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.

项目摘要/摘要 胶质母细胞瘤仍然是最致命的癌症之一，在过去的20年中，没有任何突破。 Xandra Breakefield提出了关键发现，证明这些肿瘤细胞释放细胞外 含有信息性核酸和蛋白质的蔬菜，将正常脑细胞转化为肿瘤支持 细胞。与一组经验丰富的调查人员合作，她继续在 将这些蔬菜用作生物标志物，以阐明它们征服小胶质细胞和其他的手段 细胞中的细胞在其微生物中，并在探索如何用于治疗目的的过程中。这个团队 由Drs组成。 Breakefield，Joseph El Khoury/Suzanne Hickman（小胶质细胞专家），Thorsten Mempel（T 淋巴细胞专家），Marike Broekman（Neurosurgeon）和Casey Maguire（Vector Expert）将推进这些 在三个相互关联的领域的见解：生物标志物，细胞到细胞通信和治疗。研究设计 提高灵敏度并揭示RNA和蛋白质的临床相关性，来自细胞外囊泡生物标志物 血清/血浆具有早期检测目标，为治疗决定和纵向评估提供信息。他们 将探讨肿瘤细胞外蔬菜如何参与改变小胶质细胞的表型 肿瘤微生物中的星形胶质细胞，使其成为肿瘤中的“生命支持”系统 违反治疗。这些见解将被遗忘成新的治疗概念，重点是吸引 先天和适应性免疫系统将大脑武装在肿瘤上。这将包括增加十字架 通过小胶质细胞介绍细胞囊泡衍生的肿瘤抗原，以浸润T淋巴细胞浸润 刺激分子。与肿瘤相关的小胶质细胞将赋予释放能力的增加 抗微生物辣椒也是抗肿瘤的，以唤起其对肿瘤的存在感 并下调耗尽细胞毒性T淋巴细胞的程序死亡配体。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 腺相关的病毒和其他载体（临床上兼容）携带盒在下面 在肿瘤附近的细胞中强烈上调的启动子，但在同一细胞类型中的其他部分中的其他部分则不 大脑。这些细胞产生的囊泡也将用于将治疗性货物传递给肿瘤细胞 提供持续的治疗影响。这些研究确认癌症的细胞质连续性 构成肿瘤质量的所有细胞类型，并在这种支撑的微环境中罢工 治疗策略的设计目的是与标准的合并而无需增加 这种毁灭性疾病的发病率已经消除了当前的治疗方法。