Mycn and Medulloblastoma

Mycn 和髓母细胞瘤

• 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
• 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

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.

髓母细胞瘤是一种常见且多发的中枢神经系统肿瘤。 儿童时期的致命肿瘤。Sonic Hedgehog(SHH)和无翼的异常 信号对遗传学有贡献，然而这些途径在少数情况下被代表 肿瘤的症状。原癌基因Mycn是推动肿瘤细胞增殖的主要因素 发育中的小脑，并在SHH相关组织中高水平表达 髓母细胞瘤。Mycn在髓母细胞瘤发病机制中的作用 三项独立研究支持SHH像差的存在，这些研究表明 大多数人髓母细胞瘤表达Mycn，而Mycn在髓母细胞瘤中不表达 胎儿期后小脑正常。我们假设异常表达的是 MYCN在髓母细胞瘤的发病机制中起作用，并且靶向 针对Mycn的治疗将在这种疾病中显示出疗效。我们的长期目标 旨在阐明Mycn在髓母细胞瘤的发生和发展中的作用，以及 确定针对Mycn的治疗对小鼠和人类的影响 髓母细胞瘤。我们将描述一种遗传工程小鼠(GEM)模型 我们实验室发展的髓母细胞瘤同时表达Mycn和Mycn 这与现有的髓母细胞瘤GEM模型不同的是 P53突变(这在人类肿瘤中并不常见)不需要达到很高的水平 洞察力。 MYCN通过激活脂蛋白激酶PI3K而稳定。我们已经展示了小的 PI3K的分子抑制剂导致该癌蛋白在体外和体内的降解。 因此，我们将测试Mycn在维持肿瘤和支持肿瘤中的作用 多西环素关闭治疗MYCN诱导的髓母细胞瘤 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图谱，我们将处理培养的和异种移植 原发人髓母细胞瘤来源的肿瘤球体评估其重要性 Mycn作为治疗人髓母细胞瘤的靶点。 目的1.GLT1-TTA转基因小鼠的评价：TrE-MYCN/Luc作为GLT1-TTA转基因小鼠模型 人髓母细胞瘤。 目的2.转基因小鼠体内异构体选择性PI3K抑制剂的临床前试验 对于GLT1-TTA：TREMYCN/Luc，以及在人髓母细胞瘤肿瘤球体中。 目的3.使用PI3K抑制剂解决Mycn和microRNA靶标的作用 受Mycn调控，在体内维持髓母细胞瘤血管生成。