Mycn and Medulloblastoma

Mycn 和髓母细胞瘤

基本信息

批准号：
8410037
负责人：
WILLIAM A WEISS
金额：
$ 29.23万
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/8410037
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的肿瘤，是一种常见的肿瘤童年的致命肿瘤。声音刺猬（SHH）和无翅的异常信号传导有助于遗传学，但是这些途径在少数群体中表示肿瘤。原始癌基因MYCN是驱动增殖的主要因素开发小脑，并在SHH相关的高水平表达髓母细胞瘤。 MYCN在髓母细胞瘤的发病机理中的作用三项独立研究表明，没有SHH畸变的缺乏大多数人类髓母细胞表达MYCN，而MYCN并未表达胎儿阶段后的正常小脑。我们假设这种异常表达的表达 MYCN有助于髓母细胞瘤的发病机理，并针对性针对MYCN的疗法将在该疾病中表现出功效。我们的长期目标是要阐明MYCN在髓母细胞瘤的启动和进展中的作用，以及确定针对MYCN在鼠和人类中针对MYCN的疗法的影响髓母细胞瘤。我们将表征一个基因工程的鼠标（GEM）模型髓母细胞瘤在我们的实验室中开发，该实验室共同表达MYCN和中枢神经系统中的荧光素酶，这与现有的GEM模型不同 p53突变（在人类肿瘤中并不常见）才能达到高外观。 MYCN通过激活脂质激酶PI3K稳定。我们已经表明了很小的 PI3K的分子抑制剂会导致这种癌蛋白体内和体内的肿瘤降解。因此，我们将测试MYCN在维持肿瘤和支撑肿瘤中的作用通过使用多西囊素处理MyCN驱动的髓母细胞瘤来关闭脉管系统 MYCN转录，或使用小分子PI3K）抑制剂降解mycn。我们将比较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源自原代人髓母细胞瘤来评估重要性的肿瘤球 MYCN作为人类髓母细胞瘤的治疗靶标。 AIM 1。对GLT1-TTA的小鼠转基因的评估：TRE-MYCN/LUC作为模型人髓母细胞瘤。 AIM 2。小鼠转基因的同工型选择PI3K抑制剂的临床前测试用于GLT1-TTA：Tremycn/Luc，以及人类髓母细胞瘤肿瘤。目标3。使用PI3K抑制剂来解决MyCN和MicroRNA靶标的角色由MYCN调节，在体内维持髓母细胞瘤血管生成。