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: 7434028
• 负责人: Harriet M. Kluger
• 金额: $ 26.89万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7434028
• 关键词: American Society of Clinical Oncology; Angiogenic Proteins; Antibodies; Apoptosis; Apoptotic; BAY 43-9006; Benign; Biological Assay; Carboplatin; Carboplatin/Paclitaxel; Clinical; Clinical Data; Data; Disease; Disease Progression; Drug Combinations; Drug Delivery Systems; Eastern Cooperative Oncology Group; Enrollment; Evaluation; Eye; Family; Future; Goals; Grant; Incidence; Individual; Induction of Apoptosis; Lesion; MEKs; Malignant - descriptor; Mediating; Mediator of activation protein; Metastatic Melanoma; Methods; Microarray Analysis; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Mutation; Natural History; Negative Staining; Neoplasm Metastasis; Nevus; Outcome; Output; Paclitaxel; Pathway interactions; Patient Selection; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase III Clinical Trials; Phosphotransferases; Pilot Projects; Population; Predictive Value; Prevalence; Principal Investigator; Protein Inhibition; Proteins; Publishing; Purpose; Randomized; Randomized Controlled Clinical Trials; Rate; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Research Personnel; Role; Sampling; Score; Specimen; Stable Disease; Testing; Thinking; Time; Tissue Microarray; Toxic effect; Treatment Protocols; Upper arm; Validation; Vascular Endothelial Growth Factors; Work; base; cancer cell; chemotherapy; cohort; improved; kinase inhibitor; melanoma; member; mortality; mutant; neovascularization; novel; programs; protein expression; response; synergism; trend; trial comparing; tumor; tumor progression

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）：由于黑色素瘤发病率增加以及疾病转移后缺乏有效治疗，死亡率正在上升。最有前途的新疗法之一是卡铂 (C)、紫杉醇 (T) 和 BAY43-9006 (B)，它们在转移性黑色素瘤的 I/II 期试验中显示出非常高的缓解率和异常长的平均疾病进展时间。 ECOG 正在开展一项比较 CT 与 CTB 的随机试验，称为 E2603。 BAY 43-9006 的精确机制尚不清楚，并且对 CTB 的反应似乎与 B-RAF 激活突变无关。我们假设 (a) B-RAF 抑制以外的机制参与了该药物组合的活性，并且 (b) CTB 将仅使一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记物，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选定标志物，并对最佳预测标志物进行全面分析。我们将使用一种新颖、客观、自动化的组织微阵列分析（AQUA）定量方法来评估已知由这些药物诱导的三组蛋白质的表达； MARK 途径、细胞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开始，然后对 I/II 期研究中接受 CTB 治疗的 50 名患者的肿瘤进行初步评估。将在 300 个存档黑色素瘤标本和 300 个良性痣样本中进一步评估有反应者和无反应者之间表达差异的标记物，以评估转移性黑色素瘤中标记物表达的流行率。同时，将前瞻性地收集 E2603 中入组患者的标本。在组织微阵列上使用 AQUA，我们将研究两个治疗组中应答者和非应答者之间标记物表达的差异，目标是开发一种检测方法来特异性预测对 CTB 的应答。我们将评估单个标记以及标记组。

项目成果

Quantitative expression of VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 in melanoma tissue microarrays.

• DOI: 10.1016/j.humpath.2009.08.016
• 发表时间: 2010-03
• 期刊: HUMAN PATHOLOGY
• 影响因子: 3.3
• 作者: Mehnert, Janice M.;McCarthy, Mary M.;Jitaveanu, Lucia;Flaherty, Keith T.;Aziz, Saadia;Camp, Robert L.;Rimm, David L.;Kluger, Harriet M.
• 通讯作者: Kluger, Harriet M.

Characterizing disease states from topological properties of transcriptional regulatory networks.

从转录调节网络的拓扑特性中表征疾病状态。

• DOI: 10.1186/1471-2105-7-236
• 发表时间: 2006-05-02
• 期刊: BMC BIOINFORMATICS
• 影响因子: 3
• 作者: Tuck, David P.;Kluger, Harriet M.;Kluger, Yuval
• 通讯作者: Kluger, Yuval