Tumor-associated macrophages in vasogenic cerebral edema in brain tumors

脑肿瘤血管源性脑水肿中的肿瘤相关巨噬细胞

基本信息

批准号：
10607181
负责人：
Dolores Hambardzumyan
金额：
$ 62万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607181
关键词：
Ablation Address Adrenal Cortex Hormones Anatomy Antibodies Antibody Therapy Antineoplastic Agents Area Automobile Driving Avastin Blood Blood - brain barrier anatomy Brain Neoplasms CD8-Positive T-Lymphocytes Cerebral Edema Chronic Clinical Complement Complication Data Dexamethasone Diabetes Mellitus Diagnosis Disease Dose Edema Endothelial Cells Exhibits Frequencies Genetic Genetic Engineering Genetically Engineered Mouse Glioblastoma Glioma Human Hypoxia Immune response Immunocompetent Immunotherapy Individual Infiltration Inflammatory Interleukin-1 Interleukin-1 beta Invaded Link Lymphoid Malignant Neoplasms Mediating Mental Depression Mesenchymal Modality Modeling Molecular Target Molecular and Cellular Biology Morbidity - disease rate Mus Myopathy NF1 gene Neoplasms PDGFB gene Pathology Patients Pericytes Perioperative Pharmacology Production Prognosis Proteins Psychoses Publishing Radiation Radiation therapy Resistance development Role Severities Signal Transduction Steroids Testing Therapeutic Tight Junctions Time Toxic effect Tumor Cell Invasion Tumor-associated macrophages VEGFA gene Vascular Endothelial Growth Factors Vascular Permeabilities Vasogenic Cerebral Edema Work anti-cancer anti-tumor immune response cell type cellular targeting efficacy evaluation epidermal growth factor receptor VIII exhaust human disease in vivo insight macrophage monocyte mouse model novel novel strategies novel therapeutic intervention novel therapeutics overexpression patient derived xenograft model public health relevance side effect targeted agent therapy resistant tool traditional therapy tumor tumor growth tumor microenvironment vasogenic edema

项目摘要

Project Summary: Glioblastomas (GBM) are among the most lethal of all human cancers, with a median survival of around one year. Vasogenic edema is a universal problem for GBM patients, and corticosteroids are commonly used perioperatively to control cerebral edema and are frequently continued throughout subsequent treatment, notably radiotherapy (RT), for the amelioration of side effects. Vasogenic edema is a significant cause of morbidity in patients with both primary and metastatic brain tumors, both from the direct impact of edema and from indirect effects related to the requirement for chronic corticosteroid use to manage it. In general, the mechanism of edema formation is still unclear. We have shown that dexamethasone (DEX) administration significantly compromises RT efficacy, together with emerging new therapies that augment the immune response to treat brain tumors. Although we and others have identified antibodies and agents targeting vascular endothelial growth factor (VEGF) at high anti-cancer doses that effectively reduce edema, their use is associated with increased infiltration of tumor growth-promoting macrophages and development of resistance. Our preliminary and published work identified the pro-inflammatory IL-1β from blood-born monocyte/monocyte-derived macrophages (MDM) as a downstream target of DEX in exerting its anti-edema effect. We have shown that targeting IL-1β is as sufficient as DEX in reducing edema but does not compromise RT efficacy. In contrast to anti-VEGFA antibody treatment, targeting IL-1β does not induce increased infiltration of tumor-promoting TAMs; on the contrary, it decreases the number of tumor-promoting TAMs and reduces the number of exhausted CD8+ T-cells. This application thus aims to use three distinct genetically engineered mouse models of GBM that exhibit significant differences in TAMs and anatomical structures of the brain-blood barrier (BBB), together with human primary GBM patient-derived xenograft models, in combination with cell type specific IL-1β ablation strategies to determine detailed mechanisms of IL-1β effects on vascular permeability and edema formation in GBM. The proposed studies will provide new mechanistic insights into the fundamental cellular and molecular biology of IL- 1β in glioblastoma. The proposed studies test whether targeting IL-1β is a promising novel anti-edema therapy for heterogeneous GBM with dual efficacy –against edema (in our renewal application) and neoplastic growth that we demonstrated in our ongoing R01.

项目概要：胶质母细胞瘤 (GBM) 是所有人类癌症中最致命的一种，中位生存期约为 1 血管源性水肿是GBM患者的普遍问题，常用皮质类固醇。围手术期控制脑水肿，并经常在后续治疗中持续进行，特别是放射治疗（RT），用于改善副作用，血管源性水肿是发病的重要原因。患有原发性和转移性脑肿瘤的患者，无论是由于水肿的直接影响还是间接影响与长期使用皮质类固醇的需求相关的影响一般而言，其机制。我们已经表明，地塞米松（DEX）给药对水肿的形成有显着影响。损害放疗疗效，以及增强免疫反应的新兴疗法尽管我们和其他人已经确定了针对血管内皮生长的抗体和药物。高抗癌剂量的因子（VEGF）可以有效减少水肿，它们的使用与增加促进肿瘤生长的巨噬细胞的浸润和耐药性的发展。已发表的工作从血源性单核细胞/单核细胞衍生的巨噬细胞中鉴定出促炎性 IL-1β (MDM) 作为 DEX 发挥其抗水肿作用的下游靶点我们已经证明，靶向 IL-1β 是有效的。与抗 VEGFA 抗体相比，它在减轻水肿方面与 DEX 一样充分，但不会损害 RT 功效。治疗时，靶向 IL-1β 不会导致促肿瘤 TAM 的浸润增加；相反，减少促肿瘤 TAM 的数量并减少耗尽的 CD8+ T 细胞的数量。因此，该申请旨在使用三种不同的 GBM 基因工程小鼠模型，这些模型表现出显着的 TAM 和脑血屏障 (BBB) 解剖结构的差异，以及人类初级 GBM 患者来源的异种移植模型，结合细胞类型特异性 IL-1β 消融策略，确定 IL-1β 对 GBM 血管通透性和水肿形成影响的详细机制。拟议的研究将为 IL- 的基本细胞和分子生物学提供新的机制见解胶质母细胞瘤中的 1β 拟议的研究测试了靶向 IL-1β 是否是一种有前途的新型抗水肿疗法。针对具有双重功效的异质 GBM – 对抗水肿（在我们的更新应用中）和肿瘤生长我们在正在进行的 R01 中展示了这一点。