An Investigation of Radial Glia as the Source of Ependymoma Stem Cells

描述（由申请人提供）：室管膜瘤是脑和脊髓的肿瘤。在过去的二十年里，这种疾病的治疗方法和死亡率几乎没有变化，这突出了对新疗法的巨大需求。室管膜瘤之间的组织学相似性使研究人员将这些肿瘤作为一个单一的实体来治疗;但我们已经表明，来自中枢神经系统不同区域的室管膜瘤包括离散的临床和分子亚型，这表明它们是不同的疾病。因此，当代治疗室管膜瘤患者的努力必须关注这些疾病亚型的生物学基础，并在必要时开发亚型特异性治疗。在上一个资助周期中，我们开发了一种跨物种基因组学方法，该方法表征了人类室管膜瘤的基因组亚型，并将这些与小鼠中的神经干细胞相匹配，以生成该疾病的准确模型。我们将在这项工作的基础上完成三个特定目标，旨在测试中心假设，即“室管膜瘤亚型是由不同的细胞信号驱动的，这些细胞信号可以靶向治疗增益。目标1将 采用新的“病毒库”筛选来测试我们先前在室管膜瘤中鉴定的前90个候选癌基因和40个肿瘤抑制基因的体内致癌作用。因此，我们将产生一个“诊所”的小鼠，概括了人类室管膜瘤亚型的全谱。目标2将使用高通量药物筛选、全激酶组结合和细胞生物学测定来询问目标1中开发的模型，以确定维持每种室管膜瘤亚型的关键细胞信号，这些室管膜瘤亚型因此可能用作治疗靶标。将这些数据与人类和小鼠肿瘤的遗传分析相结合，将进一步验证候选药物靶点。目标2中确定的靶向信号治疗的未来临床试验 将要求选择具有适当疾病亚型的患者。因此，目标3将开发一种稳健的Affyssin Quantigene检测方法，以使用福尔马林固定石蜡包埋组织可靠快速地诊断室管膜瘤亚型。

DESCRIPTION (provided by applicant): Ependymomas are tumors of the brain and spinal cord. Treatment approaches and mortality rates for this disease have changed little over the last twenty years, highlighting the great need for new therapies. Histologic similarities among ependymomas have led investigators to treat these tumors as a single entity; but we have shown that ependymomas from different regions of the central nervous system include discrete clinical and molecular subtypes, suggesting they are different diseases. Thus, contemporary efforts to cure all patients with ependymoma must be concerned with understanding the biological basis of these disease subtypes, and where necessary, developing subtype-specific therapies. During the last funding cycle we developed a cross- species genomics approach that characterized genomic subtypes of human ependymoma and matched these with neural stem cells in the mouse to generate accurate models of the disease. We will build on this work to complete three Specific Aims designed to test the central hypothesis that 'Ependymoma subtypes are driven by distinct cell signals that can be targeted for therapeutic gain.' Aim 1 will employ new 'virus-pool' screens to test the in vivo oncogenic role of the top 90 candidate oncogenes and 40 tumor suppressor genes that we previously identified in ependymoma. We will thereby generate a 'clinic' of mice that recapitulate the full spectrum on human ependymoma subtypes. Aim 2 will interrogate the models developed in Aim 1 using high- throughput drug screens, kinome-wide binding and cell biology assays to pinpoint the key cell signals that maintain each ependymoma subtype that might therefore serve as therapeutic targets. Integration of these data with genetic analyses of human and mouse tumors will further validate candidate drug targets. Future clinical trials of therapies that target signals identified in Aim 2 will demand the selection of patients with the appropriate disease subtype. Therefore, Aim 3 will develop a robust Affymetrix Quantigene assay to reliably and rapidly diagnose ependymoma subtypes using formalin fixed paraffin embedded tissue.