Predictive Markers in Metastatic Renal Cancer

转移性肾癌的预测标志物

• 批准号: 7663304
• 负责人: Frederic M. Waldman
• 金额: $ 64.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-22 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663304
• 关键词: Address; American Society of Clinical Oncology; Angiogenesis Inhibitors; Angiogenic Factor; Angiopoietin-2; Antibodies; Binding; Biological; Biological Markers; Biology; Bladder; 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; 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; Renal Cell Carcinoma; Renal carcinoma; Research; Resistance; Resources; Risk; Risk Factors; Sampling; Specimen; Stratification; Testing; Therapeutic; Time; Tissue Microarray; Tissues; Treatment Protocols; Upper arm; Urine; VHL gene; VHL mutation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; angiogenesis; 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; public health relevance; receptor; response; standard of care; trend; tumor

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(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、化疗和免疫治疗的耐药性几乎一致。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癌的治疗格局。一种这样的方法涉及到与血管内皮生长因子结合的抗体贝伐单抗。CALGB已经在732名转移性肾癌患者中完成了干扰素α(IFNA)加贝伐单抗与单独使用IFNA的组间第三阶段试验(CALGB 90206)，这是迄今为止在肾癌中进行的最大规模的第三阶段试验之一。除了在基线和治疗6周后采集血浆和尿样外，还收集了591名患者的基线石蜡包埋组织。这是分析这一组织的独特机会，可以深入了解肾癌的生物学、对基于贝伐单抗的治疗的反应机制，并利用广泛的生物标记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通路的基因的基因组变化和表达变化可以预测接受干扰素1贝伐单抗治疗的肾癌患者的预后。我们将测试总存活率是否与以下因素有关：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)使用组织芯片自动定量分析(AQUA)的新方法表达蛋白质靶标，以及4)基线和治疗6周后的血浆和尿液生物标记物水平。然后，我们将利用临床、病理和分子标志物，开发一种新的预测转移性肾癌患者风险分层的多变量模型。公共卫生相关性：确定贝伐单抗治疗后与结果相关的分子改变将对肾癌和其他癌症的治疗具有广泛的意义。这种药物和抗血管生成的方法现在被广泛认为是一种在许多肿瘤类型中有效的治疗方式。对贝伐单抗基线反应的分子基础的洞察将提供一个知识基础，以便在未来合理地选择患者进行此类治疗。NCI肾脏和膀胱癌进展审查小组(2001年)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风险因素潜在的生物学机制，2)确定肿瘤中的全球遗传、表观遗传学、RNA表达和蛋白质组变化，并将其置于对膀胱癌和肾癌亚型的发生、进展、治疗反应和维持至关重要的特定生物学途径中；该建议直接针对这两个最优先事项。