Mycn and Medulloblastoma

髓母细胞瘤是一种中枢神经系统肿瘤， 致命的儿童肿瘤英文名称：Sonic Hedgehog（SHH）and Wingless 信号传导有助于遗传学，然而这些途径在少数情况下代表 肿瘤。原癌基因Mycn是驱动肿瘤细胞增殖的主要因素。 小脑发育，并在高水平表达SHH相关 髓母细胞瘤Mycn在髓母细胞瘤发病机制中的作用 没有SHH畸变得到了三项独立研究的支持， 大多数人髓母细胞瘤表达Mycn，而Mycn在人髓母细胞瘤中不表达。 胎儿期后正常小脑。我们假设， Mycn有助于髓母细胞瘤的发病机制， 针对Mycn的疗法将在这种疾病中显示出有效性。我们的长期目标 目的是阐明Mycn在髓母细胞瘤发生和发展中的作用， 确定针对Mycn的治疗在鼠和人中的影响 髓母细胞瘤我们将描述基因工程小鼠（GEM）模型， 在我们的实验室中开发的髓母细胞瘤共表达Mycn和 荧光素酶在中枢神经系统，并不同于现有的创业板模型髓母细胞瘤， p53突变（这在人类肿瘤中并不常见）并不需要达到高水平， 外显率 Mycn通过激活脂质激酶PI 3 K而稳定。我们已经证明， PI 3 K的分子抑制剂导致这种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生长方面的作用。 通过使用强力霉素治疗MYCN驱动的髓母细胞瘤来关闭血管 MYCN转录，或使用小分子PI 3 K）抑制剂降解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分析，我们将治疗培养和异种移植 肿瘤球来源于原发性人髓母细胞瘤，以评估 Mycn作为人髓母细胞瘤的治疗靶点。 目标1。评估Glt 1-tTA：TRE-MYCN/Luc转基因小鼠作为糖尿病模型 人髓母细胞瘤 目标2.在转基因小鼠中的亚型选择性PI 3 K抑制剂的临床前测试 对于Glt 1-tTA：TREMYCN/Luc，以及在人髓母细胞瘤肿瘤球中。 目标3。使用PI 3 K抑制剂解决Mycn和microRNA靶标的作用 由Mycn调节，在维持髓母细胞瘤体内血管生成中。

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.