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

• 批准号: 7211613
• 负责人: RAKESH K GOYAL
• 金额: $ 16.44万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211613
• 关键词: 5' Flanking Region; 5' -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

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(申请人提供)：这项研究的最终目标是确定涉及Ara-C转运和生物转化的基因的遗传变异在确定急性髓细胞白血病(AML)治疗效果和毒性方面的作用。该初步建议的目的是1)鉴定和表征人类平衡核苷转运体(ENT1)、脱氧胞苷酸激酶(CDK)、胞液5‘-核苷酸酶II(NT5C2)和胞苷脱氨酶(CDA)基因的遗传变异，并评估该变异对体内外基因表达的影响；2)确定患者ENT1、DCK、NT5C2和CDA基因的特定单倍型是否可以预测接受化疗的儿童和青少年的总生存率；3)确定这些座位的特定单倍型是否与这些患者的黏膜毒性、骨髓抑制和感染的风险有关。目的是确定人群中相对常见的变异，这些变异可能有助于预测相当一部分患者的反应。这项探索性的R21建议(响应PA-03-064，由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，并在单一合作小组III期试验中对大量接受治疗的年轻AML患者进行选择的单倍型和单个基因基因型与治疗结果之间的相关性分析。这项工作应该会导致一项更大规模的R01研究，以检查Ara-C途径中的其他酶，并在儿科和成人AML患者的重复研究中测试从这项研究中出现的显著发现。综述：新药治疗和骨髓移植极大地提高了儿童急性髓系白血病的存活率。然而，就治疗结果和治疗的毒副作用而言，患者之间存在很大的差异。最终目标是前瞻性地使用这些信息来优化个人治疗，以最大限度地提高疗效并将药物不良反应降至最低。