Cellular and Molecular Origins of Medulloblastoma Subgroups

在过去的10年里，大约750名患有髓母细胞瘤的儿童接受了联合治疗 临床试验，估计费用超过1.5亿美元。尽管付出了巨大的努力，但几乎没有什么有意义的 分子数据已经产生，将为下一代临床研究提供信息。因此，所有 患者目前接受同样激进的手术、放射和化疗组合。这 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。vbl.使用 基因表达微阵列图谱，我们已经确定了人类髓母细胞瘤的亚群 基因表达、染色体改变、组织学和预后的不同模式。这一切的总和 研究表明，髓母细胞瘤由几个亚型组成，可能需要不同的 治疗的类型或强度；然而，我们仍然缺乏对这些亚组的全面了解 有必要开发新的治疗方法。我们小组和其他人的研究表明，大脑的不同亚群 肿瘤是由癌症干细胞(CSC)产生的，它们共享不同神经的基因表达谱 祖细胞，允许识别它们的候选起源细胞。我们的初步数据显示， 两个新出现的髓母细胞瘤亚群包含Sonic Hedgehog的激活突变 途径(这里称为SHH-亚群)和β-连环蛋白(CTNNB1-亚群)显示该基因 小脑前区颗粒神经元前体细胞和前体细胞的表达谱 神经上皮细胞(PCN)。这些数据表明，假设：不同的种群 发育中的后脑中的祖细胞容易获得不同的基因突变 将这些转化为CSC。由于这些CSC具有不同的细胞起源和分子特性，因此它们 产生表现出不同生物学和临床特征的疾病亚组。我们将对此进行测试 通过关注髓母细胞瘤的SHH和CTTV/VBF-亚组进行假说：(I)发展有史以来第一个 CI/V/VBf亚组疾病的自发小鼠模型；(Ii)确定SHH和CTNNB1亚组 由不同类型的CSC和相关的CSC生态位产生，(Iii)开发经批准的诊断测试 可以选择患有这些肿瘤的患者进行临床试验的SHH和CTWA/fif亚组肿瘤，以及 在一项大型前瞻性临床试验中验证CTNNB1疾病的预后意义。

Over the last 10 years approximately 750 children with medulloblastoma have been treated on consortiabased 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 CTTV/VBf-subgroups of medulloblastoma to: (i) develop the first ever spontaneous mouse model of CI/V/VBf-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 CTWA/fif-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.