Chemoprevention of Superficial Bladder Cancer

浅表性膀胱癌的化学预防

• 批准号: 6802621
• 负责人: ARIE S BELLDEGRUN
• 金额: $ 8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-07 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6802621
• 关键词: alternative medicine; antineoplastics; biomarker; bladder neoplasm; cancer prevention; chemoprevention; clinical research; clinical trials; cooperative study; drug screening /evaluation; fibroblast growth factor; genetic susceptibility; high throughput technology; human subject; human therapy evaluation; microarray technology; neoplasm /cancer chemotherapy; neoplasm /cancer remission /regression; patient oriented research; plant extracts; preneoplastic state; quinazolines; tea

The overall goals of this grant application are to 1) develop an effective chemoprevention strategy to reduce the risk of bladder cancer recurrence and to 2) investigate surrogate biomarkers that can serve as intermediate endpoints of the interventional efficacy of chemoprevention. Bladder cancer represents an important health problem in the United States and it currently ranks as the fourth most common cancer site in men and the eight most leading site in women. Since these tumors have a very high incidence of recurrence, the psychological and economic burden to the health care system of repeated diagnostic evaluations and therapy are substantial. Bladder cancer is an ideal model for studies of risk assessment early detection, chemoprevention and the development of intermediate biomarkers. Cigarette smoking represents the single most significant, preventable cause of bladder cancer and its carcinogenesis has a long latency period of close to twenty years following initial exposure, providing ample opportunities for intervention. Recently several potential surrogate end point markers have been developed for the detection of the clinically occult, premalignant phase of bladder cancer. These markers include the QFIA biomarker profile (DNA/M344/Actin Associated Protein) urinary basic fibroblast growth factor (bFGF) measurement, and Microsatellite Instability (MI) markers. Using the tumor recurrence rate as a primary end point and the biomarkers as secondary end points, we propose to perform a randomized, placebo-controlled, clinical trial using two promising chemoprevention agents targeting specific biochemical pathways on a cohort of high risk individuals who are former smokers with a grater than 30 pack year smoking history. Eligible subjects will have had a previous episode of low grade, low stage cancer of the bladder who are at high risk to develop disease recurrence, but for whom the standard of care would be observation. We will also construct tissue microarrays using specimens obtained during the evaluation of this clinical cohort to perform present and future translational high throughput studies to study the expression of markers associated with genetic susceptibility and tumor progression, and to identify potential therapeutic targets for cancer prevention. This grant application will involve a multi-disciplinary approached based on organization into program cores. An Administrative Core will perform the overall oversight for all aspects of the proposed work. A Clinical Core will run the clinical trial. The development and evaluation of the proposed biomarkers will be performed by the Biomarker and Nutritional Cores. All tissue samples will be collected and stored, and tissue arrays constructed by the Tissue Core. Finally, the Biostatistics Core will help design the clinical trial and evaluate the measured endpoints.

该赠款应用的总体目标是1）制定有效的化学预防策略，以降低膀胱癌复发的风险，并降低2）调查可以用作化学预防介入功效的中间终点的替代生物标志物。膀胱癌代表着美国的一个重要健康问题，目前，它是男性中第四个最常见的癌症部位，也是女性八个最领先地点。由于这些肿瘤复发的发生率很高，因此重复诊断评估和治疗的医疗保健系统的心理和经济负担很大。膀胱癌是研究风险评估早期检测，化学预防和中间生物标志物的发展的理想模型。吸烟是膀胱癌最重要的，可预防的唯一原因，其癌变在初次暴露后的较长潜伏期将近二十年，为干预提供了充足的机会。最近，已经开发了几种潜在的替代终点标记，以检测临床神秘的膀胱癌前阶段。这些标记包括QFIA生物标志物谱（DNA/M344/Actin相关蛋白）尿碱性成纤维细胞生长因子（BFGF）测量和微卫星不稳定性（MI）标记。使用肿瘤复发率作为主要终点，并将生物标志物作为次要终点，我们建议使用两种有前途的化学预防剂进行随机，安慰剂对照的临床试验，旨在针对特定的生物化学途径的同类群体，这些途径是前吸烟者，该疗程比30岁的吸烟者比30岁的吸烟史一起吸烟。符合条件的受试者将有先前的低级，低阶段膀胱癌的发作，他们有疾病复发的高风险，但要遵守护理标准。我们还将使用在评估该临床队列时获得的标本来构建组织微阵列，以进行当前和将来的转化高吞吐量研究，以研究与遗传敏感性和肿瘤进展相关的标志物的表达，并确定预防癌症预防的潜在治疗靶标。该赠款申请将涉及基于组织中的多学科方法。行政核心将对拟议工作的各个方面进行整体监督。临床核心将进行临床试验。提出的生物标志物的开发和评估将由生物标志物和营养核心进行。所有组织样品将被收集和存储，以及由组织芯构建的组织阵列。最后，生物统计学核心将有助于设计临床试验并评估测得的终点。