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: 8488358
• 负责人: MARY V RELLING
• 金额: $ 27.8万
• 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/8488358
• 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）： 在这种抗癌药物研究的药物基因组学（PAAR4KICLS）的应用中，目的是充分定义儿童急性淋巴细胞淋巴细胞性白血病的药物基因组学（全部），这是最常见的儿童恶性肿瘤，是为了改善这种疾病患者的生活，以及与任何药物治疗的患者的生活。我们的目的是定义基因组变异（种系和获得）对于用于治疗反应和用于治疗儿童全部药物的药物毒性的介入差异很重要，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者合作，以利用与其他疾病的相关药剂基因组知识，以利用所有疾病和其他疾病和其他疾病（以及其他疾病）（以及 - 和其他疾病）（纽约市）（纽约市）（我们）和纽约市（Ies-nee-nee-nee-nee-nee-neversa）。这是由该领导者的多学科团队完成的。该研究利用了研究所有在儿童肿瘤学组（COG）和圣裘德儿童研究医院方案的患者的能力，可为美国所有人提供近乎人口的覆盖范围。儿科所有人为药物基因组发现和转化为诊所提供了出色的机会，因为这是一种致命的疾病，通过广泛使用具有狭窄治疗指数的药物来治愈。这些代理在癌症和一般医学实践中广泛使用，因此PAAR4KID的发现在小儿所有人之外具有适用性，如PGRN内外的多次合作所证明的那样。 PAAR4KIDS研究药物基因组学，药代动力学（细胞和血浆），糖皮质激素，甲氨蝶呤，硫代嘌呤，天冬酰胺酶，蒽环酸和vincristine的抗白血病和毒性作用。该方法以四个主要步骤进行了总结。在步骤1中，基因型/表型研究是在一组核心III期前线临床试验中进行的，涉及10,000多名患者，这些患者用作发现和复制队列。包括非基因协变量。在步骤2中，基因组变异将优先考虑进一步随访。第3步是确认和验证，包括机械实验实验室模型，人体组织的调查和/或其他临床试验中的其他基因型/表型分析，通常使用PGRN资源。在步骤4中，经过验证的具有较大效应大小的基因组关联被整合到临床环境中。 PAAR4KIDS拥有世界一流的科学家，将最先进的基因组学技术应用于来自广泛表型患者，杰出的统计学家，药理学家和临床医生的细菌和肿瘤细胞的生殖细胞和肿瘤细胞。 Paar4kids准备全面攻击儿童时期的药物基因组学。 公共卫生相关性：急性淋巴细胞白血病是儿童中最常见的癌症。使用多种药物，其中许多药物通常也用于治疗成人和儿童的其他癌症和非癌症状况，有些患者已治愈，但没有治愈，有些患者则具有严重的副作用。通过阐明药物反应变异性的基因组基础，这项研究将导致这些药物的安全性和有效性提高。