Core D: Biomarkers and Bioinformatics

摘要 核心D的总体目标是提供MPN-RC中主要标本的相关生物标志物分析 组织库以及来自所有MPN-RC临床试验和前瞻性组织库的样本 努力Core D将对来自以下来源的所有MPN-RC样本进行体细胞基因组变异评估 组织库的工作，并从治疗试验在基线和时间的反应评估。核心 还将对其他基于机制的生物标志物（如血清细胞因子、基因）进行动态分析。 表达谱分析、细胞遗传学和组织病理学），其与每个生物学和临床研究相关 项目1-4。基因组图谱的使用将为项目1-3提供遗传选择的能力， 用于生物学研究的注释样品，旨在研究体细胞突变之间的关系， 疾病发病机制的生物学特征和治疗依赖性。这些试验的目的是 提供全面的遗传学和生物学相关研究，并帮助确定 项目4中临床试验的假设驱动的治疗干预的影响。核心也将执行 并分析项目1-3的检测试剂盒，这些检测试剂盒对这些项目是通用的。拟议的分析将导致 整合了大量临床注释的基因组、基因表达和细胞因子数据， 治疗的病人。同样，项目4中提出的临床试验也是基于机制的， 从项目1-3开始。相关的生物标志物测定与所提出的方法直接相关。 描述的治疗剂的作用机制，将在项目4中进行研究。这些 研究将允许对特定治疗干预的机制影响进行评估， 让我们来验证新的治疗靶点和途径。同时，这些研究将允许生物评估 治疗反应者和无反应者的差异，从而深入了解耐药机制。重要的是， 我们已经开发了严格的组织工具，以保持数据的完整性，可追溯性， 再现性标准时，处理的数量和各种数据涉及的大规模 生物标志物分析。提供的最先进和新型生物标志物测定的整合 核心D，具有强大的临床前和临床研究将提供一个独特的机会，获得新的基因组， 表观基因组和生物学的见解MPN发病机制。

Abstract The overall aim of Core D is to provide correlative biomarker analyses of primary specimens in the MPN-RC tissue bank as well as from samples arising from all MPN-RC clinical trials and prospective tissue banking efforts. Core D will carry out assessment of somatic genomic alterations on all MPN-RC samples derived from tissue banking efforts, and from therapeutic trials at baseline and the time of response assessment. The core will also carry out dynamic analyses of other mechanism-based biomarkers (such as serum cytokines, gene expression profiling, cytogenetics, and histopathology) which pertain to each of the biologic and clinical studies in Projects 1-4. The use of genomic profiling will provide Projects 1-3 with the ability to select genetically annotated samples for biologic studies aimed at investigating the relationship between somatic mutations, biological features of disease pathogenesis, and therapeutic dependencies. The goal of these assays is to provide comprehensive genetic and biologic correlative studies as well as to help determine the mechanistic impact of the hypothesis-driven therapeutic interventions of clinical trials in Project 4. The core will also perform and analyze assays for Project 1-3, which are common to these projects. The proposed analyses will result in integrated genomic, gene expression, and cytokine data of a large number of clinically annotated and homogenously treated patients. As well, the clinical trials proposed in Project 4 are mechanistically based, and stem from work in Projects 1-3. The correlative biomarker assays are directly related to the proposed mechanisms of action of the therapeutic agents delineated and which will be investigated in Project 4. These studies will allow for an assessment of the mechanistic impact of specific therapeutic interventions and allow us to credential novel therapeutic targets and pathways. As well, these studies will allow biological assessment of treatment responders and non-responders, thus giving insight into mechanisms of resistance. Importantly, we have developed rigorous organizational tools in order to maintain data integrity, traceability and reproducibility standards when dealing with the amount and the variety of data involved in the large-scale biomarker analyses for this core. The integration of state-of-the-art and novel biomarker assays offered by Core D, with robust preclinical and clinical studies will afford a unique opportunity to gain new genomic, epigenomic and biologic insights into MPN pathogenesis.