Somatic genetic predictors of response to therapy in metastatic melanoma

目前可用于晚期黑色素瘤的治疗是不够的。没有任何疗法可以 延长生存期由于在大多数黑色素瘤病例中发现了BRAF突变， MAP激酶途径已成为黑色素瘤新治疗策略的中心。索拉非尼a 具有抗BRAF效力的新型丝氨酸苏氨酸激酶抑制剂，是该抑制剂的唯一小分子抑制剂。 目标是在I期试验之后取得进展。根据索拉非尼在美国的II期试验结果， 联合化疗治疗黑色素瘤，一项随机、安慰剂对照的III期试验（E2603）， 通过ECOG进行，以比较索拉非尼、卡铂和紫杉醇的疗效 （实验组）与卡铂和紫杉醇（对照组）在不可切除的III期或 静脉注射黑素瘤。要求提交E2603受试者的肿瘤组织块，并将构成 无价的资源为了识别最有可能应答的患者亚组以及 其他研究性疗法可能具有更高的优先级，在大规模背景下进行生物标志物分析 临床试验至关重要。黑色素瘤遗传变化的复杂性是一个活跃的研究领域 最近的数据表明，三种相互作用途径（RAS信号传导[MAPK， PI 3 K/Akt]、p16-CDK 4-Rb和p53）在黑色素瘤中起重要作用。这些基因的变化 途径不是独立的，并且通常显示途径“排他性”。因此，要了解 我们需要建立一个完整的突变谱， 考虑到单个途径的不同水平以及多个同时受影响的途径。我们 提出了三种方法来确定与反应有关的遗传变化。具体目标1侧重于 已知在黑色素瘤发生中重要的基因的遗传变化;分子研究将在550年完成 参与者分成两组。Specific Aim 2使用基于阵列的比较基因组 杂交（aCGH），以充分表征与E2603应答相关的基因组变化 在200个黑色素瘤中（每组50个应答者和50个无应答者）。具体目标3侧重于 鉴定无应答者中扩增的基因作为下一组临床试验的潜在靶点， 表达谱分析和aCGH，并在功能研究中进行验证。这些目标将提供宝贵的 关于选择黑色素瘤患者进行靶向治疗的信息，并为进一步治疗提供基础。 治疗发展

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.