Genetic determinants associated with pemetrexed response and toxicity

与培美曲塞反应和毒性相关的遗传决定因素

基本信息

批准号：
8469831
负责人：
Mary Eileen Dolan
金额：
$ 29.98万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8469831
关键词：
Adverse reactions African Alleles Apoptosis Apoptotic Asians Bioinformatics Biological Markers Canada Cancer Patient Cancer and Leukemia Group B Candidate Disease Gene Caucasians Caucasoid Race Cell Line Clinical Clinical Trials Data Development Dihydrofolate Reductase Drug Kinetics Drug Targeting Eastern Cooperative Oncology Group Enzymes Erlotinib European Exhibits Exons Family Folate Frequencies Gene Chips Gene Expression Gene Targeting Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Transcription Genetic Variation Genome Genotype Goals Human Hydroxymethyltransferases Individual Institution International Laboratories Malignant neoplasm of lung Micronutrients Modeling Multicenter Trials Non-Small-Cell Lung Carcinoma Normal Cell North Central Cancer Treatment Group Patients Pattern Pemetrexed Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Phenotype Play Population Predisposition Public Domains Relative (related person)Research Resistance Reverse Transcriptase Polymerase Chain Reaction Ribonucleotides Risk Role Sampling Small Interfering RNA Southwest Oncology Group System Test Result Testing Thymidylate Synthase Time Toxic effect Urine Variant Western Blotting base chemotherapeutic agent cytotoxic cytotoxicity drug metabolism genetic linkage analysis genetic pedigree genetic variant genome-wide glycine amide high throughput screening insight lymphoblastoid cell line novel protein expression response trait

项目摘要

ABSTRACT Pemetrexed is a multitargeted antifolate recently approved for second line therapy of non-small cell lung cancer (NSCLC). The most significant interaction at clinically achievable concentrations is with thymidylate synthase (TYMS), although the drug is known to target at least two other folate dependent enzymes. The goal of this proposal is to identify additional genetic variants that influence pemetrexed-associated toxicity and response by employing a genome-wide, comprehensive approach to test the hypothesis that genetic polymorphisms significantly influence susceptibility to toxicities and response associated with pemetrexed. To this end, lymphoblastoid cell lines, derived from large reference Centre d' Etude du Polymorphisme Humain pedigrees and HapMap (Caucasian, Yoruban, Asian) samples, will be phenotyped for pemetrexed cytotoxicity and apoptosis. Genotypic information is available in the public domain enabling us to apply familial genetic strategies, including linkage analysis, to examine regions in the genome harboring the genetic variants responsible for susceptibility to pemetrexed-induced cytotoxicity and apoptosis. In addition, inter-individual and inter-ethnic variation in pemetrexed-induced cytotoxicity will be compared using the International HapMap samples from populations of African, European and Asian descent. Exon expression array generated in our laboratory will be incorporated to identify genetic variants acting through their effect on baseline gene expression that associate with sensitivity to pemetrexed. Genetic variants identified through this whole genome approach will be validated in a separate sample set of LCLs and by quantitative PCR and siRNA. We will evaluate both novel SNPs and known candidate variants in TYMS, GARFT, DHFR to determine genotypes associated with response or toxicity in an intergroup (NCCTG, CALGB, ECOG, SWOG, NCI-C) study of pemetrexed compared to erlotinib as second line therapy for NSCLC. Our long-term goal is to identify a "pharmacogenetic signature" that will predict patients with a decreased chance for response or an increased risk for adverse reactions to pemetrexed. Specific aims are: 1. To determine the genetic contribution of susceptibility to the cytotoxic and apoptotic effects of pemetrexed. 2. To examine baseline and time dependent patterns of expression following pemetrexed treatment. 3. Identify SNPs, through data available from the International HapMap project, associated with both pemetrexed cytotoxicity and gene expression in cell lines derived from Europeans (CEU), Africans (YRI) and Asians (CHB, JPT). 4. To determine if a common polymorphism in TYMS, GARFT, and DHFR, as well as candidate polymorphisms identified in specific aims 1- 3 correlate with response and/or toxicity in advanced NSCLC patients treated with pemetrexed in a multicenter trial.

抽象的 pemetrexed是一种多核抗酸盐，最近批准用于非小细胞肺的二线治疗癌症（NSCLC）。在临床上可实现的浓度下最显着的相互作用是与胸腺丙酸合酶（TYMS），尽管已知该药物至少靶向另外两种叶酸依赖性酶。目标该提案的内容是确定影响雷塞莫（Pemetrexed）相关毒性和通过采用全基因组，全面的方法来检验遗传的假设来反应多态性显着影响对毒性的敏感性和与刺激性相关的反应。到这一末端是淋巴细胞细胞系，源自大型参考中心d'Etude du多态性Humain 谱系和hapmap（高加索人，约鲁巴人，亚洲）样品将被表型用于刺激性的细胞毒性和凋亡。基因型信息可在公共领域获得，使我们能够应用家族性遗传包括连锁分析在内的策略，以检查具有遗传变异的基因组中的区域负责促刺激性诱导的细胞毒性和凋亡的易感性。另外，个人间使用国际HAPMAP，将比较Pemetrexed诱导的细胞毒性的种族间变异来自非洲，欧洲和亚洲血统的样本。我们在我们的外显子表达阵列中生成的阵列实验室将合并以确定通过其对基线基因的影响作用的遗传变异与对Pemetrexed的敏感性相关的表达。通过整个基因组鉴定的遗传变异方法将在单独的LCL样品集和定量PCR和siRNA中进行验证。我们将评估Tyms，Garft，DHFR中的新型SNP和已知候选变体以确定基因型与组间（NCCTG，CALGB，ECOG，SWOG，NCI-C）的反应或毒性有关与Erlotinib作为NSCLC的二线治疗相比，Pemetrexed。我们的长期目标是确定 “药物遗传学签名”将预测患者的反应机会减少或增加对Pemetrexed的不良反应的风险。具体目的是：1。确定对Pemetrexed的细胞毒性和凋亡作用的敏感性。 2。检查基线和时间依赖刺激性处理后的表达模式。 3。通过可从中可用的数据来识别SNP 国际Hapmap项目，与细胞系中的刺激性细胞毒性和基因表达相关源自欧洲人（CEU），非洲人（YRI）和亚洲人（CHB，JPT）。 4。确定是否常见 TYM，GARFT和DHFR中的多态性以及在特定目的中确定的候选多态性1- 3与在多中心接受Pemetrex治疗的晚期NSCLC患者中的反应和/或毒性相关审判。