Collaborating Mutations in Medulloblastoma

髓母细胞瘤中的协同突变

基本信息

批准号：
9149702
负责人：
MARTINE F. ROUSSEL (SHERR)
金额：
$ 44.3万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9149702
关键词：
Adult Affect Age Allografting Animals Blood - brain barrier anatomy Brain Bromodomain ChIP-seq Child Clinical Trials Cooperative Group Collaborations Complex Data Development Disease EZH2 gene Enzymes Epigenetic Process Evaluation FDA approved Funding Gene Expression Gene Silencing Histone H3 Histones Human In Vitro Incidence Lead Libraries Luciferases Lysine MYCN gene Maintenance Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of brain Methyltransferase Modification Molecular Multi-Institutional Clinical Trial Mus Mutation Names Neoplasm Metastasis Neoplasms Pathway interactions Patients Pattern Pemetrexed Peptides Pharmaceutical Preparations Post-Translational Protein Processing Proteins Radiosurgery Recurrence Regimen Resources Role SHH gene Sonic Hedgehog Pathway Subgroup Testing Therapeutic Therapeutic Intervention Xenograft procedure base chemotherapy combinatorial disorder subtype effective therapy epigenetic regulation experience gain of function gemcitabine genome sequencing genome-wide high throughput screening hindbrain human data improved in vivo inhibitor/antagonist insight loss of function mutation medulloblastoma mouse model neurodevelopment novel outcome forecast overexpression programs small molecule success therapeutic target transcriptome treatment effect treatment group tumor tumor growth tumorigenesis whole genome

项目摘要

Summary – Project 3 Medulloblastoma (MB) is a tumor of the hindbrain that occurs in children with a peak incidence between the ages of 3 and 7, although it can occur rarely in adults. Based on accumulating molecular evidence, medulloblastoma is now classified into four major subgroups. Two subgroups are characterized by constitutive activation of developmental pathways, Sonic Hedgehog (SHH) and Wingless (WNT). Group 3 (G3), in which C-MYC (MYC) is over-expressed, and Group 4 (G4), are less well characterized and carry the worse prognosis. During the last funding cycle, in collaboration with our P01 colleagues, we developed a mouse model that mimicked the histological and molecular features of human G3 MB. This mouse model allowed the identification of two FDA-approved drugs by high-throughput screening, that increased survival of mice bearing either mouse of human G3 MBs, when used alone or in combination. Recent genome-wide sequencing of MBs showed that mutations in enzymes that modify histone H3 are among the most common abnormalities in MB. In G3 MB, loss of function mutations of the histone H3 lysine 27 (H3K27) de-methylase KDM6A or mutually exclusive patterns of overexpression of the H3K27 methylase EZH2 drive elevated levels of histone H3 lysine 27 trimethylation. We will use our mouse model and patient- derived xenografts of G3 medulloblastoma to investigate the role of histone H3 modification in G3 MB, including specific evaluation of the contribution of EZH2 and KDM6A to G3 MB development and the epigenetic signature of G3 MBs. We will screen libraries of well-annotated and validated compounds targeting epigenetic modifers that will be assessed in mouse and human G3 tumor-bearing animals as single agents or in combination with current therapeutic regimens. These studies will provide new insights into the connections between MYC, epigenetics, neural development and MB tumorigenesis.

摘要 – 项目 3 髓母细胞瘤 (MB) 是一种发生于儿童的后脑肿瘤，其发病率高峰在 3 岁和 7 岁的儿童，尽管根据不断积累的分子证据，这种情况在成人中很少发生。髓母细胞瘤现在分为四个主要亚组，两个亚组的特征在于组成型。激活发育途径，Sonic Hedgehog (SHH) 和 Wingless (WNT)，其中。 C-MYC (MYC) 过度表达，而第 4 组 (G4) 的特征不太明确，且表现更差在上一个资助周期中，我们与 P01 同事合作开发了一种小鼠。该模型模拟了人类 G3 MB 的组织学和分子特征。通过高通量筛选鉴定出两种 FDA 批准的药物，可提高小鼠的存活率小鼠或人类 G3 MB，单独或组合使用时。最近的 MB 全基因组测序表明，修饰组蛋白 H3 的酶的突变是 MB 中最常见的异常之一是组蛋白 H3 赖氨酸的功能缺失突变。 27 (H3K27) 去甲基化酶 KDM6A 或 H3K27 甲基化酶过度表达的互斥模式 EZH2 驱动组蛋白 H3 赖氨酸 27 三甲基化水平升高我们将使用我们的小鼠模型和患者。 G3 髓母细胞瘤衍生的异种移植物，以研究组蛋白 H3 修饰在 G3 MB 中的作用，包括对 EZH2 和 KDM6A 对 G3 MB 发育的贡献的具体评估以及我们将筛选经过充分注释和验证的靶向化合物库。表观遗传修饰剂将作为单一药物在小鼠和人类 G3 荷瘤动物中进行评估，或与目前的治疗方案相结合。这些研究将为 MYC、表观遗传学、神经网络之间的联系提供新的见解。发育和MB肿瘤发生。