Predictive Markers in Metastatic Renal Cancer

转移性肾癌的预测标志物

基本信息

批准号：
8113158
负责人：
PHILLIP G FEBBO
金额：
$ 60.26万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-22 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113158
关键词：
Address American Society of Clinical Oncology Angiogenesis Inhibitors Angiogenic Factor Angiopoietin-2 Antibodies Binding Biological Biological Markers Biology Cancer and Leukemia Group B Chromosome abnormality Clinical Development Disease Enrollment Epigenetic Process Family Fibroblast Growth Factor 2 Future Genes Genetic Genetic Transcription Genomics Goals Health Immunotherapy Individual Interferon-alpha Interferons Kidney Link Maintenance Therapy Malignant - descriptor Malignant Neoplasms Malignant neoplasm of urinary bladder Metastatic Renal Cell Cancer Methods Methylation Modality Modeling Molecular Outcome PGF gene Paraffin Embedding Pathologic Pathway interactions Patients Pattern Phase III Clinical Trials Phenotype Phosphotransferases Plasma Predictive Value Progress Review Group Progression-Free Survivals Proteomics Radiation therapy Reaction Time Regimen Renal Cell Carcinoma Renal carcinoma Research Resistance Resources Risk Risk Factors Sampling Specimen Stratification Testing Therapeutic Time Tissue Microarray Tissues Urine VHL gene VHL mutation Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors angiogenesis arm base bevacizumab candidate marker chemotherapy comparative genomic hybridization design effective therapy follow-up insight knowledge base molecular marker neoplastic cell outcome forecast overexpression predictive modeling prognostic protein expression receptor response standard of care trend tumor

项目摘要

DESCRIPTION (provided by applicant): Metastatic renal cell carcinoma (RCC) is a dismal disease, with nearly uniform resistance to radiotherapy, chemotherapy and immunotherapy. Recently, the availability of molecularly-targeted therapy against vascular endothelial growth factor (VEGF) has dramatically altered the therapeutic landscape of RCC. One such approach involves the VEGF-binding antibody, bevacizumab. The CALGB has completed an Intergroup Phase III trial of interferon alpha (IFNA) plus bevacizumab versus IFNA alone in 732 patients with metastatic renal cell carcinoma (CALGB 90206), representing one of the largest phase III trials conducted to date in RCC. Baseline paraffin-embedded tissue was collected on 591 of these patients in addition to plasma and urine samples obtained at baseline and after 6 weeks of therapy. This is a unique opportunity for analysis of this tissue to provide insight into the biology of RCC, the mechanisms of response to bevacizumab-based therapy, and to develop a new predictive model for response using extensive biomarker analyses. Our central hypothesis is that genomic alterations and expression changes in genes involved in angiogenesis and other receptor kinase pathways are predictive of outcome in patients with renal cell carcinoma treated with interferon 1 bevacizumab. We will test whether overall survival is associated with: 1) von Hippel Lindau gene mutation and methylation, 2) patterns of genomic alterations by array-CGH, 3) expression of protein targets using a new method of automated quantitative analysis of tissue microarrays (AQUA), and 4) plasma and urine biomarker levels at baseline and 6 weeks into therapy. We will then develop a new predictive multivariate model for risk stratification of patients with metastatic renal cell carcinoma, using clinical, pathologic, and molecular markers. PUBLIC HEALTH RELEVANCE: Identification of molecular alterations associated with outcome after bevacizumab- based therapy will have broad implications for treatment of RCC and other cancers. This agent and the anti-angiogenic approach in general are now widely recognized as an effective treatment modality in a number of tumor types. Insight into the molecular basis for baseline response to bevacizumab will provide a knowledge base upon which to rationally select patients for such therapies in the future. The NCI Progress Review Group for Kidney and Bladder Cancer (2001) identified 13 priorities as research goals. The first two priorities were 1) Understand the biological mechanism underlying the risk factors for kidney and bladder cancer phenotypes, and 2) Identify global genetic, epigenetic, RNA expression, and proteomic alterations in tumors and place them in specific biological pathways that are essential to development, progression, response to therapy, and maintenance of subtypes of bladder and kidney cancers; This proposal directly addresses these two top priorities.

描述（由申请人提供）：转移性肾细胞癌（RCC）是一种令人沮丧的疾病，对放疗、化疗和免疫治疗几乎均具有抵抗力。最近，针对血管内皮生长因子（VEGF）的分子靶向治疗的出现极大地改变了肾细胞癌的治疗前景。其中一种方法涉及 VEGF 结合抗体贝伐珠单抗。 CALGB 已在 732 名转移性肾细胞癌患者中完成了干扰素 α (IFNA) 加贝伐单抗与单用 IFNA 的组间 III 期试验 (CALGB 90206)，这是迄今为止在 RCC 中进行的最大的 III 期试验之一。除了在基线和治疗 6 周后获得的血浆和尿液样本外，还收集了其中 591 名患者的基线石蜡包埋组织。这是分析该组织的独特机会，可以深入了解肾细胞癌的生物学、对基于贝伐单抗的治疗的反应机制，并使用广泛的生物标志物分析开发新的反应预测模型。我们的中心假设是，参与血管生成和其他受体激酶途径的基因的基因组改变和表达变化可以预测接受干扰素 1 贝伐珠单抗治疗的肾细胞癌患者的预后。我们将测试总体生存是否与以下因素相关：1) von Hippel Lindau 基因突变和甲基化，2) 阵列 CGH 的基因组改变模式，3) 使用组织微阵列自动定量分析新方法 (AQUA) 表达蛋白质靶标)，以及 4) 基线和治疗 6 周时的血浆和尿液生物标志物水平。然后，我们将使用临床、病理和分子标志物开发一种新的预测性多变量模型，用于转移性肾细胞癌患者的风险分层。公共卫生相关性：确定与贝伐单抗治疗后结果相关的分子改变将对肾细胞癌和其他癌症的治疗产生广泛影响。这种药物和抗血管生成方法现在被广泛认为是许多肿瘤类型的有效治疗方式。深入了解贝伐珠单抗基线反应的分子基础将为未来合理选择接受此类治疗的患者提供知识基础。 NCI 肾癌和膀胱癌进展审查小组 (2001) 确定了 13 个优先事项作为研究目标。前两个优先事项是 1) 了解肾癌和膀胱癌表型危险因素背后的生物学机制，2) 识别肿瘤中的整体遗传、表观遗传、RNA 表达和蛋白质组改变，并将它们置于特定的生物学途径中，这对于膀胱癌和肾癌亚型的发生、进展、治疗反应和维持；该提案直接解决了这两个首要任务。