Cellular and Molecular Origins of Medulloblastoma Subgroups

在过去的10年中，大约750名患有髓母细胞瘤的儿童在基于财团的临床试验中接受了治疗，估计费用超过1.5亿美元。尽管付出了巨大的努力，但几乎没有产生有意义的分子数据，这些数据将为下一代临床研究提供信息。因此，所有患者目前都接受相同的手术，放疗和化疗的积极组合。这种治疗对幸存者造成毁灭性的副作用，并未能治愈约四分之一的患者。使用基因表达微阵列分析，我们已经确定了人类髓母细胞瘤的亚群， 不同的基因表达模式、染色体改变、组织学和预后。这项研究的总结表明，髓母细胞瘤包括几个可能需要不同类型或强度治疗的亚组;然而，我们仍然缺乏对这些亚组的全面了解，这些亚组是开发新治疗所必需的。我们小组和其他人的工作表明，脑肿瘤的亚组是由癌症干细胞（CSC）产生的，这些干细胞共享不同神经祖细胞的基因表达谱，从而可以识别其候选细胞来源。我们的初步数据显示，两个新出现的髓母细胞瘤亚组，包含激活突变的Sonic hedgehog途径（从这里称为SHH亚组）和β-连环蛋白（CTNNB 1亚组）显示颗粒神经元前体细胞（GNPC）和前体细胞的基因表达谱小脑神经上皮细胞（PCN），分别。这些数据表明了这样的假设：发育中的后脑内的祖细胞的不同群体倾向于获得不同的基因突变， 将其转化为CSC。由于这些CSC具有不同的细胞起源和分子特性，因此它们产生显示不同生物学和临床特征的疾病亚组。我们将通过关注成神经管细胞瘤的SHH和CTNNB 1亚组来检验这一假设，以：（i）开发有史以来第一个CTNNB 1亚组疾病的自发小鼠模型;（ii）确定SHH和CTNNB 1亚组是否由不同类型的CSC和相关CSC小生境产生，（iii）开发批准的SHH和CTNNB 1亚组肿瘤的诊断测试，可以选择患有这些肿瘤的患者进行临床试验， 在大型前瞻性临床试验中验证CTNNB 1疾病的预后意义。

Over the last 10 years approximately 750 children with medulloblastoma have been treated on consortia-based clinical trials at an estimated cost of over $150 million. Despite this enormous effort, little meaningful molecular data have been generated that will inform the next generation of clinical studies. Consequently, all patients currently receive the same aggressive combination of surgery, radiation and chemotherapy. This treatment inflicts devastating side effects on survivors and fails to cure about one quarter of patients. Using gene expression microarray profiling, we have identified subgroups of human medulloblastoma that display distinct patterns of gene expression, chromosomal alteration, histology and prognosis. The sum of this research suggests that medulloblastoma comprises several subgroups that are likely to require different types or intensities of therapy; however, we still lack the comprehensive understanding of these subgroups necessary to develop new treatments. Work from our group and others has shown that subgroups of brain tumors are generated by cancer stem cells (CSC) that share the gene expression profiles of distinct neural progenitor cells, allowing the identification of their candidate cells-of-origin. Our preliminary data show that two emerging subgroups of medulloblastoma that contain activating mutations in the Sonic hedgehog pathway (from here termed SHH-subgroup) and BETA-CATENIN (CTNNB1-subgroup) display the gene expression profiles of granule neuron precursor cells (GNPC) and precursor cells within the precerebellar neuroepithelium (PCN), respectively. These data suggest the hypothesis that: distinct populations of progenitor cells within the developing hindbrain are predisposed to acquire different gene mutations that transform these into CSC. Since these CSC have distinct cellular origins and molecular properties, then they generate disease subgroups that display different biological and clinical characteristics. We will test this hypothesis by focusing on the SHH and CTNNB1-subgroups of medulloblastoma to: (i) develop the first ever spontaneous mouse model of CTNNB1-subgroup disease; (ii) Determine if SHH and CTNNB1-subgroups are generated by distinct types of CSC and associated CSC niches, (iii) Develop approved diagnostic tests of SHH and CTNNB1-subgroup tumors that can select patients with these tumors for clinical trial, and validate the prognostic significance of CTNNB1- disease in a large prospective clinical trial.