Pharmacogenetics advanced colorectal cancer

晚期结直肠癌的药物遗传学

基本信息

批准号：
6784151
负责人：
HOWARD L MCLEOD
金额：
$ 15.85万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2005-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6784151
关键词：
behavioral /social science research tag clinical research colorectal neoplasms combination chemotherapy decision making fluorouracil genetic markers genetic polymorphism genotype human subject human therapy evaluation irinotecan longitudinal human study method development neoplasm /cancer chemotherapy pharmacogenetics quality of life

项目摘要

DESCRIPTION (provided by applicant): The treatment of advanced colorectal cancer offers an ideal environment for the development and evaluation of pharmacogenetics. The availability of multiple therapeutic options with clear antitumor activity requires clinical decisions to be made for individual patients and these decisions are best made with quantitative information. However, there are currently insufficient tools to guide the selection of therapy for advanced colorectal cancer. The recent FDA approval of irinotecan (CPT-11) and oxaliplatin (OXAL) for advanced colorectal cancer, in addition to the historical standard 5-fluorouracil (5FU), has led to the development of several active combination chemotherapy regimens for this disease. Indeed, the recently completed Gastrointestinal Intergroup study N9741 compared 5FU/CPT-11, 5FU/OXAL, and CPT-11/OXAL, with observed objective response rates of 28-38%. The previous reports of genetic variants associated with toxicity and/or activity from these three agents provides a promising approach for the development of a pharmacogenetic strategy to select therapy for advanced colorectal cancer. Therefore, this project will address the following Specific Aims: 1. Determine the predictive impact of genetic variants in candidate genes on severe toxicity from 5FU, CPT-11, or OXAL therapy in 575 patients from the N9741 study. 2. Define the association of genetic variants in candidate genes with response to therapy, time to progression, overall survival, and quality of life after 5FU, CPT-11, or OXAL regimens for advanced colorectal cancer. 3. Develop methods for incorporating Genetic Polymorphism Profiles into Decision Making. These aims provide a comprehensive framework for our strategy to provide the first prospective information on the integration of pharmacogenetic information into the selection of therapy for advanced colorectal cancer.

描述（由申请人提供）：晚期结直肠癌的治疗为药物遗传学的开发和评估提供了理想的环境。具有明确抗肿瘤活性的多种治疗选择的可用性需要针对个体患者做出临床决策，并且这些决策最好利用定量信息来做出。然而，目前没有足够的工具来指导晚期结直肠癌的治疗选择。最近 FDA 批准了伊立替康 (CPT-11) 和奥沙利铂 (OXAL) 用于治疗晚期结直肠癌，以及历史标准 5-氟尿嘧啶 (5FU)，导致了针对该疾病的几种活性联合化疗方案的开发。事实上，最近完成的胃肠道组间研究 N9741 比较了 5FU/CPT-11、5FU/OXAL 和 CPT-11/OXAL，观察到的客观缓解率为 28-38%。先前关于这三种药物的毒性和/或活性相关遗传变异的报道为开发药物遗传学策略以选择晚期结直肠癌的治疗方法提供了一种有前景的方法。因此，该项目将解决以下具体目标： 1. 确定候选基因中的遗传变异对 N9741 研究中 575 名患者接受 5FU、CPT-11 或 OXAL 治疗的严重毒性的预测影响。 2. 定义候选基因中的遗传变异与晚期结直肠癌 5FU、CPT-11 或 OXAL 方案后的治疗反应、进展时间、总体生存率和生活质量之间的关系。 3. 开发将遗传多态性谱纳入决策的方法。这些目标为我们的战略提供了一个全面的框架，以提供有关将药物遗传学信息整合到晚期结直肠癌治疗选择中的第一个前瞻性信息。