Predicting Melanoma Response to BAY 43-9006/Chemotherapy

描述(申请人提供)：由于黑色素瘤发病率的增加和一旦疾病转移缺乏有效的治疗，黑色素瘤的死亡率正在上升。最有希望的新疗法之一是卡铂(C)、紫杉醇(T)和BAY43-9006(B)，它们在L/11期转移性黑色素瘤试验中显示出非常高的应答率和异常长的疾病进展平均时间。ECOG正在开展一项随机试验，将CT与CTB进行比较，名为E2603。Bay 43-9006的确切机制尚不清楚，而且对CTB的反应似乎与B-RAF激活突变无关。我们假设(A)这种药物组合的活性涉及B-RAF抑制以外的机制，以及(B)CTB只会使部分黑色素瘤患者受益。我们努力寻找预测个体患者反应的标志物，以便最终只治疗那些可能有反应的患者。我们将筛选与治疗反应相关的标记物，并对最好的预测标记物进行综合分析。我们将使用一种新的、客观的、自动化的组织微阵列分析(AQUA)方法来评估这些药物诱导的三组蛋白的表达：Mark途径、凋亡途径和促血管生成蛋白。我们将首先对这些蛋白质的一个子集进行严格的抗体验证，然后在L/11期研究中对50名接受CTB治疗的患者的肿瘤进行初步评估。在300个黑色素瘤档案标本和300个良性痣标本上，将进一步评估有反应者和无反应者之间表达差异的标记，以评估转移性黑色素瘤中标记表达的流行率。同时，还将前瞻性地收集参加E2603的患者的样本。利用组织微阵列上的Aqua，我们将研究两个治疗臂上应答者和无应答者之间标志物表达的差异，目标是开发一种专门预测CTB应答的方法。我们将评估单个标记以及标记面板。

DESCRIPTION (provided by applicant): Mortality from melanoma is rising due to the increase in incidence and lack of effective therapy once the disease has metastasized. One of the most promising new therapies is carboplatin (C), paclitaxel (T) and BAY43-9006 (B), which revealed very high response rates with unusually long mean time to disease progression in a Phase l/ll trial in metastatic melanoma. ECOG is opening a randomized trial comparing CT to CTB, called E2603. The precise mechanism of BAY 43-9006 is unknown, and response to CTB appears not to be associated with B-RAF activating mutations. We hypothesize that (a) mechanisms other than B-RAF inhibition are involved in the activity of this combination of drugs and (b) CTB will benefit only a subset of melanoma patients. We strive to find markers that predict response in the individual patient in order to ultimately treat only those patients that are likely to respond. We will screen selected markers for association with response to therapy, and perform comprehensive analysis on the best predictive markers. We will use a novel, objective, automated quantitative method of tissue microarray analysis (AQUA) to evaluate expression of proteins from three groups that are known to be induced by these drugs; the MARK pathway, apoptotic pathways and pro-angiogenic proteins. We will start with rigorous validation of antibodies to a subset of these proteins, followed by initial evaluation on tumors from 50 patients treated with CTB in the Phase l/ll study. Markers with differences in expression between responders and non-responders will be further evaluated on 300 archival melanoma specimens and 300 benign nevi to assess prevalence of markers expression in metastatic melanomas. Concurrently, specimens from patients enrolled in E2603 will be prospectively collected. Using AQUA on tissue microarrays, we will study differences in marker expression between responders and non-responders on both treatment arms, with the goal of developing an assay to specifically predict response to CTB. We will assess individual markers as well as panels of markers.