PAAR4Kids-Pharmacogenomics of Anticancer Agents Research in Children

PAAR4Kids-儿童抗癌药物的药物基因组学研究

基本信息

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
项目类别：
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&apos 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&apos 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

项目摘要

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）：在这项儿童抗癌药物研究的药物基因组学 (PAAR4Kicls) 申请中，目标是全面定义儿童急性淋巴细胞白血病 (ALL)（最常见的儿童恶性肿瘤）的药物基因组学，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。我们的目标是定义基因组变异（种系和后天性），这对于治疗儿童 ALL 的治疗反应和药物毒性的患者间变异非常重要，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，利用儿科的相关药物基因组学知识全部针对其他疾病和学科（反之亦然）。这是由该领域的多学科领导团队完成的。该研究利用了对接受儿童肿瘤组 (COG) 和圣裘德儿童研究医院方案治疗的 ALL 患者进行研究的力量，在美国实现了接近人口水平的 ALL 覆盖率。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，因为这是一种致命的疾病，可以通过广泛使用治疗指数狭窄的药物来治愈。这些药物广泛用于癌症和一般医疗实践，因此 PAAR4Kids 的研究结果在儿科 ALL 之外也适用，PGRN 内外的多次合作证明了这一点。 PAAR4Kids 研究糖皮质激素、甲氨蝶呤、硫嘌呤、天冬酰胺酶、蒽环类药物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。在第一步中，基因型/表型研究是在一组核心 III 期一线临床试验中进行的，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，优先考虑基因组变异以进行进一步的随访。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。在第 4 步中，经过验证的具有大效应量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、杰出的统计学家、药理学家和临床医生，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完美编目样本集合的种系和肿瘤细胞。 PAAR4Kids 准备全面攻克儿童 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中最常见的癌症。使用多种药物（其中许多药物也经常用于治疗成人和儿童的其他癌症和非癌症疾病），一些患者被治愈，但另一些患者却没有治愈，有些患者还产生严重的副作用。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。