Core D: Biomarkers and Bioinformatics

摘要 核心D的总体目标是提供MPN-RC中初级标本的相关生物标记物分析 组织库以及来自所有MPN-RC临床试验和预期组织库的样本 努力。核心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化评估 组织库努力，以及基线和反应评估时间的治疗试验。其核心是 还将对其他以机制为基础的生物标志物(如血清细胞因子、基因 表达谱、细胞遗传学和组织病理学)，这与每个生物和临床研究有关 在项目1-4中。基因组图谱的使用将为项目1-3提供从基因上选择的能力 用于生物研究的注释样本，旨在调查体细胞突变之间的关系， 疾病发病机制的生物学特征，以及治疗的依赖性。这些化验的目标是 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的分析，这些项目是常见的。拟议的分析将导致 整合了大量有临床注释和细胞因子的 接受同种治疗的患者。此外，项目4中提议的临床试验是基于机械的，并且 源于项目1-3中的工作。相关的生物标志物分析直接与拟议的 这些治疗剂的作用机制将在项目4中进行研究。这些 研究将允许评估特定治疗干预的机制影响，并允许 我们要证明新的治疗靶点和途径。此外，这些研究还将允许进行生物学评估 对治疗应答者和无应答者进行比较，从而深入了解耐药机制。重要的是 我们开发了严格的组织工具，以维护数据完整性、可跟踪性和 在处理大规模涉及的数据量和种类时的可重复性标准 这个岩心的生物标志物分析。提供最先进的和新的生物标志物分析的集成 具有强大的临床前和临床研究的核心D将提供获得新基因组的独特机会， 对MPN发病机制的表观基因组学和生物学见解。

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.