Cellular and Molecular Origins of Medulloblastoma Subgroups

摘要-项目4 髓母细胞瘤包括四种分子亚型，它们具有不同的表达（WNT，Sonic Hedgehog， [SHH]、第3组和第4组）。尽管存在这些差异，所有髓母细胞瘤儿童接受相同的治疗。 手术放疗化疗这种治疗不能治愈大多数第3类疾病， 对患有WNT-髓母细胞瘤的儿童的长期副作用。因此，今后努力治愈所有 患有髓母细胞瘤的儿童必须提供对疾病生物学的理解， 开发治愈性的、相对无毒的、亚型特异性的疗法。在上一个融资周期， 专注于了解WNT-髓母细胞瘤，补充我们的P01同事的其他研究 疾病亚型。我们鉴定了下菱形唇的祖细胞为WNT的起源- 髓母细胞瘤，并产生了这种疾病亚型的第一个小鼠模型。此外，使用整体 通过基因组测序（WGS），我们在髓母细胞瘤中发现了40多个新的突变，包括高度 WNT和SHH肿瘤的新候选癌基因DDX 3X中的复发突变。拟议的研究将 在这些数据的基础上，通过三个新的具体目标将解决我们的中心假设： 髓母细胞瘤亚型由不同的细胞信号驱动，这些信号可以靶向治疗增益。' 通过一系列全面的体外和体内表型和肿瘤发生试验，Aim 1将 确定DDX 3X在后脑发育和髓母细胞瘤中的作用。目标2将采用创新的， 多平台方法，整合了高通量药物筛选、细胞生物学测定和基因组学， 确定WNT-髓母细胞瘤的关键分子治疗靶点和匹配的抑制剂，包括DDX 3X。 目标3将测试目标2中确定的潜在新疗法在新的， 在具有WNT、SHH和第3组肿瘤的小鼠中进行的联合、神经外科、放射和化学疗法试验。 通过这种方式，我们将对新的亚型特异性治疗进行最严格的临床前测试。 迄今为止，髓母细胞瘤，从而优化组合治疗的选择， 临床试验

Summary – Project 4 Medulloblastoma encompasses four molecular subtypes that have different prognoses (WNT, Sonic Hedgehog [SHH], Group-3 and Group-4). Despite these differences, all children with medulloblastoma receive the same surgery, radiation, and chemotherapy. This treatment fails to cure most cases of Group-3 disease, and inflicts debilitating long-term side effects on children with WNT-medulloblastoma. Therefore, future efforts to cure all children with medulloblastoma must provide an understanding of disease biology that can guide the development of curative, relatively non-toxic, subtype-specific therapies. During the last funding cycle we focused on understanding WNT-medulloblastoma, complementing studies by our P01 colleagues of the other disease subtypes. We identified progenitor cells of the lower rhombic lip as the origin of WNT- medulloblastoma, and generated the first mouse model of this disease subtype. In addition, using whole genome sequencing (WGS), we identified over 40 novel mutations in medulloblastoma, including highly recurrent mutations in a new candidate oncogene of WNT and SHH-tumors, DDX3X. The proposed studies will build on these data, and through three new Specific Aims will address our central hypothesis: `Medulloblastoma subtypes are driven by distinct cell signals that can be targeted for therapeutic gain.' Through a comprehensive series of in vitro and in vivo phenotype and tumorigenesis assays, Aim 1 will determine the role of DDX3X in hindbrain development and medulloblastoma. Aim 2 will employ an innovative, multiplatform approach that integrates high-throughput drug screening, cell biology assays, and genomics to pinpoint key molecular therapeutic targets and matched inhibitors of WNT-medulloblastoma, including DDX3X. Aim 3 will test the subtype-specificity of potential new therapies identified in Aim 2 in the context of novel, combination, neurosurgical, irradiation, and chemotherapy trials in mice with WNT, SHH and Group-3 tumors. In this manner we will perform the most rigorous preclinical testing of new subtype-specific treatments of medulloblastoma to date, and thereby optimize the selection of combination treatments for translation to clinical trial.