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

• 批准号: 8096819
• 负责人: Mary Eileen Dolan
• 金额: $ 31.89万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096819
• 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 Delivery Systems; Drug Kinetics; Eastern Cooperative Oncology Group; Enzymes; Erlotinib; European; Exhibits; Exons; Family; Folate; Frequencies; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genome; Genotype; Goals; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The objective of this research is to identify lung cancer patients at risk for toxicities or lack of response following treatment with pemetrexed, a chemotherapeutic agent. The project aims to build a model using cell lines to better understand how genetic variation explains differences in patient response to drug. In addition, we will test the results of our model in lung cancer patients treated with pemetrexed. Ultimately, we hope to find predictive markers of pemetrexed response and toxicity.

描述（由申请人提供）：Pemetrexed是一种多静脉抗酸盐，最近批准用于非小细胞肺癌（NSCLC）的二线治疗。临床上可实现的浓度下最显着的相互作用是与胸苷酸合酶（TYMS），尽管已知该药物至少靶向另外两种其他叶酸依赖性酶。该提案的目的是通过采用全基因组，全面的方法来检验以下假设，即遗传多态性显着影响对毒性的易感性和与Pemetreded相关的反应，从而确定影响与培美术相关的毒性和反应的其他遗传变异。为此，将对催眠症的细胞毒性和凋亡进行表型，以大型参考中心d'Etude du多态性humain谱系和Hapmap（高加索人，亚洲）样品（高加索人，亚洲）样品得出的淋巴细胞细胞系。基因型信息可在公共领域中获得，使我们能够应用家庭遗传策略，包括连锁分析，以检查具有负责对Pemetrexed诱导的细胞毒性和凋亡易感性的基因组中的区域。此外，将使用来自非洲，欧洲和亚洲血统的国际HAPMAP样本比较Pemetrexed诱导的细胞毒性的个体间和种族间差异。在我们的实验室中产生的外显子表达阵列将被合并，以鉴定其对基线基因表达作用的遗传变异，这些遗传变异与对Pemetrexed的敏感性相关。通过整个基因组方法鉴定的遗传变异将在单独的LCL样品集和定量PCR和siRNA中验证。我们将评估TYM，GARFT，DHFR中的新型SNP和已知的候选变体，以确定与Erlotinib作为NSCLC的第二行治疗相比，对Pemetrexed的pemetrexede的组间（NCCTG，CALGB，ECOG，SWOG，NCI-C）研究中与反应或毒性有关的基因型。我们的长期目标是确定一种“药物遗传学特征”，该遗传学特征将预测患者的反应机会减少或增加对pemetrexed反应的风险增加。具体目的是：1。确定对Pemetrexed的细胞毒性和凋亡作用的易感性的遗传贡献。 2。检查雷菜式处理后的基线和时间依赖性表达模式。 3。通过来自国际HAPMAP项目的数据来识别SNP，与来自欧洲人（CEU），非洲人（YRI）和亚洲人（CHB，JPT）的细胞系中的Pemetrexed细胞毒性和基因表达相关。 4。确定在特定目标中确定的TYMS，GARFT和DHFR中的常见多态性以及在多中心试验中接受过Pemetrexed治疗的晚期NSCLC患者的反应和/或毒性中确定的候选多态性。公共卫生相关性：这项研究的目的是确定有毒性风险的肺癌患者，或用化学治疗剂Pemetrexed治疗后缺乏反应。该项目旨在使用细胞系建立模型，以更好地了解遗传变异如何解释患者对药物反应的差异。此外，我们将测试用Pemetrexed治疗的肺癌患者中模型的结果。最终，我们希望找到Pemetrexed反应和毒性的预测标记。