Genetic Etiology of Cancer Drug Response

癌症药物反应的遗传病因学

基本信息

批准号：
10179327
负责人：
Tim Wiltshire
金额：
$ 41.16万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179327
关键词：
Adverse event American Antineoplastic Agents Asians Bioinformatics Biological Models Candidate Disease Gene Cell Line Chemotherapy-Oncologic Procedure Chromosome Mapping Clinical Clinical Trials Combined Modality Therapy Complex Computer software Cytotoxic agent Data Dose Drug Combinations Drug Exposure Etiology European FDA approved Genes Genetic Genetic Predisposition to Disease Genome Goals Heritability Human Genome Project In Vitro Individual Knowledge Malignant Neoplasms Monoclonal Antibodies Outcome Pharmaceutical Preparations Pharmacogenomics Phenotype Population Resources Sample Size Selection for Treatments Statistical Methods Therapeutic Translating Tyrosine Kinase Inhibitor Variant Work anti-cancer cancer therapy cell killing chemotherapy cohort cost efficient cytotoxic drug action drug response prediction experimental study follow-up genetic information genetic signature genetic variant genome wide association study genome-wide analysis individual patient innovation insight interest method development novel novel drug class predicting response racial diversity rare variant response success synergism therapeutic development trait treatment response

项目摘要

Abstract: 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.

抽象的：在治疗最常见的癌症方面继续取得重要的进展，但是治疗益处仍然很难预测，严重或致命的不良事件经常发生。人类基因组项目已经推动了遗传信息可以产生有效且具有成本效益的疗法的观念个别患者，但经过验证的遗传特征，可以预测大多数化学疗法的反应仍有待确定。许多基因可能会影响药物反应，但目前的候选基因方法受到有关涉及基因和中等知识的先验知识的要求而限制大多数临床试验的大小通常会限制癌症体外基因组关联研究（GWAS）的功能药物基因组学发现。针对这些局限性，我们对细胞毒性进行了彻底的药物基因组学评估大多数FDA使用离体模型系统批准的抗癌化合物的影响药物诱导的细胞杀伤的遗传力将药物用于药物基因组映射的优先级。这些结果是重要的第一步，虽然特质的高遗传力并不能保证成功的关联映射结果，它代表了重要的第一步，结果将用于优先考虑具有较高遗产的药物用于全基因组关联映射。在当前的建议中，细胞毒性剂的GWA映射将是在欧美人口中进行，然后在东亚人口。除了发现和验证预测药物反应的遗传变异，收集的数据的财富将用于剖析药物反应特征的潜在病因，包括评估变异的遗传，环境和相互作用成分的相对贡献。这些结果将提供至关重要的见识，以优先考虑遗传变异的宝贵临床人群的随访资源，并有可能揭示对药物反应的整体病因的新见解。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The influence of Neanderthal alleles on cytotoxic response.

DOI：
10.7717/peerj.5691
发表时间：
2018
期刊：
PeerJ
影响因子：
2.7
作者：
Akhtari FS;Havener TM;Fukudo M;Jack JR;McLeod HL;Wiltshire T;Motsinger-Reif AA
通讯作者：
Motsinger-Reif AA

The pharmacogenomics of drug resistance to protein kinase inhibitors.

DOI：
10.1016/j.drup.2016.06.008
发表时间：
2016-09
期刊：
DRUG RESISTANCE UPDATES
影响因子：
24.3
作者：
Gillis, Nancy K.;McLeod, Howard L.
通讯作者：
McLeod, Howard L.

Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study.

DOI：
10.1289/ehp.1408775
发表时间：
2015-05
期刊：
Environmental health perspectives
影响因子：
10.4
作者：
Abdo N;Xia M;Brown CC;Kosyk O;Huang R;Sakamuru S;Zhou YH;Jack JR;Gallins P;Xia K;Li Y;Chiu WA;Motsinger-Reif AA;Austin CP;Tice RR;Rusyn I;Wright FA
通讯作者：
Wright FA

Discordance of Somatic Mutations Between Asian and Caucasian Patient Populations with Gastric Cancer.