Genetic Etiology of Cancer Drug Response

癌症药物反应的遗传病因学

• 批准号: 8616048
• 负责人: RONALD M KRAUSS
• 金额: $ 45.49万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616048
• 关键词: Adverse event; American; Antineoplastic Agents; Asians; Biological Models; Candidate Disease Gene; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Cytotoxic agent; Data; Etiology; European; FDA approved; Future; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genotype; Goals; Heritability; Human Genome Project; In Vitro; Individual; Knowledge; Malignant Neoplasms; Maps; Outcome; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Population; Relative (related person); Resources; Therapeutic; Variant; Work; cell killing; cohort; cost effective; cytotoxic; follow-up; gene environment interaction; genetic association; genetic variant; genome wide association study; genome-wide; insight; interest; response; trait

DESCRIPTION (provided by applicant): Important progress continues to be made in the treatment of most common cancers, but therapeutic benefit remains difficult to predict and severe or fatal adverse events occur frequently. The Human Genome Project has fueled the notion that genetic information can produce effective and cost-efficient selection of therapies for individual patients, but validated genetic signatures that predict response to most chemotherapy regimens remain to be identified. Numerous genes potentially influence drug response, but current candidate-gene approaches are limited by the requirement of a priori knowledge about the genes involved and the moderate size of most clinical trials often limits the power of in vitro genome wide association studies (GWAS) for cancer pharmacogenomics discovery. In response to these limitations, we have undertaken a thorough, pharmacogenomic assessment of cytotoxic effect of the majority of FDA approved anti-cancer compounds using an ex vivo model system to determine the heritability of drug-induced cell killing to prioritize drugs for pharmacogenomic mapping. These results are an important first step, and while high heritability of a trait does not guarantee successful association mapping results, it represents an important first step and the results will be used to prioritize drugs with high heritabilities for genome-wide association mapping. In the current proposal, GWAS mapping of cytotoxic agents will be performed in a European American population, and then replication GWAS mapping will be performed in an East Asian population. In addition to discovering and validating genetic variants that predict drug response, the wealth of data collected will be used to dissect the underlying etiology of drug response traits, including assessing the relative contribution of genetic, environmental, and interaction components of variation. These results will provide crucial insight to prioritize genetic variants for follow-up in precious clinical population resources, and potentially reveal new insight into the overall etiology of drug responses.

描述（申请人提供）：在治疗最常见的癌症时，继续取得了重要的进展，但是治疗益处仍然难以预测，严重或致命的不良事件经常发生。人类基因组项目助长了这样一种观念，即遗传信息可以为个别患者产生有效且具有成本效益的疗法选择，但是经过验证的遗传信号可以预测对大多数化学疗法方案的反应。许多基因可能影响药物反应，但是当前的候选基因方法受到有关涉及基因的先验知识的要求，大多数临床试验的中等大小通常会限制对癌症药物基因组学发现的体外基因组广泛关联研究（GWAS）的功能。为了应对这些局限性，我们使用了离体模型系统对大多数FDA认可的抗癌化合物的细胞毒性作用进行了彻底的药物基因组学评估，以确定药物诱导的细胞杀伤的可遗传力，以使药物映射的药物优先级。这些结果是重要的第一步，尽管性状的高遗传力不能保证成功的关联映射结果，但它代表了重要的第一步，结果将用于优先考虑具有较高基因组关联映射的遗传性较高的药物。在当前的提案中，将在欧美人群中进行细胞毒性剂的GWA映射，然后在东亚人群中进行复制GWAS映射。除了发现和验证预测药物反应的遗传变异外，收集到的数据的财富还将用于剖析药物反应特征的潜在病因，包括评估遗传，环境和相互作用的相对贡献。这些结果将提供至关重要的见解，以优先考虑遗传变异，以进行宝贵的临床人群资源的随访，并有可能揭示对药物反应的整体病因的新见解。