Isolation, characterization and translational development of glioma stem cells

神经胶质瘤干细胞的分离、表征和转化发育

• 批准号: 10090574
• 负责人: Luis Fernando Parada
• 金额: $ 107.76万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090574
• 关键词: Adult; Astrocytes; Biological; Cells; Chemicals; Data; Dependence; Development; Developmental Biology; Disease; Embryo; Event; Fibroblasts; Gene Expression Profile; Genes; Genetically Engineered Mouse; Genotype; Glioblastoma; Glioma; Growth; Human; Lead; Malignant Neoplasms; Modeling; Molecular; Mus; Mutate; Mutation; NF1 gene; Neonatal; Neurosciences; Oncogenes; PTEN gene; Pathway interactions; Pattern; Phenotype; Population; Public Health; Research; Solid Neoplasm; Stratification; Suppressor Mutations; TP53 gene; Toxic effect; Tumor Suppressor Proteins; Tumor-Derived; cancer cell; cancer stem cell; driver mutation; improved; in vivo; insight; mouse model; nanomolar; neoplastic cell; novel; novel strategies; patient derived xenograft model; programs; small molecule; stem; stem cells; therapeutic development; therapy development; tool; tumor; tumorigenic

Project Summary/Abstract Solid tumors arise as the consequence of accumulation of oncogene and/or tumor suppressor mutations. How these mutations arise and accumulate in one cell over a lifetime remains a mystery. It is likely that an improved understanding of the early events that form a pre-tumorigenic cell could have implications for analysis of mature tumor cells and insights into improved therapy development. We have developed fully penetrant genetically engineered mouse models of glioblastoma multiforme (GBM) by mutation of three tumor suppressors commonly found mutated in human GBM (P53, PTEN, & NF1). Using our combined background in developmental biology and neuroscience, we have traced the origin of these tumors to the adult stem/progenitor cell population. We have developed tools to uncover functional GBM subtypes that are predicated on the tumor cell of origin rather than on specific driver mutations (Alcantara, Cancer Cell, 2015). These studies will be extended to identify cell of origin and relationship to genotype and phenotype. Moreover, using gene expression signatures from the novel mouse GBM subtypes, we have identified human GBM counterpart signatures that suggest similar biological origins and a novel strategy for human GBM molecular stratification. Our data provide evidence for additional human GBM subtypes that may also relate to novel cells of origin. The mouse models demonstrate an endogenous GBM tumor cell hierarchy placing a cancer stem cell at the apex. Our ongoing studies suggest that each of the new stratified GBM subtypes are governed by a cancer stem cell pattern of growth. We will expand and confirm these observations. Using a phenotypic high throughput small chemical compound screen we have identified small molecules that have nanomolar toxicity on primary low passage GBM derived cells but not on primary normally dividing cells such as mouse embryo fibroblasts or neonatal astrocytes. In addition, lead compounds including a benzimidazolium compound and its derivatives demonstrate toxicity on primary human GBM derived tumor spheres. These compounds hold promise for in vivo studies and identifying novel key GBM dependency pathways for therapeutic development. We are developing a comprehensive GBM patient derived xenograft program that will be employed to further validate our mouse model finding and to identify, isolate and neutralize human GBM cancer stem cells.

项目总结/文摘