Mycn and Medulloblastoma

Mycn 和髓母细胞瘤

基本信息

批准号：
8204726
负责人：
WILLIAM A WEISS
金额：
$ 31.1万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8204726
关键词：
Address Age Agreement Anaplasia Apoptosis Automobile Driving Autopsy Biology Blood Vessels Brain Brain Neoplasms Catalytic Domain Central Nervous System Neoplasms Cerebellum Characteristics Child Clinical Collaborations Development Diagnostic Neoplasm Staging Disease Doxycycline Epigenetic Process Erinaceidae Evaluation Event Gene Expression Genes Genetic Genetically Engineered Mouse Genomics Human In Vitro Laboratories Lead Link Lipids Luciferases MYCN gene Maintenance Malignant Neoplasms Measures Mediating MicroRNAs Minority Modeling Mus Mutation Natural History Natural regeneration Oncogene Proteins Outcome Pathogenesis Pathway interactions Patients Pediatric Neoplasm Penetrance Phosphotransferases Play Preclinical Testing Protein Isoforms Proteins Proto-Oncogenes Role Safety Signal Transduction Staging System Testing Tetanus Helper Peptide Toxic effect Transgenic Mice Translating Tumor stage WNT Signaling Pathway Xenograft procedure angiogenesis c-myc Genes fetal high risk human disease in vivo inhibitor/antagonist medulloblastoma mouse model small molecule therapeutic target transcription factor tumor tumor initiation tumor progression tumorigenesis

项目摘要

Medulloblastoma, a tumor of the central nervous system, is a common and frequently lethal tumor of childhood. Abnormalities in Sonic Hedgehog (SHH) and Wingless signaling contribute to genetics, however these pathways are represented in a minority of tumors. The proto-oncogene Mycn is the major factor driving proliferation in the developing cerebellum, and is expressed at high levels in SHH-associated medulloblastoma. A role for Mycn in the pathogenesis of medulloblastoma in the absence of SHH aberrations is supported by three independent studies showing a majority of human medulloblastomas express Mycn, whereas Mycn is not expressed in normal cerebellum after fetal stages. We hypothesize that aberrant expression of Mycn contributes to the pathogenesis of medulloblastoma, and that targeted therapies against Mycn will show efficacy in this disease. Our long term objectives are to clarify the role of Mycn in the initiation and progression of medulloblastoma, and to determine the impact of therapies directed against Mycn in murine and human medulloblastoma. We will characterize a genetically engineered mouse (GEM) model for medulloblastoma developed in our laboratory that co-expresses both Mycn and luciferase in the CNS, and that differs from existing GEM models for medulloblastoma in that p53 mutation (which is uncommon in human tumors) is not required to achieve high penetrance. Mycn is stabilized through activation of the lipid kinase PI3K. We have shown that small molecule inhibitors of PI3K lead to degradation of this oncoprotein in-vitro and in-vivo. We will therefore test the role of Mycn in maintaining tumors and in supporting tumor vasculature by treating MYCN-driven medulloblastomas using doxycyline to turn off MYCN transcriptionally, or using small molecule PI3K) inhibitors to degrade Mycn. We will compare genetic and epigenetic abnormalities between murine and human tumors, including microRNA profiling, and we will treat cultured and xenotransplated tumorspheres derived from primary human medulloblastomas to assess the importance of Mycn as a therapeutic target in human medulloblastoma. Aim 1. Evaluation of mice transgenic for Glt1-tTA:TRE-MYCN/Luc as a model for human medulloblastoma. Aim 2. Preclinical testing of isoform-selective PI3K inhibitors in mice transgenic for Glt1-tTA:TREMYCN/Luc, and in human medulloblastoma tumorspheres. Aim 3. Use of PI3K inhibitors to address a role for Mycn and microRNA targets regulated by Mycn, in maintaining medulloblastoma angiogenesis in vivo.

髓母细胞瘤是一种中枢神经系统肿瘤，是一种常见且常见的肿瘤儿童时期致命的肿瘤。 Sonic Hedgehog (SHH) 和 Wingless 中的异常信号传导对遗传学有贡献，但这些途径只占少数肿瘤。原癌基因Mycn是驱动细胞增殖的主要因素发育中的小脑，并在 SHH 相关的细胞中高水平表达髓母细胞瘤。 Mycn 在髓母细胞瘤发病机制中的作用三项独立研究证实不存在 SHH 像差大多数人髓母细胞瘤表达 Mycn，而 Mycn 不表达胎儿期后的正常小脑。我们假设异常表达 Mycn 有助于髓母细胞瘤的发病机制，并且靶向针对 Mycn 的疗法将对这种疾病显示出疗效。我们的长期目标旨在阐明 Mycn 在髓母细胞瘤发生和进展中的作用，并确定针对 Mycn 的疗法对小鼠和人类的影响髓母细胞瘤。我们将描述基因工程小鼠 (GEM) 模型的特征我们实验室开发的髓母细胞瘤共表达 Mycn 和 CNS 中的荧光素酶，这与现有的髓母细胞瘤 GEM 模型不同 p53 突变（在人类肿瘤中并不常见）不需要达到高外显率。 Mycn 通过激活脂质激酶 PI3K 来稳定。我们已经证明了小 PI3K 分子抑制剂会导致该癌蛋白在体外和体内降解。因此，我们将测试 Mycn 在维持肿瘤和支持肿瘤方面的作用通过使用强力霉素关闭 MYCN 驱动的髓母细胞瘤来治疗脉管系统 MYCN 转录，或使用小分子 PI3K) 抑制剂来降解 Mycn。我们将比较小鼠和人类肿瘤之间的遗传和表观遗传异常，包括 microRNA 分析，我们将处理培养和异种移植来自原发性人髓母细胞瘤的肿瘤球以评估重要性 Mycn 作为人类髓母细胞瘤的治疗靶点。目的 1. 评估 Glt1-tTA:TRE-MYCN/Luc 转基因小鼠作为模型人类髓母细胞瘤。目标 2. 转基因小鼠中异构体选择性 PI3K 抑制剂的临床前测试对于 Glt1-tTA:TREMYCN/Luc 以及人髓母细胞瘤肿瘤球。目标 3. 使用 PI3K 抑制剂来发挥 Mycn 和 microRNA 靶标的作用受 Mycn 调节，维持体内髓母细胞瘤血管生成。