Predicting Melanoma Response to BAY 43-9006/Chemotherapy

预测黑色素瘤对 BAY 43-9006/化疗的反应

• 批准号: 6955905
• 负责人: Harriet M. Kluger
• 金额: $ 29.06万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6955905
• 关键词: angiogenesis; antineoplastics; apoptosis; biomarker; cancer registry /resource; carboplatin; clinical research; combination chemotherapy; high throughput technology; human tissue; kinase inhibitor; melanoma; metastasis; microarray technology; mitogen activated protein kinase; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic growth; paclitaxel; pharmacogenetics; protein quantitation /detection; angiogenesis; antineoplastics; apoptosis; biomarker; cancer registry /resource; carboplatin; clinical research; combination chemotherapy; high throughput technology; human tissue; kinase inhibitor; melanoma; metastasis; microarray technology; mitogen activated protein kinase; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic growth; paclitaxel; pharmacogenetics; protein quantitation /detection

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.

描述（由申请人提供）：由于疾病转移的发病率增加和缺乏有效的治疗，黑色素瘤的死亡率正在增加。最有希望的新疗法之一是卡泊粉素（C），紫杉醇（T）和BAY43-9006（B），在转移性黑色素瘤中，在L/LL试验中，其反应率非常高，平均疾病进展的平均时间非常长。 ECOG正在开放一个随机试验，将CT与CTB进行了比较，称为E2603。 BAY 43-9006的确切机制尚不清楚，对CTB的反应似乎与B-RAF激活突变无关。我们假设（a）B-RAF抑制以外的其他机制参与了这种药物组合的活性和（b）CTB仅受益于黑色素瘤患者的一部分。我们努力找到可以预测个别患者反应的标记，以最终仅治疗那些可能反应的患者。我们将筛选所选标记，以与治疗的反应相关，并对最佳预测标记进行全面分析。我们将使用一种新颖的，客观的，自动化的定量方法的组织微阵列分析（Aqua）来评估来自这些药物诱导的三组的蛋白质表达。标记途径，凋亡途径和促血管生成蛋白。我们将从对这些蛋白质子集的抗体进行严格验证，然后对50名在L/LL研究中接受CTB治疗的患者的肿瘤进行初步评估。将进一步评估300个档案黑色素瘤标本和300个良性NEVI，以评估转移性黑色素瘤中标志物表达的流行率，将进一步评估反应者和非反应者之间表达差异的标记。同时，将预先收集来自E2603招募的患者的标本。在组织微阵列上使用Aqua，我们将研究两个处理臂上反应者和无反应者之间标记物表达的差异，目的是开发一种测定法以明确预测对CTB的反应。我们将评估单个标记和标记面板。