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.

项目概要/摘要 胶质母细胞瘤仍然是最致命的癌症之一，过去 20 年来在治疗方面没有取得突破。 Xandra Breakefield 取得了重要发现，证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 她与经验丰富的研究人员团队合作，继续在细胞领域取得突破性进展。 使用这些囊泡作为生物标志物，阐明它们抑制小胶质细胞和其他细胞的方式 该团队正在探索如何将它们用于治疗目的。 由 Breakefield 博士、Joseph El Khoury/Suzanne Hickman（小胶质细胞专家）、Thorsten Mempel（T）组成 淋巴细胞专家）、Marike Broekman（神经外科医生）和 Casey Maguire（媒介专家）将推进这些研究 设计了三个相关领域的见解：生物标志物、细胞间通讯和治疗。 提高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/血浆的目标是早期检测、为治疗决策和纵向评估提供信息。 将探讨肿瘤细胞外囊泡如何参与改变小胶质细胞、巨噬细胞的表型 肿瘤微环境中的星形胶质细胞和星形胶质细胞，使其成为肿瘤的“生命支持”系统 这些见解将被塑造成新的治疗概念，重点是参与治疗。 先天性和适应性免疫系统可以增强大脑对抗肿瘤的能力。 使用co-将细胞外囊泡衍生的肿瘤抗原通过小胶质细胞呈递给浸润T淋巴细胞 与肿瘤相关的小胶质细胞将被赋予更高的释放能力。 抗微生物肽，也具有抗肿瘤作用，可以重新唤醒他们对肿瘤存在的感觉 并下调耗尽肿瘤相关细胞的死亡配体程序， 包括反应性星形胶质细胞、小胶质细胞和巨噬细胞将通过全身给药进行操纵 腺相关病毒和其他携带转基因盒的载体（临床上兼容） 启动子在肿瘤附近的细胞中强烈上调，但在肿瘤其他部位的相同细胞类型中则不上调 这些细胞产生的囊泡也将用于向肿瘤细胞输送治疗物质。 这些研究承认癌症的细胞质连续体。 构成肿瘤块的所有细胞类型，并攻击维持这种支持性微环境 治疗策略旨在与标准护理相结合，而不增加肿瘤的风险。 这种毁灭性疾病的发病率已经无法满足当前的治疗方法。