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（由申请人提供）：髓母细胞瘤是一种中枢神经系统肿瘤，是一种常见且经常致命的儿童肿瘤。 Sonic Hedgehog (SHH) 和 Wingless 信号传导的异常会影响遗传学，但这些通路仅在少数肿瘤中存在。原癌基因 Mycn 是驱动发育中小脑增殖的主要因素，在 SHH 相关髓母细胞瘤中高水平表达。三项独立研究支持 Mycn 在不存在 SHH 畸变的髓母细胞瘤发病机制中的作用，显示大多数人类髓母细胞瘤表达 Mycn，而 Mycn 在胎儿期后的正常小脑中不表达。我们假设 Mycn 的异常表达导致了髓母细胞瘤的发病机制，并且针对 Mycn 的靶向治疗将在这种疾病中显示出疗效。我们的长期目标是阐明 Mycn 在髓母细胞瘤发生和进展中的作用，并确定针对 Mycn 的疗法对小鼠和人类髓母细胞瘤的影响。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 CNS 中共表达 Mycn 和荧光素酶，并且与现有的髓母细胞瘤 GEM 模型的不同之处在于 p53 突变（这在人类肿瘤中并不常见）不需要达到高渗透率。 Mycn 通过激活脂质激酶 PI3K 来稳定。我们已经证明，PI3K 的小分子抑制剂会导致这种癌蛋白在体外和体内降解。因此，我们将通过使用强力霉素关闭 MYCN 转录或使用小分子 PI3K）抑制剂来降解 Mycn 来治疗 MYCN 驱动的髓母细胞瘤，从而测试 Mycn 在维持肿瘤和支持肿瘤脉管系统方面的作用。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，并且我们将处理源自原发性人类髓母细胞瘤的培养和异种移植肿瘤球，以评估 Mycn 作为人类髓母细胞瘤治疗靶点的重要性。目标 1. 评估 Glt1-tTA:TRE-MYCN/Luc 转基因小鼠作为人髓母细胞瘤模型的效果。目标 2. 在 Glt1-tTA:TREMYCN/Luc 转基因小鼠和人髓母细胞瘤肿瘤球中对异构体选择性 PI3K 抑制剂进行临床前测试。目标 3. 使用 PI3K 抑制剂来解决 Mycn 和 Mycn 调节的 microRNA 靶标在维持体内髓母细胞瘤血管生成中的作用。公共卫生相关性：髓母细胞瘤是儿童常见且经常致命的肿瘤，目前的治疗方法往往无效。转录因子 Mycn 在大多数肿瘤中表达，我们假设这一事件与肿瘤形成有关。本申请的长期目标是表征我们实验室开发并由 MYCN 驱动的髓母细胞瘤小鼠模型，以阐明 Mycn 作为该疾病治疗靶点的重要性。我们还确定了 MYCN 的小分子抑制剂，将在此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，并将评估一种可能应用于患有这种重要肿瘤的儿童的 Mycn 抑制剂。