Extracellular Vesicles (EVs) and Genes in the Biology and Therapy of Gliomas

神经胶质瘤生物学和治疗中的细胞外囊泡 (EV) 和基因

• 批准号: 10213213
• 负责人: XANDRA OWENS BREAKEFIELD
• 金额: $ 131.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213213
• 关键词: Adjuvant; Basic Science; Behavior; Biological Assay; Biological Markers; Biology; Biometry; Biopsy; Blood; Blood specimen; Brain; Brain Neoplasms; Cells; Cerebrospinal Fluid; Clinical; Clinical Trials; Data; Diagnosis; Disease; Effectiveness; Genes; Genetically Engineered Mouse; Genomics; Glioblastoma; Glioma; Goals; Heterogeneity; Human; Immune; Immune checkpoint inhibitor; Immunosuppression; Immunotherapy; Knowledge; Laboratories; Leadership; Malignant Glioma; Malignant Neoplasms; Mediating; Metastasis Suppression; Microglia; Monitor; Mus; Newly Diagnosed; Oncogenic; Patients; Phase II Clinical Trials; Phenotype; Plasma; Pre-Clinical Model; Prognosis; Program Research Project Grants; Proteins; RNA; Randomized Clinical Trials; Research; Research Personnel; Resistance; Resolution; Resources; Role; Sampling; Structure; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Transfer RNA; Tumor Cell Invasion; Tumor Subtype; Tumor Suppression; Tumor-Derived; Vesicle; angiogenesis; anticancer research; biobank; cancer cell; cancer therapy; cancer type; checkpoint inhibition; cytotoxic; effective therapy; extracellular vesicles; improved; macrophage; neoplastic cell; new technology; new therapeutic target; novel; pre-clinical; preclinical trial; programs; response; standard of care; stem-like cell; therapy resistant; treatment response; tumor; tumor microenvironment; tumor progression; tumorigenesis; vesicular release; virtual biopsy

Glioblastoma multiforme (GBM) has an abysmal prognosis despite advances in genomics, new targeted therapies, and increased understanding of its pathobiology. The goal of our Program Project Grant (PPG) is to improve knowledge about GBM biology and develop effective therapies. Investigators in this PPG have made two notable advances, among many: 1- Tumor extracellular vesicles (tEVs) and their contents transfer functional information among cells in the GBM microenvironment, thereby increasing oncogenic behaviors, and 2- a Phase II clinical trial in patients with newly diagnosed GBM utilizing Gene-mediated Cytotoxic Immunotherapy (GMCI) as an adjuvant to standard-of-care (SOC) has shown encouraging, albeit non- definitive, results. The major hypotheses of this PPG's competitive renewal are that GBM therapy can be improved by combining SOC and GMCI with immune checkpoint inhibition, and that therapeutic responses can be monitored in biofluids by assessing protein and RNA content in tEVs. Three synergistic projects and three supporting cores will test these hypotheses. Project 1 (Xandra Breakefield) will evaluate whether glioma EVs and their contents are fundamental regulators of glioma heterogeneity within the tumor and immune suppression in the tumor microenvironment, thus contributing to tumor progression, immuno-evasion, and therapeutic resistance. Project 2 (Ralph Weissleder) will validate novel technological advances from his laboratory, such as single EV analysis (SEA), to assay tEV contents in biofluids, thus overcoming the limitation of scant materials available from preclinical and clinical trials. Project 3 (E. Antonio Chiocca) will test if SOC/GMCI combined with immune checkpoint inhibition will be an effective therapy in preclinical models of glioma and, ultimately, in a randomized clinical trial. Core A (Breakefield/Chiocca) will provide the necessary administrative structure, scientific oversight, and overall leadership functions for the PPG, including basic science (Breakefield) and preclinical/clinical (Chiocca) efforts. Core B (Carter) will maintain the Clinical Sample Core that biobanks cerebral spinal fluid and serum/plasma samples from patients and clinical trials for tEV analysis, as well as serve as the biostatistics resource. Core C (Charest) will provide genetically engineered mouse models of gliomas and mouse/human glioma “stem-like” cells from different GBM subtypes. Together these investigators will generate the necessary scientific justification and preclinical data to ultimately support the proposed clinical trial of GMCI with immune checkpoint inhibition in newly diagnosed GBM patients, in which tEVs will be evaluated for their potential as biomarkers and modulators of the therapeutic response.

多形性胶质母细胞瘤（GBM）的预后很差，尽管在基因组学和新靶点方面取得了进展

项目成果

Immune Checkpoint Blockade Biology in Mouse Models of Glioblastoma.

胶质母细胞瘤小鼠模型中的免疫检查点阻断生物学。

• DOI: 10.1002/jcb.25948
• 发表时间: 2017-09
• 期刊: Journal of cellular biochemistry
• 影响因子: 4
• 作者: Yeo AT;Charest A
• 通讯作者: Charest A

MiR-21 in the extracellular vesicles (EVs) of cerebrospinal fluid (CSF): a platform for glioblastoma biomarker development.

脑脊液（CSF）的细胞外囊泡（EV）中的miR-21：胶质母细胞瘤生物标志物发育的平台。

• DOI: 10.1371/journal.pone.0078115
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Akers JC;Ramakrishnan V;Kim R;Skog J;Nakano I;Pingle S;Kalinina J;Hua W;Kesari S;Mao Y;Breakefield XO;Hochberg FH;Van Meir EG;Carter BS;Chen CC
• 通讯作者: Chen CC

Advances in local therapy for glioblastoma - taking the fight to the tumour.

• DOI: 10.1038/s41582-022-00621-0
• 发表时间: 2022-04
• 期刊: Nature reviews. Neurology

Proteomics-based analysis of invasion-related proteins in malignant gliomas.

• DOI: 10.1111/j.1440-1789.2012.01361.x
• 发表时间: 2013-06
• 期刊: Neuropathology : official journal of the Japanese Society of Neuropathology
• 作者: Maruo T;Ichikawa T;Kanzaki H;Inoue S;Kurozumi K;Onishi M;Yoshida K;Kambara H;Ouchida M;Shimizu K;Tamaru S;Chiocca EA;Date I
• 通讯作者: Date I

Down-regulation of miR-101 in endothelial cells promotes blood vessel formation through reduced repression of EZH2.

• DOI: 10.1371/journal.pone.0016282
• 发表时间: 2011-01-28
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Smits M;Mir SE;Nilsson RJ;van der Stoop PM;Niers JM;Marquez VE;Cloos J;Breakefield XO;Krichevsky AM;Noske DP;Tannous BA;Würdinger T
• 通讯作者: Würdinger T