Integrative Oncogenomics of Multiple Myeloma

多发性骨髓瘤的综合肿瘤基因组学

• 批准号: 10226185
• 负责人: Nikhil C. Munshi
• 金额: $ 206.59万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226185
• 关键词: Address; Affect; Algorithms; Architecture; Automobile Driving; Basic Science; Behavior; Bioinformatics; Biological; Biology; Biometry; Bone Marrow; Cell Communication; Cells; Cessation of life; Clinical; Clinical Research; Clinical Sciences; Clinical Trials; Clonal Evolution; Collaborations; Communication; DNA Sequencing Facility; Dependence; Diagnosis; Disease; Disease Outcome; Disease remission; Drug resistance; Enhancers; Extramedullary; Funding; Genomic Instability; Genomics; Goals; HDAC6 gene; Individual; Institutes; International; Interruption; Lead; Lesion; Magnetic Resonance Imaging; Maintenance; Mediator of activation protein; Methods; Modeling; Molecular; Multiple Myeloma; Mutation; Newly Diagnosed; Outcome; PET/CT scan; Pathogenesis; Patient-Focused Outcomes; Patients; Pattern; Process; Prognosis; Program Research Project Grants; Randomized; Research Personnel; Residual Neoplasm; Resistance; Risk; Role; Sampling; Signal Transduction; Stromal Cells; Talents; Therapeutic; Tissues; Translating; Translations; Transplantation; United States; base; bench to bedside; bone cell; cancer genomics; cell growth; clinical practice; clinically relevant; collaborative trial; data and analysis portal; drug development; epigenomics; follow-up; improved; malignant phenotype; new therapeutic target; next generation; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; programs; relapse patients; response; risk stratification; sequencing platform; standard of care; stem; survival outcome; targeted sequencing; targeted treatment; transcriptome sequencing

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.

项目概要（总体） 这一更新申请源于我们成功的第一个四年的一个新的计划项目赠款资助， 2011年，它汇集了一组有才华的研究人员与基础生物学（DFCI和 Whitehead Institute at MIT）、临床科学（IFM）以及基因组和细胞信号传导（桑格研究所UK 和DFCI）。在过去4年的融资期内，我们有1。定义了器官移植在 新的药物; 2确立了分子微小残留病（MRD）在骨髓瘤中的作用。3.建立 MRI和PET/CT在MM诊断和随访中的作用。4.识别和验证编号 新的目标。和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的靶向测序平台，开发了一个管道，以确定 使用RNA-seq的突变，并开发了一个公开的数据分析门户网站（Canevolve.org）。基础上 该计划的总体具体目标是：1）确定维护是否可以 根据MRD状态以及达到MRD阴性状态是否提供更好的上级结局进行定制， 一项1260例患者的随机临床研究，并开发新的风险模型（项目1）。临床注释 来自该临床试验的患者样品将用于研究基因组和表观基因组相关性; 2）鉴定 表观基因组损伤和增强子依赖性的谱，其是发病机制、进展和 MM的临床结局（项目2）。新的临床相关的表观基因组为中心的目标确定将是 3）识别和验证负责持续MM细胞的分子回路/环 生长和发展的战略，中断这些循环作为一种新的治疗方法。（项目3）。新 靶向治疗药物将转化为临床试验，以改善患者的结果;以及4）定义 治疗对克隆进化影响和鉴定作为疾病预后基础的基因组不稳定性介质 和MM的进展（项目4）。确定的新临床相关过程将用于了解 进步的过程。这4个项目将得到行政和通信核心（1）的支持， 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）。这种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。