PHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL)

儿童白血病的药物基因组学（全部）

• 批准号: 8466934
• 负责人: WILLIAM E EVANS
• 金额: $ 61.59万
• 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/8466934
• 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（参见说明）： 尽管过去二十年取得了重大进展，癌症仍然是疾病死亡的主要原因 在美国 1 至 15 岁的儿童中。急性淋巴细胞白血病（ALL）是最常见的 儿童癌症，如今治愈率已接近 80%。不幸的是，20% 患有 ALL 的儿童 目前的治疗未能治愈，使得复发 ALL 病例数大于总病例数 大多数儿童癌症的新病例。先前的工作已证实新发耐药性是一种 儿童 ALL 治疗失败的主要原因。然而，耐药性的基因组决定因素 仍然不明确。该 MERIT 奖支持的研究重点是阐明 ALL 儿童药物反应患者间差异的基因组决定因素，导致许多 对儿童 ALL 药物基因组学的新见解。我们的科学目标集中在一些 最广泛使用的抗白血病药物、硫嘌呤和糖皮质激素（L- 天冬酰胺酶和长春新碱）。第一个目标是确定影响硫嘌呤反应的基因 （巯嘌呤、硫鸟嘌呤），使用全基因组方法对 ALL 细胞进行基因表达分析， 对种系和所有细胞 DNA 进行 SNP 分析，以识别 SNP 和拷贝数变异 (CNV) 与药物敏感性和反应显着相关。目标 2 中的研究旨在阐明这些 T-ALL 的药物基因组特征，这是一种不太常见的亚型，对治疗性化疗更具抵抗力， 并将这些发现与 B 系 ALL 进行比较。一旦我们识别出这些基因或基因组异常 （SNP、CNV）影响 ALL 耐药性和治疗反应，我们进行生化和 基因组研究以确定这些基因或其变体影响敏感性的机制 ALL 细胞对这些化疗药物的影响。在继续这项研究计划的过程中，我们 通过利用新的全基因组策略来扩展我们过去 4 年资助的发现，以识别 药物反应的基因组决定因素（例如 100 万个 SNP 阵列、基因表达阵列、miRNA 阵列）， 以确定 CNV 或特定的 mlRNA 是否会修饰基因的表达，从而改变 ALL 细胞对这些化疗药物的敏感性。我们的初步调查结果确实揭示了 影响所有细胞对这些药物敏感性的特定 mlRNA，我们最近也发现 发现 ALL 细胞中的特定 CNV 可以显着影响耐药性。的延续 这些研究将为治疗失败的基因组决定因素和点提供重要的新见解 制定克服儿童 ALL 耐药性的策略的新目标。