Cellular and Molecular Origins of Medulloblastoma Subgroups

髓母细胞瘤亚群的细胞和分子起源

• 批准号: 8243627
• 负责人: Richard James Gilbertson
• 金额: $ 32.06万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8243627
• 关键词: Adverse effects; Biological; Biological Assay; Biological Markers; Biology; Blood Vessels; Brain; Brain Neoplasms; CTNNB1 gene; Cell Culture Techniques; Cell Transplants; Cells; Characteristics; Child; Childhood Brain Neoplasm; Chromosome abnormality; Clinical; Clinical Research; Clinical Trials; Colony-Forming Units Assay; Cultured Cells; Cytoplasmic Granules; Data; Dependency; Development; Diagnostic tests; Disease; Dose; Enrollment; Gene Expression; Gene Mutation; Genomics; Histologic; Histology; Human; Malignant - descriptor; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Neoplasms; Neurons; Outcome; Patients; Pattern; Play; Population; Property; Radiation; Radiosurgery; Research; Retrospective Studies; Role; SHH gene; Signal Transduction; Sonic Hedgehog Pathway; Stem cells; Subgroup; Sum; Survivors; Testing; Translations; Validation; Variant; Work; base; cancer stem cell; chemotherapy; clinical practice; cost; hindbrain; insight; medulloblastoma; migration; mouse model; mutant; nerve stem cell; neuroepithelium; next generation; outcome forecast; precursor cell; prognostic; prospective; response; self-renewal; stem cell niche; tumor; tumorigenic

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.

在过去的10年里，大约750名髓母细胞瘤儿童接受了基于财团的临床试验治疗，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，可以为下一代临床研究提供信息。因此，目前所有患者都接受同样的手术、放疗和化疗联合治疗。这种治疗对幸存者造成了毁灭性的副作用，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亚群显示