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）：中枢神经系统的肿瘤髓母细胞瘤是一种常见且经常致命的儿童肿瘤。声音刺猬（SHH）和无翼信号传导的异常有助于遗传学，但是这些途径在少数肿瘤中表示。原始癌基因MYCN是驱动发育中的小脑增殖的主要因素，在SHH相关的髓母细胞瘤中以高水平表达。三项独立的研究表明，在没有SHH畸变的情况下，MYCN在缺乏SHH畸变的情况下的作用，表明大多数人类髓母细胞瘤Express MYCN MYCN，而MyCN在胎儿阶段后在正常的小脑中未表达。我们假设MYCN的异常表达有助于髓母细胞瘤的发病机理，而针对MYCN的靶向疗法将在该疾病中显示出疗效。我们的长期目标是阐明MYCN在髓母细胞瘤的启动和进展中的作用，并确定针对MYCN在鼠类和人类髓母细胞瘤中针对MYCN的疗法的影响。我们将表征在实验室中开发的髓样细胞瘤的基因工程小鼠模型（GEM）模型，该模型在CNS中共表达MYCN和荧光素酶，并且与现有的p53突变中的髓母细胞瘤的GEM模型不同（在人类肿瘤中是罕见的）。 MYCN通过激活脂质激酶PI3K稳定。我们已经表明，PI3K的小分子抑制剂导致这种癌蛋白在体外和体内降解。因此，我们将通过使用多敏囊线处理MYCN驱动的髓母细胞瘤来测试MYCN在维持肿瘤和支持肿瘤脉管中的作用，以转录MYCN，或使用小分子PI3K）抑制剂降低了MYCN。我们将比较包括microRNA分析在内的鼠和人类肿瘤之间的遗传和表观遗传异常，我们将处理源自原代人类髓母细胞瘤以评估MYCN作为人类髓母细胞瘤中疗法靶点的重要性的培养和异种移植肿瘤。 AIM 1。对GLT1-TTA的小鼠转基因评估：TRE-MYCN/LUC作为人髓母细胞瘤的模型。 AIM 2。临床前测试GLT1-TTA的小鼠转基因中的同工型选择性PI3K抑制剂：Tremycn/Luc和人髓母细胞瘤肿瘤。 AIM 3。使用PI3K抑制剂来解决由MYCN调节的MyCN和microRNA靶标的在体内维持髓母细胞瘤血管生成方面的作用。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，目前的疗法通常无效。转录因子MYCN在这些肿瘤的大多数中表达，我们假设的事件与肿瘤形成有关。该应用的长期目标是表征我们实验室中开发并由MYCN驱动的髓母细胞瘤的小鼠模型，以阐明MYCN作为该疾病的治疗靶点的重要性。我们还确定了MYCN的小分子抑制剂，该抑制剂将在此和衍生模型中进行测试。这项研究将阐明MYCN作为髓母细胞瘤的治疗靶标的重要性，并将评估可能将其可能转化为患有这种重要肿瘤的儿童的MYCN抑制剂。