Somatic genetic predictors of response to therapy in metastatic melanoma

描述（由申请人提供）：目前可用于晚期黑色素瘤的疗法不足。没有任何治疗方法可以延长生存期。由于在大多数黑色素瘤病例中鉴定出BRAF突变，靶向MAP激酶途径已成为黑色素瘤新治疗策略的核心。索拉非尼是一种新型丝氨酸苏氨酸激酶抑制剂，具有抗BRAF的效力，是唯一一种超过I期试验的小分子抑制剂。基于索拉非尼联合化疗治疗黑色素瘤的II期试验结果，正在通过ECOG进行一项随机、安慰剂对照的III期试验（E2603），以比较索拉非尼、卡铂和紫杉醇（实验组）与卡铂和紫杉醇（对照组）在不可切除的III期或IV期黑色素瘤患者中的疗效。要求提交E2603受试者的肿瘤组织块，这将构成宝贵的资源。为了确定最有可能缓解的患者亚组以及其他研究性治疗可能具有更高优先级的患者亚组，在大规模临床试验背景下进行生物标志物分析至关重要。黑色素瘤中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，三种相互作用的途径（RAS信号传导[MAPK，PI 3 K/Akt]，p16-CDK 4-Rb和p53）中的遗传变化在黑色素瘤中起重要作用。这些通路中的遗传变化不是独立的，通常显示通路“排他性”。因此，为了了解E2603治疗患者的反应决定因素，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遗传变化，因为它们涉及到响应。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名参与者中进行，分为两组。特定目标2使用基于阵列的比较基因组杂交（aCGH）来充分表征基因组变化，因为它们与200个黑色素瘤（每组50个应答者和50个非应答者）中E2603的应答相关。具体目标3的重点是在无应答者中鉴定扩增的基因，作为下一组临床试验的潜在靶点，使用表达谱和aCGH，并在功能研究中进行验证。这些目标将为选择黑色素瘤患者进行靶向治疗提供有价值的信息，并为进一步的治疗开发提供基础。

DESCRIPTION (provided by applicant): 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 of cases 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.