uses array based comparative genomic hybridization (aCGH) to fully characterize genomic changes as they are associated with response in E2603 in 200 melanomas (50 responders and 50 non-responders on each arm). Specific Aim 3 focuses on the identification of amplified genes in non-responders as potential targets for the next set of clinical trials using expression profiling and aCGH with validation in functional studies. These aims will provide valuable information about selecting patients with melanoma for targeted therapies and provide a basis for further therapeutic development.