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（由申请方提供）：培美曲塞是一种多靶点抗叶酸剂，最近获批用于非小细胞肺癌（NSCLC）的二线治疗。在临床可达到的浓度下，最显著的相互作用是与胸苷酸合成酶（TYMS）的相互作用，尽管已知该药物靶向至少两种其他叶酸依赖性酶。本提案的目的是通过采用全基因组综合方法来验证遗传多态性显著影响培美曲塞相关毒性和反应易感性的假设，从而确定影响培美曲塞相关毒性和反应的其他遗传变异。为此，将对来自大型参考Centre d' Etude du Polymorphisme Humain谱系和HapMap（高加索人、约鲁邦人、亚洲人）样本的淋巴母细胞样细胞系进行培美曲塞细胞毒性和细胞凋亡的表型分析。基因型信息是在公共领域，使我们能够应用家族遗传策略，包括连锁分析，以检查区域的基因组窝藏的遗传变异负责敏感性培美塞汀诱导的细胞毒性和细胞凋亡。此外，将使用来自非洲、欧洲和亚洲血统人群的国际HapMap样本比较培美塞诱导细胞毒性的个体间和种族间差异。将纳入我们实验室生成的外显子表达阵列，以识别通过影响基线基因表达而起作用的遗传变异，这些基因表达与培美曲塞敏感性相关。通过这种全基因组方法鉴定的遗传变异将在单独的LCL样品组中通过定量PCR和siRNA进行验证。我们将评估TYMS、GARFT、DHFR中的新型SNP和已知候选变体，以确定与培美曲塞相比厄洛替尼作为NSCLC二线治疗的组间（NCCTG、CALGB、ECOG、SWOG、NCI-C）研究中的缓解或毒性相关的基因型。我们的长期目标是确定一个“药物遗传学特征”，预测患者对培美曲塞的反应机会减少或不良反应风险增加。具体目标是：1。确定培美曲塞细胞毒性和凋亡效应易感性的遗传贡献。2.检查培美曲塞治疗后的基线和时间依赖性表达模式。3.通过国际人类基因组单体型图项目提供的数据，在欧洲人（CEU）、非洲人（YRI）和亚洲人（CHB、JPT）细胞系中鉴定与培美曲塞细胞毒性和基因表达相关的SNP。4.在一项多中心试验中，确定TYMS、GARFT和DHFR中的常见多态性以及特定目标1- 3中确定的候选多态性是否与接受培美曲塞治疗的晚期NSCLC患者的疗效和/或毒性相关。公共卫生相关性：本研究的目的是确定肺癌患者在接受培美曲塞（一种化疗药物）治疗后存在毒性风险或缺乏反应。该项目旨在建立一个使用细胞系的模型，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，我们将在接受培美曲塞治疗的肺癌患者中测试我们的模型结果。最终，我们希望找到培美曲塞反应和毒性的预测标志物。