Identification and targeting of mechanisms specific to glioma stem cells in glioblastoma

胶质母细胞瘤中胶质瘤干细胞特异性机制的鉴定和靶向

• 批准号: 10434100
• 负责人: DANIEL J BRAT
• 金额: $ 35.57万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434100
• 关键词: Automobile Driving; BRAT gene; Behavior; Biological; Biology; Brain Neoplasms; CDK5 gene; CXCR4 gene; Cell division; Cells; Data; Daughter; Development; Drosophila genus; Dyes; Equilibrium; Gene Targeting; Genes; Genetic; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Growth; Human; Hypoxia; In Vitro; Lasers; Lead; Malignant - descriptor; Malignant Glioma; Malignant neoplasm of brain; Microscopic; Molecular; Mus; Mutate; Necrosis; Necrosis Induction; Neoplasms; Nervous system structure; Orthologous Gene; Pathway interactions; Pattern; Pharmacology; Phenotype; Primary Brain Neoplasms; Process; Prognosis; Property; Recurrence; Rose Bengal; Self-Direction; Signal Transduction; Study models; System; Techniques; Therapeutic; Thrombosis; Time; Tumor Stem Cells; Tumor Suppressor Proteins; Tumorigenicity; Up-Regulation; Work; Xenograft Model; Xenograft procedure; cranium; daughter cell; human model; in vivo; in vivo Model; inhibitor; migration; mouse model; multiphoton microscopy; neoplastic; neoplastic cell; nestin protein; neuroblast; novel; novel therapeutics; photoactivation; pluripotency; pre-clinical; programs; response; self-renewal; stem; stem cell expansion; stem cell function; stem cells; stemness; targeted treatment; therapeutic target; therapy resistant; treatment strategy; tumor growth; tumor microenvironment

Project Summary/Abstract Glioblastoma (GBM) is the most common and most malignant primary brain tumor and has a dismal prognosis. Abundant evidence now indicates that a small subset of neoplastic cells, referred to as Glioma Stem Cells (GSCs), governs biologic behavior and resistance to therapy. GSCs inhabit specific biologic niches and have properties of self-renewal, pluripotency and high tumorigenicity. They can be identified by expression of markers, such as CD133, CD15 and nestin, yet molecular mechanisms responsible for their specific stem-like behavior in glioblastomas have not been fully defined. This proposal aims to define mechanisms underlying fundamental biological properties of GSCs, including: 1) their marked accumulation following the development of necrosis and tendency to localize to the hypoxic niche; and 2) a disrupted program of asymmetric cell division that favors self-renewing division over differentiation. We have developed novel in vitro and in vivo models and analytic techniques to study the differential behavior of stem and non-stem glioma cells within the tumor micro-environment, especially as it relates to their accumulation in regions of hypoxia. These include an in vivo orthotopic xenograft model in which stem cells are interrogated for patterns and mechanisms of accumulation following the induction of necrosis using a photo-activated dye. We also dissect pathways that direct asymmetric cellular division in Drosophila nervous system provide clues to understand the stem/non-stem dynamics in malignant gliomas. We have previously demonstrated that the human ortholog of Drosophila Brat, Trim3, is a tumor suppressor that regulates glioma stem cell dynamics and promotes stemness when lost. Here we propose to investigate novel regulatory mechanisms that arise during transition to the stem cell phenotype that can be antagonized therapeutically. Regulatory networks and potential therapeutic targets are further explored in xenografts and genetically engineered mouse models that recapitulates human gliomas to show efficacy.

项目总结/文摘

项目成果

cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas.

• DOI: 10.1007/s00401-020-02127-9
• 发表时间: 2020-03
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Brat DJ;Aldape K;Colman H;Figrarella-Branger D;Fuller GN;Giannini C;Holland EC;Jenkins RB;Kleinschmidt-DeMasters B;Komori T;Kros JM;Louis DN;McLean C;Perry A;Reifenberger G;Sarkar C;Stupp R;van den Bent MJ;von Deimling A;Weller M
• 通讯作者: Weller M