Center for Precision Medicine in Leukemia (CPML)

 描述(申请人提供)：在我们作为急性淋巴细胞白血病(ALL)世界领导者和药物基因组学研究网络(PGRN)领导者的成功基础上，我们成立了白血病精准医学中心。我们的目标是确定抗白血病药物反应中患者间差异的潜在机制。我们将结合最先进的体细胞、转录组和表观基因组学询问所有肿瘤细胞，宿主生殖系DNA变异，以及对儿童和成人ALL治疗变量和非遗传特征的综合评估，结合实验室机制研究，以确定患者之间反应差异的来源和机制。许多ALL药物也被用于治疗其他儿童和成人癌症以及非恶性疾病：例如，糖皮质激素、甲氨蝶呤和硫嘌呤通常用于非恶性疾病，如哮喘、自身免疫性疾病和炎症性疾病，因此所有这些都可以作为如何优化治疗使用的模型，这将具有广泛的影响。我们的研究人员包括成人和儿童ALL、药物基因组学、人类基因组学、临床药理学、计算生物学、生物信息学和生物统计学的领导者。我们有三个主要目标，通过三个高度集成的项目(所有这些项目都利用了一线所有临床试验)和三个中心核心来实现。在项目1中，我们将定义所有亚型之间的基因组变异图景，并确定与患者所有治疗反应相关的遗传和躯体获得性基因组变异以及其他临床特征。在项目2中，我们将确定初诊和复发患者的原代ALL细胞中与从头开始和获得性耐药相关的基因组变异，并阐明基因组变异影响耐药和治疗反应的机制。在项目3中，我们将确定与抗白血病药物(骨坏死、肝毒性、胰腺炎和神经病)特定严重不良反应相关的基因组变异，建立骨坏死表型的机制和测试干预措施。该中心的协同作用源于三个项目之间患者和基因组数据的大量重叠；研究人员之间的专业互补和先前的合作；我们行政核心的领导与现有的药物基因组、基因组和临床癌症网络有着广泛的联系；以及我们核心提供的统一的数据分析、管理、集成和沉积方法。我们中心的首要目标是利用从这三个项目中获得的研究知识，建立一种全面的精准医学方法，以最大限度地减少复发，同时将不良反应降至最低。该中心将使我们能够吸引更多的成人ALL和基因组学合作者，加快基因组学发现和转化为更有效和毒性更低的治疗方法的进展，并为将基因组方法和知识整合到精确医学中提供其他疾病的范例。

 DESCRIPTION (provided by applicant): Building on our success as world leaders in acute lymphoblastic leukemia (ALL) and as leaders in the Pharmacogenomics Research Network (PGRN), we have formed a Center for Precision Medicine in Leukemia. Our goal is to identify the mechanisms underlying interpatient variability in response to antileukemia medications. We will integrate state-of-the-art genomic, transcriptomic, and epigenomic interrogation of somatic cell ALL tumor cells, host germline DNA variation, and comprehensive assessment of treatment variables and non-genetic features in children and adults with ALL, coupled with laboratory mechanistic studies, to identify sources and mechanisms of interpatient variation in response. Many ALL medications are also used to treat other pediatric and adult cancers and also nonmalignant diseases: for example, glucocorticoids, methotrexate, and thiopurines are commonly used for nonmalignant diseases such as asthma, autoimmune, and inflammatory diseases, and so ALL can serve as a model for how to optimize use of therapy that will have broad implications beyond ALL. Our investigators include leaders in adult and childhood ALL, pharmacogenomics, human genomics, clinical pharmacology, computational biology, bioinformatics, and biostatistics. We have three major aims, addressed in three highly integrated projects (all of which capitalize on front-line ALL clinical trials) and three Center cores. In Proect 1, we will define the landscape of genome variation among ALL subtypes and identify the inherited and somatically acquired genomic variation, along with other clinical features, that are associated with ALL treatment response in patients. In Project 2, we will identify the genome variation associated with de novo and acquired drug resistance in primary ALL cells from patients at diagnosis and at relapse, and will elucidate mechanisms by which genomic variation influences drug resistance and treatment response. In Project 3, we will identify genomic variation associated with specific serious adverse effects of antileukemic agents (osteonecrosis, hepatotoxicity, pancreatitis, and neuropathy), establishing mechanisms and testing interventions for the phenotype of osteonecrosis. Synergies in the Center stem from the substantial overlap in patients and genomic data among the three projects; the complementary expertise and prior collaborations among investigators; the leadership of our Administrative Core with extensive ties to existing pharmacogenomic, genomic, and clinical cancer networks; and uniform approaches to data analysis, management, integration, and deposition provided by our Cores. Our Center's overarching aim is to use the knowledge gained from the research in the three projects to build a comprehensive precision medicine approach to minimize relapse while also minimizing adverse effects. This Center will allow us to engage additional adult ALL and genomics collaborators, accelerate progress in the discovery and translation of genomics into more effective and less toxic treatments, and provide a paradigm for other diseases for the integration of genomic methods and knowledge into precision medicine.