The power of extracellular vesicles in glioblastoma

细胞外囊泡在胶质母细胞瘤中的作用

• 批准号: 10250329
• 负责人: XANDRA OWENS BREAKEFIELD
• 金额: $ 100.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-06 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10250329
• 关键词: Adaptive Immune System; Area; Astrocytes; Biological Markers; Brain; Cell Communication; Cell Therapy; Cells; Cessation of life; Clinical; Cross Presentation; Cytotoxic T-Lymphocytes; DNA cassette; Dependovirus; Disease; Early Diagnosis; Evaluation; Glioblastoma; Goals; Life Support Systems; Ligands; Malignant Neoplasms; Microglia; Morbidity - disease rate; Neurosurgeon; Normal Cell; Nucleic Acids; Phenotype; Plasma; Proteins; RNA; Research Personnel; Seasons; T-Lymphocyte; Therapeutic; Tumor Antigens; Tumor-Derived; Vesicle; antimicrobial peptide; arm; brain cell; cell type; combinatorial; design; exhaust; extracellular vesicles; insight; macrophage; neoplastic cell; novel; novel therapeutics; programs; promoter; response; standard of care; tumor; tumor growth; tumorigenic; vector; vesicular release

Project Summary/Abstract Glioblastomas remain one of the most deadly cancers with no breakthroughs in therapy for the past 20 years. Xandra Breakefield has made critical discoveries demonstrating that these tumor cells release extracellular vesicles containing informative nucleic acids and proteins that convert normal brain cells to tumor supportive cells. Working with a team of seasoned investigators she has continued to make breakthrough advances in the use of these vesicles as biomarkers, in elucidating the means by which they subjugate microglia and other cells in their microenvirons, and in exploring how they may be channeled for therapeutic purposes. This team consisting of Drs. Breakefield, Joseph El Khoury/Suzanne Hickman (microglia experts), Thorsten Mempel (T lymphocyte expert), Marike Broekman (neurosurgeon) and Casey Maguire (vector expert) will advance these insights in three interrelated areas: biomarkers, cell-to-cell communication and therapy. Studies are designed to increase sensitivity and reveal clinical correlates of RNA and protein in extracellular vesicle biomarkers from serum/plasma with goals of early detection, informing therapeutic decisions and longitudinal evaluation. They will explore how tumor extracellular vesicles participate in changing the phenotype of microglia, macrophages and astrocytes in the tumor microenvirons, such that they become a “life support” system for the tumor in defiance of therapy. These insights will be forged into new therapeutic concepts with a focus on engaging the innate and adaptive immune systems to arm the brain against the tumor. This will include increasing cross presentation of extracellular vesicle-derived tumor antigens via microglia to infiltrating T lymphocytes using co- stimulatory molecules. Microglia associated with the tumor will be endowed with increased capacity to release anti-microbial peptides, which are also anti-tumorigenic, to reawaken their sense of the presence of the tumor and to down-regulate program death-ligands that exhaust cytotoxic T lymphocytes. Tumor-associated cells, including reactive astrocytes, microglia and macrophages will be manipulated using systemically administered adeno-associated virus and other vectors (which are clinically compatible) carrying transgene cassettes under promoters that are strongly up-regulated in cells near the tumor, but not in the same cell types in other parts of the brain. Vesicles produced by these cells will also be used to deliver therapeutic cargo to tumors cells to provide sustained therapeutic impact. These studies acknowledge the cytoplasmic continuum of cancer among all the cell types that make up the tumor mass, and strike at this supportive microenvironment which sustains the tumor. Therapeutic strategies are designed to be combinatorial with standard-of-care without increasing morbidity for this devastating disease that has defied current therapeutic approaches.

项目总结/摘要 胶质母细胞瘤仍然是最致命的癌症之一，在过去的20年里，治疗没有突破。 Xandra Breakefield的重大发现表明，这些肿瘤细胞释放细胞外 含有信息核酸和蛋白质的囊泡，可将正常脑细胞转化为肿瘤支持细胞， 细胞她与一组经验丰富的调查人员合作，继续在 这些囊泡作为生物标志物在阐明它们使小胶质细胞和其他神经胶质细胞屈服的方式中的用途， 细胞在其微环境，并在探索他们如何可能被引导用于治疗目的。这支球队 由布雷克菲尔德博士、约瑟夫·埃尔·库里/苏珊娜·希克曼（小胶质细胞专家）、托尔斯滕·曼佩尔（T 淋巴细胞专家），Marike Broekman（神经外科医生）和凯西马奎尔（载体专家）将推进这些 在三个相互关联的领域的见解：生物标志物，细胞间通讯和治疗。研究设计 增加敏感性并揭示细胞外囊泡生物标志物中RNA和蛋白质的临床相关性， 血清/血浆的检测，目的是早期发现，告知治疗决策和纵向评估。他们 将探讨肿瘤细胞外囊泡如何参与改变小胶质细胞、巨噬细胞 肿瘤微环境中的星形胶质细胞，使它们成为肿瘤的“生命支持”系统， 无视治疗这些见解将被锻造成新的治疗概念，重点是让人们参与其中 先天和适应性免疫系统来武装大脑对抗肿瘤。这将包括增加交叉 使用共刺激技术通过小胶质细胞向浸润性T淋巴细胞呈递细胞外囊泡来源的肿瘤抗原 刺激分子与肿瘤相关的小胶质细胞将被赋予增加的释放能力， 抗微生物肽，也是抗肿瘤的，以重新唤醒它们对肿瘤存在的感觉 并下调耗尽细胞毒性T淋巴细胞的程序性死亡配体。肿瘤相关细胞， 包括反应性星形胶质细胞、小胶质细胞和巨噬细胞将使用全身给药 腺相关病毒和携带转基因盒的其他载体（临床上相容的）， 启动子在肿瘤附近的细胞中强烈上调，但在肿瘤的其他部分的相同细胞类型中不上调。 大脑由这些细胞产生的囊泡也将用于将治疗性货物递送至肿瘤细胞， 提供持续的治疗效果。这些研究承认癌症的细胞质连续体， 所有组成肿瘤的细胞类型，并攻击这个支持性的微环境， 肿瘤治疗策略被设计为与标准治疗相结合，而不增加 这种毁灭性疾病的发病率已经挑战了目前的治疗方法。