PAAR4Kids-Pharmacogenomics of Anticancer Agents Research in Children

PAAR4Kids-儿童抗癌药物的药物基因组学研究

• 批准号: 8292285
• 负责人: MARY V RELLING
• 金额: $ 156.32万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292285
• 关键词: Acute; Acute Lymphocytic Leukemia; Adult; Adverse effects; Anthracyclines; Antineoplastic Agents; Body Size; Cataloging; Catalogs; Cells; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Children' s Oncology Group; Clinic; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Databases; Discipline; Disease; Drug Kinetics; Drug resistance; Effectiveness; Genomics; Genotype; Glucocorticoids; Goals; Knowledge; Laboratories; Lead; Malignant Neoplasms; Medical; Methotrexate; Modeling; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phase; Phenotype; Plasma; Population; Protocols documentation; Relapse; Renal function; Research; Research Personnel; Resources; Safety; Saint Jude Children' s Research Hospital; Scientist; Source; Surveys; Techniques; Therapeutic Index; Toxic effect; Translating; Translations; Validation; Variant; Vincristine; antileukemic agent; asparaginase; base; cohort; follow-up; human tissue; improved; leukemia; liver function; multidisciplinary; neoplastic cell; non-genetic; public health relevance; response; sample collection; thiopurine; treatment response; treatment strategy; tumor

DESCRIPTION (provided by applicant): In this application for the Pharmacogenomics of Anticancer Agents Research in Children (PAAR4Kicls), the goal is to fully define the pharmacogenomics of childhood acute lymphoblastic leukemia (ALL), the most common childhood malignancy, in order to improve the lives of children with this disease, as well as any patients treated with the same medications. Our aims are to define genomic variations (germline and acquired) important for interpatient variability in treatment response and toxicity from medications used to treat childhood ALL, to translate pharmacogenomics into clinical treatment strategies, and to collaborate with pharmacogenomics investigators to leverage relevant pharmacogenomic knowledge from pediatric ALL to other diseases and disciplines (and wee-versa). This is accomplished by a multidisciplinary team of leaders in the field. The research harnesses the power of studying patients with ALL treated on Children's Oncology Group (COG) and St. Jude Children's Research Hospital protocols, achieving near-population-level coverage for ALL in the US. Pediatric ALL provides outstanding opportunities for pharmacogenomic discoveries and translation to the clinic, because this is an otherwise fatal disease that is cured through extensive use of agents that have a narrow therapeutic index. The agents are broadly used in cancer and in general medical practice and thus the findings from PAAR4Kids have applicability outside of pediatric ALL, as demonstrated by multiple collaborations within and outside of the PGRN. PAAR4Kids studies the pharmacogenomics, pharmacokinetics (cellular and plasma), antileukemic and toxic effects of glucocorticoids, methotrexate, thiopurines, asparaginase, anthracyclines, and vincristine. The approach is summarized in four major Steps. In Step 1 genotype/phenotype studies are undertaken in a set of core phase III front-line clinical trials involving over 10,000 patients that serve as discovery and replication cohorts. Non-genetic covariates are included. In Step 2, genomic variation is prioritized for further follow-up. Step 3 is confirmation and validation, consisting of mechanistic experimental laboratory models, surveys of human tissues, and/or additional genotype/phenotype analyses in other clinical trials, often using PGRN resources. In Step 4, validated genomic associations with large effect sizes are integrated into clinical settings. PAAR4Kids has world class scientists applying state-of-the-art genomics techniques to the germline and tumor cells of impeccably cataloged specimen collections from extensively phenotyped patients, and outstanding statisticians, pharmacologists, and clinicians. PAAR4Kids is poised to comprehensively attack the pharmacogenomics of childhood ALL. PUBLIC HEALTH RELEVANCE: Acute lymphoblastic leukemia is the most common cancer in children. Using multiple medications, many of which are also often used to treat other cancers and non-cancer conditions in adults and children, some patients are cured but not others, and some have severe side effects. By unraveling the genomic basis of variability in medication response, this research will lead to increased safety and effectiveness of these medications.

描述（由申请人提供）： 在儿童抗癌药物研究的药物基因组学（PAAR 4Kicls）中，目标是充分定义儿童急性淋巴细胞白血病（ALL）的药物基因组学，这是最常见的儿童恶性肿瘤，以改善患有这种疾病的儿童的生活，以及任何接受相同药物治疗的患者。我们的目标是确定基因组变异（生殖系和获得性），这些变异对治疗儿童ALL的药物治疗反应和毒性的患者间变异性很重要，将药物基因组学转化为临床治疗策略，并与药物基因组学研究人员合作，利用儿科ALL的相关药物基因组学知识，以其他疾病和学科（反之亦然）。这是由一个多学科领导人小组在外地完成的。这项研究利用了研究儿童肿瘤学小组（COG）和圣裘德儿童研究医院方案治疗的ALL患者的力量，实现了美国ALL的近人口水平覆盖。儿科ALL为药物基因组学发现和临床转化提供了绝佳的机会，因为这是一种通过广泛使用治疗指数较窄的药物治愈的致命疾病。这些药物广泛用于癌症和一般医疗实践，因此PAAR 4Kids的发现在儿科ALL之外具有适用性，正如PGRN内外的多项合作所证明的那样。PAAR 4Kids研究糖皮质激素、甲氨蝶呤、硫嘌呤、天冬酰胺酶、蒽环类和长春新碱的药物基因组学、药代动力学（细胞和血浆）、抗白血病和毒性作用。该方法概括为四个主要步骤。在第1步中，在一组核心III期一线临床试验中进行基因型/表型研究，这些试验涉及10，000多名患者，作为发现和复制队列。包括非遗传协变量。在步骤2中，基因组变异被优先考虑以进行进一步的随访。第3步是确认和验证，包括机械实验室模型、人体组织调查和/或其他临床试验中的额外基因型/表型分析，通常使用PGRN资源。在步骤4中，将具有大效应量的经验证的基因组关联整合到临床环境中。PAAR 4Kids拥有世界一流的科学家，他们将最先进的基因组学技术应用于来自广泛表型患者的可分类标本集的种系和肿瘤细胞，以及杰出的统计学家，药理学家和临床医生。PAAR 4Kids准备全面攻击儿童ALL的药物基因组学。 公共卫生相关性：急性淋巴细胞白血病是儿童最常见的癌症。使用多种药物，其中许多也经常用于治疗成人和儿童的其他癌症和非癌症疾病，一些患者治愈，但其他人没有，有些人有严重的副作用。通过揭示药物反应变异性的基因组基础，这项研究将提高这些药物的安全性和有效性。