Variation in Ara-C Pathway Genes and Treatment Outcomes in AML

AML 中 Ara-C 通路基因的变异和治疗结果

基本信息

批准号：
7414055
负责人：
RAKESH K GOYAL
金额：
$ 15.29万
依托单位：
CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7414055
关键词：
5&apos Flanking Region 5&apos -Nucleotidase Acute Myelocytic Leukemia Adolescent Adult Adverse effects Ara-C Bone Marrow Transplantation Child Childhood Childhood Acute Myeloid Leukemia Cyclin-Dependent Kinases Cytidine Deaminase DNA Resequencing Data Databases Deoxycytidine Kinase Enzymes Evaluation Gene Expression Genes Genetic Polymorphism Genetic Variation Genotype Goals Haplotypes Human In Vitro Individual Infection Lead Leukemic Cell Level of Evidence Literature Metabolic Biotransformation Metabolic Pathway Myelosuppression Nucleoside Transporter Pathway interactions Patients Pharmaceutical Preparations Phase III Clinical Trials Population RNA Splicing Rate Reaction Remission Induction Research Risk Role Site Testing Toxic effect Translational Research Treatment Failure Treatment outcome Variant Work chemotherapy cohort experience improved in vivo interest response

项目摘要

DESCRIPTION (provided by applicant): The ultimate goal of this research is to define the role of genetic variation in the genes involved in ara-C transport and biotransformation in determining the efficacy and toxicity of treatment of acute myelogenous leukemia (AML). The aims of this initial proposal are 1) to identify and characterize genetic variation in the human equilibrative nucleoside transporter (ENT1), deoxycytidine kinase (CDK), cytosolic 5'-nucleotidase II (NT5C2) and cytidine deaminase (CDA) genes and assess the impact of this variation on gene expression in vitro and in vivo; 2) to determine if specific haplotypes in patient ENT1, DCK, NT5C2 and CDA genes predict overall survival in children and adolescents undergoing chemotherapy for de novo AML and 3) to determine if specific haplotypes at these loci is associated with the risk of mucosal toxicity, myelosuppression and infection in these patients. The objective is to identify relatively common variation in the population that may be useful in predicting response in a significant fraction of the patient population. This exploratory R21 proposal (in response to PA-03-064, replaced by PA-05-062) will study genetic variation in four key enzymes in ara-C metabolic pathway and perform correlative analyses between selected haplotypes and genotypes of the individual gene versus treatment outcomes in a large cohort of young patients with AML treated on a single cooperative group phase III trial. This work should lead to a larger-scale R01 study to also examine other enzymes in ara-C pathway as well as test salient findings emerging from this study in replicate studies of pediatric and adult patients with AML. Lay summary: New drug treatment and bone marrow transplantation have greatly improved the survival of children with acute myelogenous leukemia. However, there is a great deal of variation among patients in terms of treatment outcomes and the toxic side effects of treatment. The ultimate goal is to use this information prospectively to optimize individual therapy to maximize response and minimize adverse drug reactions.

描述（由申请人提供）：本研究的最终目标是确定参与ara-C转运和生物转化的基因的遗传变异在确定急性髓性白血病（AML）治疗的功效和毒性中的作用。该初步提案的目的是 1) 识别和表征人类平衡核苷转运蛋白 (ENT1)、脱氧胞苷激酶 (CDK)、胞质 5'-核苷酸酶 II (NT5C2) 和胞苷脱氨酶 (CDA) 基因的遗传变异，并评估这种变异对体外和体内基因表达的影响； 2) 确定患者 ENT1、DCK、NT5C2 和 CDA 基因中的特定单倍型是否可以预测接受新发 AML 化疗的儿童和青少年的总体生存率，以及 3) 确定这些基因座的特定单倍型是否与粘膜毒性风险相关，这些患者的骨髓抑制和感染。目的是确定人群中相对常见的变异，这可能有助于预测大部分患者群体的反应。这个探索性 R21 提案（响应 PA-03-064，被 PA-05-062 取代）将研究 ara-C 代谢途径中四种关键酶的遗传变异，并在选定的单倍型和单个基因的基因型与在单一合作组 III 期试验中治疗的一大群年轻 AML 患者的治疗结果。这项工作应该会导致更大规模的 R01 研究，以检查 ara-C 途径中的其他酶，并在儿童和成人 AML 患者的重复研究中测试本研究中出现的显着结果。总结：新药治疗和骨髓移植极大地提高了急性髓性白血病儿童的生存率。然而，患者之间在治疗结果和治疗毒副作用方面存在很大差异。最终目标是前瞻性地使用这些信息来优化个体治疗，以最大限度地提高反应并最大限度地减少药物不良反应。