Embryonal Brain Tumor Networks

胚胎脑肿瘤网络

• 批准号: 8685406
• 负责人: Ernest Fraenkel
• 金额: $ 75.21万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685406
• 关键词: Affect; Algorithms; Behavior; Biological; Brain Neoplasms; Cancer Biology; Cancer Etiology; Cell Culture Techniques; ChIP-seq; Childhood; Childhood Brain Neoplasm; Clinical; Collaborations; Computing Methodologies; Copy Number Polymorphism; Data; Data Set; Drug Targeting; Environment; Epigenetic Process; Formalin; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genome; Genomics; Histologic; Hospitals; Human; Immunohistochemistry; Individual; Link; Malignant Neoplasms; Massive Parallel Sequencing; Measures; Methods; MicroRNAs; Modeling; Molecular; Molecular Profiling; Mutation; Nervous System Physiology; Neuraxis; Neurocognitive; Neurologic; Oncogenic; Outcome; Paraffin Embedding; Pathway interactions; Patients; Pattern; Pediatric Neoplasm; Phenotype; Plant Roots; Prize; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Sampling; Set protein; Signal Pathway; Slide; Somatic Mutation; Survival Rate; Survivors; System; Systems Biology; Techniques; Testing; Time; Training; Translational Research; Tumor Cell Line; Work; base; bisulfite; chromatin immunoprecipitation; data modeling; drug development; epigenome; epigenomics; exome sequencing; forest; innovation; mRNA Expression; medulloblastoma; mutant; network models; novel; novel strategies; novel therapeutics; overexpression; programs; protein expression; protein function; public health relevance; response; small hairpin RNA; small molecule; software development; therapeutic target; tool; transcriptome sequencing; treatment strategy; tumor; tumor growth

DESCRIPTION (provided by applicant): We propose an innovative, systems biology approach to uncover new therapeutic strategies for childhood embryonal tumors. Our project is a collaboration between labs in two separate Integrative Cancer Biology Program (ICBP) centers and a leading hospital-based translational research lab that is not within the ICBP network. Embryonal tumors are the most common central nervous system malignancies in childhood, and there is a pressing need for better therapies. Current survival rates range from 30 - 80%, and nearly all survivors have impaired neurological and neurocognitive function. Extensive genomic analysis of medulloblastomas, the most common embryonal tumors, failed to identify "driver genes" that could explain the origin of most tumors or suggest new strategies. Nevertheless, these tumors can be grouped into a small number of subtypes that share transcriptional patterns and clinical outcomes. We believe that it is time for a fundamentally new approach that seeks oncogenic "driver pathways" rather than "driver genes." As many different genomic changes can all affect the same driver pathway, such pathways cannot be uncovered by looking for recurring genomic changes. Rather, we will use a systems biology approach to identify these oncogenic driver pathways. We will collect comprehensive datasets in human medulloblastoma tumors and cell lines by measuring mutations, copy number variations, mRNA expression, miRNA expression and epigenomic data. We will then construct network models identifying shared pathways altered across many patients within a subtype. Finally, we will functionally test driver pathways nominated from the network modeling. By merging these diverse genomic and transcriptional data collected from tumors of individual patients, we will have an unprecedented ability to uncover the root causes of cancer, providing new therapeutic strategies. The collective expertise of our collaboration provides a unique environment for solving this critical barrier in cancer, by combining strengths in analyzing genomic data, modeling signaling pathways and transcriptional regulatory networks and clinical expertise in embryonal brain tumors. Together, we will generate and merge all types of transcriptional, genomic and epigenomic data, extract biologically-relevant network models and experimentally validate novel drug targets.

描述（由申请人提供）：我们提出了一种创新的系统生物学方法来发现儿童胚胎肿瘤的新治疗策略。我们的项目是两个独立的综合癌症生物学计划 (ICBP) 中心的实验室和一个不在 ICBP 网络内的领先的医院转化研究实验室之间的合作。胚胎肿瘤是儿童时期最常见的中枢神经系统恶性肿瘤，迫切需要更好的治疗方法。目前的存活率在 30% - 80% 之间，几乎所有幸存者的神经和神经认知功能均受损。对最常见的胚胎肿瘤髓母细胞瘤的广泛基因组分析未能识别出可以解释大多数肿瘤起源或提出新策略的“驱动基因”。然而，这些肿瘤可以分为少数具有共同转录模式和临床结果的亚型。我们认为，现在是时候采取一种全新的方法来寻找致癌的“驱动途径”而不是“驱动基因”。由于许多不同的基因组变化都会影响相同的驱动途径，因此无法通过寻找重复的基因组变化来发现这些途径。相反，我们将使用系统生物学方法来识别这些致癌驱动途径。我们将通过测量突变、拷贝数变异、mRNA 表达、miRNA 表达和表观基因组数据来收集人类髓母细胞瘤肿瘤和细胞系的综合数据集。然后，我们将构建网络模型，识别亚型内许多患者之间改变的共享途径。最后，我们将对网络建模指定的驱动程序路径进行功能测试。通过合并从个体患者的肿瘤收集的这些不同的基因组和转录数据，我们将拥有前所未有的能力来揭示癌症的根本原因，提供新的治疗策略。我们合作的集体专业知识为解决癌症的这一关键障碍提供了一个独特的环境，通过结合分析基因组数据、建模信号通路和转录调控网络的优势以及胚胎脑肿瘤的临床专业知识。我们将共同生成并合并所有类型的转录、基因组和表观基因组数据，提取生物学相关的网络模型并通过实验验证新的药物靶点。