Hypoxia-induced Proteins as Lung Cancer Biomarkers

缺氧诱导的蛋白质作为肺癌生物标志物

• 批准号: 6983520
• 负责人: PHILIP C MACK
• 金额: $ 22.17万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6983520
• 关键词: biomarker; clinical research; fluorescent dye /probe; human tissue; hypoxia; immunocytochemistry; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; nonsmall cell lung cancer; osteopontin; patient oriented research; plasminogen activator inhibitors; prognosis; small cell lung cancer; tirapazamine; vascular endothelial growth factors

DESCRIPTION (provided by applicant): There is compelling evidence that tumor-associated hypoxia negatively influences response to chemotherapy and leads to the selection of tumor cells with increased aggressiveness and metastatic potential. Recent studies have identified secreted markers of tumor hypoxia that can be measured in patient plasma. The status of these factors in cancer patients may provide valuable prognostic information and be predictive of response to therapy. In two preliminary studies, we have quantified plasma concentration of three hypoxic markers, plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor (VEGF) and osteopontin (OPN), demonstrating feasibility and providing sufficient evidence of correlation to warrant testing in larger patient cohorts. We propose to investigate these markers in patient samples from three multi-institution clinical trials to test their predictive and prognostic utility in lung cancer. The ability to accurately predict patient outcome using plasma markers will provide a rapid, minimally-invasive test that can be used to optimize therapy regimens on an individual patient basis. Our central hypothesis is that levels of secreted markers of hypoxia will correlate with response to therapy and overall survival. Aim 1: Determine whether markers of hypoxia correlate with patient outcome under the influence of chemotherapy and radiation, with and without tirapazamine. This Aim will be conducted in two parts. 1A: Investigate pretreatment plasma concentrations of PAI-1, VEGF and OPN, using established ELISA techniques in plasma isolated prior to initiation of treatment. Expression levels will be correlated with patient response, progression-free survival and overall survival using univariate and multivariate statistical analyses. 1B. Investigate protein expression of hypoxic markers in archival tumor tissue to correlate this measure of tumor hypoxia with plasma concentrations of secreted hypoxic markers. We will investigate the expression of six proteins associated with tumor hypoxia in archival specimens as measured by immunohistochemistry. Aim 2: Determine whether treatment-induced changes in plasma concentrations of PAI-1, VEGF and OPN correlate with patient outcome. We will investigate whether increases or decreases in plasma concentration of secreted markers of hypoxia under the influence of therapy correlate with patient response to therapy, progression-free survival and/or overall survival.

描述（由申请人提供）：有令人信服的证据表明，肿瘤相关的缺氧会对化疗反应产生负面影响，并导致选择具有增加的侵袭性和转移潜力的肿瘤细胞。最近的研究已经确定了可以在患者血浆中测量的肿瘤缺氧的分泌标记物。癌症患者中这些因素的状态可以提供有价值的预后信息并预测对治疗的反应。在两项初步研究中，我们量化了三种缺氧标记物的血浆浓度：纤溶酶原激活剂抑制剂-1 (PAI-1)、血管内皮生长因子 (VEGF) 和骨桥蛋白 (OPN)，证明了可行性并提供了足够的相关性证据来保证测试在更大的患者群体中。我们建议在三个多机构临床试验的患者样本中研究这些标志物，以测试它们在肺癌中的预测和预后效用。使用血浆标记物准确预测患者结果的能力将提供快速、微创测试，可用于优化个体患者的治疗方案。我们的中心假设是，分泌的缺氧标志物的水平与治疗反应和总体生存率相关。目标 1：确定缺氧标志物是否与化疗和放疗影响下的患者预后相关，无论是否使用替拉扎明。该目标将分两部分进行。 1A：使用已建立的 ELISA 技术在开始治疗前分离的血浆中研究 PAI-1、VEGF 和 OPN 的治疗前血浆浓度。使用单变量和多变量统计分析，表达水平将与患者反应、无进展生存期和总生存期相关。 1B.研究档案肿瘤组织中缺氧标志物的蛋白质表达，将肿瘤缺氧的测量与分泌的缺氧标志物的血浆浓度相关联。我们将研究通过免疫组织化学测量的档案标本中与肿瘤缺氧相关的六种蛋白质的表达。目标 2：确定治疗引起的 PAI-1、VEGF 和 OPN 血浆浓度变化是否与患者预后相关。我们将研究治疗影响下缺氧分泌标记物血浆浓度的增加或减少是否与患者对治疗的反应、无进展生存期和/或总生存期相关。