PHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL)

儿童白血病的药物基因组学（全部）

• 批准号: 8117114
• 负责人: WILLIAM E EVANS
• 金额: $ 65.79万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117114
• 关键词: 15 year old; 6-Mercaptopurine; Acute Lymphocytic Leukemia; Applications Grants; Award; Biochemical; Cause of Death; Cells; Child; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Copy Number Polymorphism; DNA; Daunorubicin; Disease; Drug resistance; Event; Funding; Gene Expression; Genes; Genetic Polymorphism; Genome; Genomics; Glucocorticoids; Instruction; Malignant Childhood Neoplasm; Malignant Neoplasms; Methylation; Newly Diagnosed; Patients; Pharmaceutical Preparations; Pharmacogenomics; Public Health; Relapse; Research; Research Support; Resistance; Side; Technology; Thioguanine; Treatment Effectiveness; Treatment Failure; Treatment Protocols; United States National Institutes of Health; Variant; Vincristine; Work; antileukemic agent; asparaginase; cancer therapy; chemotherapeutic agent; chemotherapy; design; drug sensitivity; genome-wide; improved; insight; novel; prednisolone; programs; promoter; response; thiopurine; trait; treatment response

PROJECT SUMMARY (See instructions): Despite substantial progress in the past two decades, cancer remains the leading cause of death by disease in US children between 1 and 15 years of age. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and cure rates are approaching ~ 80% today. Unfortunately, 20% of children with ALL are not cured with current therapy, making the number of cases of relapsed ALL greater than the total number of new cases of most childhood cancers. Previous work has established that de novo drug resistance is a primary cause of treatment failure in childhood ALL. However, the genomic determinants of drug resistance remain poorly defined. The research supported by this MERIT award has focused on elucidating the genomic determinants of inter-patient differences in drug response in children with ALL, leading to a number of new insights into the pharmacogenomics of childhood ALL. Our scientific aims are focused on some of the most widely used antileukemic agents, thiopurines and glucocorticoids (with complementary studies of L- asparaginase and vincristine). The first aim is to identify genes that influence the response to thiopurines (mercaptopurine, thioguanine), using genomewide approaches for gene expression analyses of ALL cells, and SNP analyses of germline and ALL cell DNA to identify SNPs and copy number variations (CNVs) that are significantly related to drug sensitivity and response. Studies in Aim 2 are designed to elucidate these pharmacogenomic traits in T-ALL, a less common subtype that is more resistant to curative chemotherapy, and compare these findings to B-lineage ALL. Once we identify these genes or genome abnormalities (SNPs, CNVs) influencing ALL drug resistance and treatment response, we perform biochemical and genomic studies to determine the mechanism by which these genes or their variants influence the sensitivity of ALL cells to these chemotherapeutic agents. In the continuation of this research program, we are extending our findings from the last 4 years of funding by exploiting new genomewide strategies to identify genomic determinants of drug response (e.g., 1 million SNP arrays, gene expression arrays, mIRNA arrays), to determine whether CNVs or specific mlRNAs modify the expression of genes and thereby alter the sensitivity of ALL cells to these chemotherapeutic agents. Our preliminary findings have indeed revealed specific mlRNAs that influence the sensitivity of ALL cells to these agents, and we have also recently discovered that specific CNVs in ALL cells can significantly influence drug resistance. The continuation of these studies will provide important new insights into the genomic determinants of treatment failure and point to novel targets for developing strategies to overcome drug resistance in childhood ALL.

项目摘要（请参阅说明）： 尽管在过去的二十年中取得了长足的进步，但癌症仍然是疾病死亡的主要原因 在1至15岁之间的美国儿童中。急性淋巴细胞白血病（ALL）是最常见的 今天的儿童癌症和治疗率接近约80％。不幸的是，有20％的儿童是 无法治愈当前疗法，使复发病例的数量大于总数 大多数童年癌症的新病例。以前的工作已经确定从头耐药性是 儿童时期治疗失败的主要原因。但是，耐药性的基因组决定因素 保持较差。该优点奖支持的研究重点是阐明 所有人患者药物反应差异的基因组决定因素，导致数量 对童年的药物基因组学的新见解。我们的科学目标集中于一些 使用最广泛使用的抗白血病药物，硫嘌呤和糖皮质激素（有L-的互补研究 天冬酰胺酶和长春新碱）。第一个目的是确定影响硫嘌呤反应的基因 （胃嘌呤，硫代氨酸），使用全基因组方法来对所有细胞进行基因表达分析， 以及对种系和所有细胞DNA的SNP分析，以识别SNP和副本编号变化（CNV） 与药物敏感性和反应显着相关。 AIM 2的研究旨在阐明这些 T-All中的药物基因组学性状，一种不太常见的亚型，对治疗化学疗法更具耐药性， 并将这些发现与b-lineage All进行比较。一旦我们识别这些基因或基因组异常 （SNP，CNV）影响所有耐药性和治疗反应，我们执行生化和 基因组研究以确定这些基因或它们变体影响灵敏度的机制 这些化学治疗剂的所有细胞。在该研究计划的延续中，我们是 通过利用新的全基因组策略来识别，将我们的发现从过去4年的资金中扩展 药物反应的基因组决定因素（例如100万SNP阵列，基因表达阵列，miRNA阵列）， 确定CNV或特定MLRNA是否会改变基因的表达，从而改变 所有细胞对这些化学治疗剂的敏感性。我们的初步发现确实揭示了 影响所有细胞对这些药物的敏感性的特定MLRNA，并且最近我们也有 发现所有细胞中的特定CNV都可以显着影响耐药性。延续 这些研究将为治疗失败和点的基因组决定因素提供重要的新见解。 为制定策略以克服童年时期耐药性的新目标。