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: 9978761
• 负责人: DANIEL J BRAT
• 金额: $ 36.56万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978761
• 关键词: Automobile Driving; BRAT gene; Behavior; Biological; Biology; Brain Neoplasms; CDK5 gene; CXCR4 gene; Cell division; Cell physiology; 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; 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/antagonist; migration; mouse model; multiphoton microscopy; neoplastic; neoplastic cell; nestin protein; neuroblast; novel; novel therapeutics; outcome forecast; photoactivation; pluripotency; pre-clinical; programs; response; self-renewal; stem; 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/摘要 胶质母细胞瘤（GBM）是最常见和最恶性的原发性脑肿瘤， 预后很差大量证据表明， 肿瘤细胞，称为胶质瘤干细胞（GSC），控制生物学行为 和对治疗的抵抗GSC栖息于特定的生物小生境，并具有 自我更新、多能性和高致瘤性。它们可以通过表情来识别 标记物，如CD 133，CD 15和巢蛋白，但分子机制负责 其在胶质母细胞瘤中的特定干细胞样行为尚未完全确定。这 该提案旨在确定基本生物学特性的机制， GSC，包括：1）坏死发展后的显著积聚 和倾向于本地化的缺氧生态位;和2）中断程序的不对称 有利于自我更新分裂而不是分化的细胞分裂。我们已经开发 新的体外和体内模型和分析技术，以研究差异 干细胞和非干细胞胶质瘤细胞在肿瘤微环境中的行为， 特别是当其涉及它们在缺氧区域中的积累时。其中包括在 体内原位异种移植模型，其中询问干细胞的模式， 使用光活化的 染料。我们也剖析了果蝇细胞不对称分裂的途径 神经系统提供线索，以了解干/非干动态恶性肿瘤 神经胶质瘤我们以前已经证明了果蝇布拉特的人类直系同源物， Trim 3是一种肿瘤抑制因子，调节胶质瘤干细胞动力学并促进胶质瘤的发生。 失去的时候，在这里，我们建议调查新的调节机制， 在向干细胞表型转变的过程中出现， 治疗上监管网络和潜在的治疗靶点还在进一步发展 在异种移植和基因工程小鼠模型中进行了探索， 人类神经胶质瘤来显示疗效。