Integrative Oncogenomics of Multiple Myeloma

项目总结(总体) 此续签申请源于我们成功地完成了一项新计划项目赠款的前四年，该项目资助于 2011年，汇集了一批具有基础生物学专业知识的有才华的研究人员(DFCI和 MIT怀特黑德研究所)、临床科学(IFM)以及基因组和细胞信号(英国桑格研究所 和DFCI)。在前4年的资助期内，我们1.明确了移植在 新药物；2确定了分子微小残留病(MRD)在骨髓瘤中的作用。3.成立 MRI和PET/CT联合检查在多发性骨髓瘤诊断和随访中的作用4.识别和验证的号码 新的目标。以及5.MM中使用的克隆进化和突变特征的定义模式。 我们的计划还开发了新颖的靶向测序平台，开发了一种流水线识别 利用RNA-seq研究突变，并开发了一个公开可用的数据分析门户网站(Canevelve.org)。在基础上建设 这些进步，该计划的总体具体目标是1)确定维护是否可以 根据MRD状态以及实现MRD阴性状态是否提供更好的结果 一项1260名患者的随机临床研究并开发新的风险模型(项目1)。临床注解 这项临床试验的患者样本将被用于研究基因组和表观基因组的相关性；2)识别 表观基因组损伤和增强子依赖的光谱是发病、进展和 MM的临床结果(项目2)。新的临床相关表观基因组中心靶点将被确定 进一步验证；3)识别和验证负责连续MM细胞的分子回路/回路 作为一种新的治疗方法，我们可以开发出阻断这些环路的策略。(项目3)。新的 靶向治疗药物将被转化为临床试验，以改善患者的预后；以及4)定义 治疗对克隆进化的影响和确定疾病预后的基因组不稳定介质 和MM的进展(项目4)。确定的新的临床相关过程将用于理解 进步的过程。这4个项目将由行政和通信核心(1)提供支助， 临床和组织核心(2)；基因组学核心(3)；基因组测序核心(4)和生物统计学和 生物信息学核心(5)。这一独特的合作努力将提高我们对骨髓瘤生物学的理解 并为这种目前无法治愈的疾病定义一种新的治疗模式。

Project Summary (Overall) This renewal application stems from our successful first four years of a new program project grant funded in 2011, which brings together a talented group of investigators with expertise in basic biology (DFCI and Whitehead Institute at MIT), clinical science (IFM), as well as genomic and cell signaling (Sanger Institute UK and DFCI). During the prior 4 years of funding period, we have 1. defined the role of transplant in the era of novel agents; 2 Established the role of molecular minimal residual disease (MRD) in myeloma. 3. Established the role of both MRI and PET/CT in diagnosis and follow up of MM patients. 4. Identified and Validated number of novel targets. and 5. Defined patterns of clonal evolution and mutational signatures being utilized in MM. Our program has also developed novel targeted sequencing platform, developed a pipeline to identify mutations using RNA-seq, and developed a publicly available data analysis portal (Canevolve.org). Building on these advances, The overall specific objectives of the program are 1) To determine whether maintenance can be tailored based upon MRD status and whether achieving MRD negative status provides superior outcome In a 1260 patient randomized clinical study and to develop novel risk model (Project 1). Clinically annotated patient samples from this clinical trial will be utilized to study genomic and epigenomic correlates; 2) To identify the spectrum of epigenomic lesions and enhancer dependencies that underlie pathogenesis, progression, and clinical outcome in MM. (Project 2). New clinically-relevant epigenomic-centered targets identified will be validated further; 3) To identify and validate the molecular circuits/loops responsible for continued MM cell growth and develop strategies to interrupt these loops as a novel therapeutic approach. (Project 3). New targeted therapeutic agents will be translated to clinical trials to improve patient outcome; and 4) To define the impact of therapy on clonal evolution and identify mediators of genomic instability underlying disease prognosis and progression in MM (Project 4). New clinically relevant processes identified will be used to understand process of progression. These 4 projects will be supported by Administrative and Communication Core (1), Clinical and Tissue Core (2); Genomics Core (3); Genomic Sequencing Core (4) and Biostatistical and Bioinformatics Cores (5). This unique collaborative effort will improve our understanding of myeloma biology and define a new treatment paradigm for this presently incurable disease.