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:
- 金额:$ 29.98万
- 依托单位:
- 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:
- 关键词:Adverse reactionsAfricanAllelesApoptosisApoptoticAsiansBioinformaticsBiological MarkersCanadaCancer PatientCancer and Leukemia Group BCandidate Disease GeneCaucasiansCaucasoid RaceCell LineClinicalClinical TrialsDataDevelopmentDihydrofolate ReductaseDrug KineticsDrug TargetingEastern Cooperative Oncology GroupEnzymesErlotinibEuropeanExhibitsExonsFamilyFolateFrequenciesGene ChipsGene ExpressionGene TargetingGenesGeneticGenetic DeterminismGenetic PolymorphismGenetic TranscriptionGenetic VariationGenomeGenotypeGoalsHumanHydroxymethyltransferasesIndividualInstitutionInternationalLaboratoriesMalignant neoplasm of lungMicronutrientsModelingMulticenter TrialsNon-Small-Cell Lung CarcinomaNormal CellNorth Central Cancer Treatment GroupPatientsPatternPemetrexedPharmaceutical PreparationsPharmacodynamicsPharmacogeneticsPhenotypePlayPopulationPredispositionPublic DomainsRelative (related person)ResearchResistanceReverse Transcriptase Polymerase Chain ReactionRibonucleotidesRiskRoleSamplingSmall Interfering RNASouthwest Oncology GroupSystemTest ResultTestingThymidylate SynthaseTimeToxic effectUrineVariantWestern Blottingbasechemotherapeutic agentcytotoxiccytotoxicitydrug metabolismgenetic linkage analysisgenetic pedigreegenetic variantgenome-wideglycine amidehigh throughput screeninginsightlymphoblastoid cell linenovelprotein expressionresponsetrait
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.
摘要
培美曲塞是一种多靶点抗叶酸药,最近被批准用于非小细胞肺癌的二线治疗
癌症(NSCLC)。在临床可达到的浓度下,最显著的相互作用是与胸苷酸
叶酸合成酶(TYMS),尽管已知该药物靶向至少两种其他叶酸依赖性酶。目标
该提案的目的是确定影响培美塞相关毒性的其他遗传变异,
通过采用全基因组的综合方法来测试遗传学的假设,
多态性显著影响对培美曲塞相关毒性和反应的易感性。到
为此,淋巴母细胞样细胞系,来源于大型参考文献人类多态性研究中心(Centre d'EtudyduPolymorphismeHumain
将对谱系和HapMap(高加索人、约鲁巴人、亚洲人)样本进行培美曲塞细胞毒性表型分析
和凋亡。基因型信息是在公共领域,使我们能够应用家族遗传学
策略,包括连锁分析,以检查基因组中携带遗传变异的区域
负责对培美塞诱导的细胞毒性和细胞凋亡的易感性。此外,个人和
将使用国际HapMap比较培美塞诱导细胞毒性的种族间差异
来自非洲人、欧洲人和亚洲人后裔的样本。外显子表达阵列产生在我们的
实验室将被纳入,以确定遗传变异通过其对基线基因的影响而起作用。
与培美曲塞敏感性相关的表达。通过整个基因组识别的遗传变异
方法将在单独的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SNP和已知候选变体,以确定基因型
与组间(NCCTG、CALGB、ECOG、SWOG、NCI-C)研究中的反应或毒性相关,
培美曲塞与厄洛替尼作为NSCLC二线治疗的比较。我们的长期目标是确定一个
“药物遗传学特征”,将预测患者的缓解机会降低或缓解机会增加
培美曲塞不良反应的风险。具体目标是:1。为了确定基因的贡献,
对培美曲塞的细胞毒性和凋亡作用的敏感性。2.检查基线和时间依赖性
培美曲塞治疗后的表达模式。3.通过可获得的数据识别SNP,
与培美曲塞细胞毒性和细胞系基因表达相关的国际HapMap项目
来自欧洲人(CEU),非洲人(YRI)和亚洲人(CHB,JPT)。4.为了确定一个共同的
TYMS、GARFT和DHFR中的多态性,以及在特定目标1-
3例与培美曲塞治疗的晚期NSCLC患者的疗效和/或毒性相关的多中心研究
审判
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Systems and genome-wide approaches unite to provide a route to personalized medicine.
系统和全基因组方法相结合,为个性化医疗提供了一条途径。
- DOI:10.1186/gm328
- 发表时间:2012
- 期刊:
- 影响因子:12.3
- 作者:Stranger,BarbaraE;Björkegren,Johan;Dolan,MEileen;Ritchie,MarylynD
- 通讯作者:Ritchie,MarylynD
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Mary Eileen Dolan其他文献
Mary Eileen Dolan的其他文献
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{{ truncateString('Mary Eileen Dolan', 18)}}的其他基金
Chicago EYES (Educators and Youth Enjoy Science) on Cancer
芝加哥之眼(教育工作者和青少年享受科学)关注癌症
- 批准号:
9769677 - 财政年份:2017
- 资助金额:
$ 29.98万 - 项目类别:
Chicago EYES (Educators and Youth Enjoy Science) on Cancer
芝加哥之眼(教育工作者和青少年享受科学)关注癌症
- 批准号:
10929574 - 财政年份:2017
- 资助金额:
$ 29.98万 - 项目类别:
Chicago EYES (Educators and Youth Enjoy Science) on Cancer
芝加哥之眼(教育工作者和青少年享受科学)关注癌症
- 批准号:
10001463 - 财政年份:2017
- 资助金额:
$ 29.98万 - 项目类别:
Chicago EYES (Educators and Youth Enjoy Science) on Cancer
芝加哥之眼(教育工作者和青少年享受科学)关注癌症
- 批准号:
10471770 - 财政年份:2017
- 资助金额:
$ 29.98万 - 项目类别:
Epigenetic and Genetic Dissection of Drug Response
药物反应的表观遗传学和遗传学剖析
- 批准号:
8309059 - 财政年份:2011
- 资助金额:
$ 29.98万 - 项目类别:
Epigenetic and Genetic Dissection of Drug Response
药物反应的表观遗传学和遗传学剖析
- 批准号:
8178832 - 财政年份:2011
- 资助金额:
$ 29.98万 - 项目类别:
CORE III - Lymphoblastoid Cell Line CORE (LCL)
CORE III - 类淋巴母细胞系 CORE (LCL)
- 批准号:
8153263 - 财政年份:2010
- 资助金额:
$ 29.98万 - 项目类别:
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 - 财政年份:2009
- 资助金额:
$ 29.98万 - 项目类别:
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:
7742080 - 财政年份:2009
- 资助金额:
$ 29.98万 - 项目类别:
Incorporation of microRNA expression in pharmacogenetic prediction models
将 microRNA 表达纳入药物遗传学预测模型
- 批准号:
7641876 - 财政年份:2009
- 资助金额:
$ 29.98万 - 项目类别:
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