Mycn and Medulloblastoma

Mycn 和髓母细胞瘤

• 批准号: 7748006
• 负责人: WILLIAM A WEISS
• 金额: $ 32.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/7748006
• 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; 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; TP53 gene; 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; public health relevance; small molecule; therapeutic target; transcription factor; tumor; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Medulloblastoma is a common and frequently lethal tumor of children, for which current therapies are often ineffective. The transcription factor Mycn is expressed in the majority of these tumors, an event we hypothesize is linked to tumor formation. The long term objective of this application is to characterize a mouse model for medulloblastoma developed in our laboratory and driven by MYCN, to clarify the importance of Mycn as a therapeutic target in this disease. We have also identified a small molecule inhibitor of MYCN, that will be tested in this and derivative models. This study will clarify the importance of Mycn as a therapeutic target in medulloblastoma, and will evaluate a Mycn inhibitor that could potentially be translated to children with this important tumor.

描述(申请人提供)：髓母细胞瘤是一种中枢神经系统肿瘤，是一种常见的儿童致命性肿瘤。Sonic Hedgehog(SHH)和Wingless信号通路的异常与遗传学有关，但这些通路在少数肿瘤中存在。原癌基因Mycn是小脑发育过程中的主要增殖因子，在SHH相关的髓母细胞瘤中高水平表达。在没有SHH异常的情况下，Mycn在髓母细胞瘤的发病机制中的作用得到了三项独立研究的支持，这些研究表明，大多数人髓母细胞瘤都表达Mycn，而Mycn在胎儿期后的正常小脑中不表达。我们假设Mycn的异常表达在髓母细胞瘤的发病机制中起作用，针对Mycn的靶向治疗将在该疾病中显示出疗效。我们的长期目标是阐明Mycn在髓母细胞瘤的发生和发展中的作用，并确定针对Mycn的治疗对鼠和人髓母细胞瘤的影响。我们将描述我们实验室开发的髓母细胞瘤基因工程小鼠(GEM)模型，该模型在中枢神经系统中同时表达Mycn和荧光素酶，它与现有的髓母细胞瘤GEM模型的不同之处在于，P53突变(这在人类肿瘤中不常见)不需要达到高外显性。MYCN通过激活脂蛋白激酶PI3K而稳定。我们已经证明，PI3K的小分子抑制剂在体外和体内都能导致这种癌蛋白的降解。因此，我们将测试Mycn在维持肿瘤和支持肿瘤血管方面的作用，方法是使用多西环素在转录上关闭MYCN，或使用小分子PI3K抑制剂降解Mycn来治疗MYCN驱动的髓母细胞瘤。我们将比较小鼠和人类肿瘤之间的遗传和表观遗传学异常，包括microRNA图谱，我们将处理来自原发人类髓母细胞瘤的培养和异种移植的肿瘤球体，以评估Mycn作为人类髓母细胞瘤治疗靶点的重要性。目的1.GLT1-TTA转基因小鼠的实验研究：TrE-MYCN/Luc作为人髓母细胞瘤模型。目的2.在转GLT1-TTA：TREMYCN/Luc的小鼠和人髓母细胞瘤肿瘤球体中进行PI3K异构体选择性抑制剂的临床前试验。目的3.使用PI3K抑制剂解决Mycn和由Mycn调控的microRNA靶点在维持髓母细胞瘤体内血管生成中的作用。公共卫生相关性：髓母细胞瘤是一种常见且经常致命的儿童肿瘤，目前的治疗方法往往无效。转录因子Mycn在大多数肿瘤中都有表达，我们推测这一事件与肿瘤的形成有关。这项应用的长期目标是描述我们实验室建立的、由MYCN驱动的髓母细胞瘤小鼠模型的特征，以阐明Mycn作为该疾病治疗靶点的重要性。我们还确定了一种MYCN的小分子抑制剂，将在这个模型和衍生模型中进行测试。这项研究将阐明Mycn作为髓母细胞瘤治疗靶点的重要性，并将评估一种Mycn抑制剂，该抑制剂可能被翻译到患有这种重要肿瘤的儿童身上。