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Investigating and Targeting TAMs in the Glioma Microenvironment

研究和靶向胶质瘤微环境中的 TAM

基本信息

批准号：
9264694
负责人：
Johanna Joyce
金额：
$ 22.05万
依托单位：
UNIVERSITY OF LAUSANNE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264694
关键词：
Address Adult Affect Biological Biological Assay Blood Vessels Brain Cells Clinic Clinical Coculture Techniques Communication Complement Complex Cytokine Signaling Data Development Diagnosis Disease Employee Strikes Exposure to Future Gene Expression Profile Gene Expression Profiling Genetically Engineered Mouse Genomics Glioblastoma Glioma Gliomagenesis Goals Grant Granulocyte-Macrophage Colony-Stimulating Factor Health Homeostasis Human Hypoxia Immune Infection Interferons Investigation Knowledge MEKs Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor Receptor Malignant Neoplasms Malignant neoplasm of brain Mediating Mediator of activation protein Memorial Sloan-Kettering Cancer Center Mesenchymal Methods Modeling Molecular Profiling Mus Mutation Normal Cell Normal tissue morphology Outcome Pathway interactions Patients Phenotype Pilot Projects Platelet-Derived Growth Factor Primary Brain Neoplasms Process Proteomics Radiosurgery Receptor Inhibition Recurrence Resistance Resistance development Signal Pathway Signal Transduction Stromal Cells Testing Therapeutic Translating Tumor Cell Invasion base cancer cell cancer type cell type chemotherapy combat design enhancing factor fighting in vivo inhibitor/antagonist innovation insight macrophage molecular subtypes mouse model neoplastic cell nestin protein novel novel therapeutic intervention novel therapeutics outcome forecast preclinical trial relating to nervous system research study response targeted treatment temozolomide therapeutic development therapeutic target therapy resistant tumor tumor growth tumor microenvironment tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): High-grade gliomas, also known as glioblastoma multiforme (GBM), are the most common and aggressive adult primary brain tumors. GBM patients have a minimal response to current therapies, including surgery, radiation and temozolomide chemotherapy. Most patients die within 14 months following diagnosis, emphasizing the urgent need for new therapies to combat this disease. GBM can be grouped into several molecular subtypes, including proneural, neural, mesenchymal and classical, based on distinct gene expression signatures. Of these subtypes, proneural GBM is particularly aggressive in younger patients, and most therapeutic approaches aimed at directly targeting tumor cells in this subtype have failed. In contrast to highly mutable tumor cells, non-cancerous stromal cells that support tumorigenesis in the tumor microenvironment (TME) represent genetically stable therapeutic targets. This means therapies targeted against the TME are less likely to result in the development of acquired resistance as a result of genetic changes in the stromal cells. Tumor-associated macrophages (TAMs) are an important cell type in the TME that correlate with increased tumor grade and poor patient prognosis in many cancers, including gliomas, suggesting important cancer-promoting functions. To examine the contribution of TAMs to glioma progression, we have used a genetically engineered mouse model of proneural GBM. We found that TAMs progressively increase with higher tumor grade in the mouse model, which parallels the increase observed during human glioma development. To investigate the functional significance of TAM accumulation, we designed preclinical trials in the proneural GBM model to therapeutically target colony stimulating factor-1 receptor (CSF-1R), which macrophages depend upon for survival and differentiation. CSF-1R inhibition as a monotherapy dramatically increased survival in these mice, and regressed established tumors after just 7 days. Macrophages were depleted in the normal brain, as we had expected, but not in gliomas of treated mice. Instead, glioma-secreted factors facilitated TAM survival in the presence of CSF-1R inhibitors. Interestingly, gene expression analysis of these surviving TAMs revealed a significant decrease in alternatively activated/ M2 polarization macrophage markers, and consistently, functional analyses revealed anti-tumorigenic phenotypes. Thus, TAM depletion is not strictly necessary for effective macrophage-targeted therapy. Rather, we propose that the presence of macrophage survival factors in the glioma TME not only enables TAMs to survive exposure to a CSF-1R inhibitor, but to be 're-educated' through this process, resulting in a striking anti-tumor response. Our preliminary data identifies TAMs as a promising therapeutic target for proneural gliomas, and establishes strong translational potential of CSF-1R inhibition in GBM. In this proposal, we will expand on these results to elucidate the mechanisms by which TAMs mediate glioma cell phenotypes, and determine how CSF-1R inhibitors interfere with this reciprocal communication to delay and block glioma progression. Our objectives are to elucidate how TAMs are initially educated by glioma cells, and then re-educated by CSF-1R inhibition in the glioma microenvironment. Next, we will investigate which glioma cell signaling pathways are enhanced by TAMs, and determine the downstream effectors that are critical to CSF-1R inhibition efficacy in vivo. Finally, we will determine whether gliomas develop resistance to CSF-1R inhibition, and identify the underlying mechanisms. To address these goals, we will employ multiple different methods including mouse glioma models and an extensive panel of co-culture assays to investigate communication between glioma cells, TAMs, and other cells in the glioma TME. We will combine analyses of known signaling pathways with the identification of novel targets using proteomics and expression profiling approaches. In addition to dissecting the underlying biological mechanisms by which TAMs promote glioma progression, the proposed experiments will also result in the development of therapeutic strategies for their specific inhibition, which if successful could ultimately be tested in the clinic. Collectively, these studies have important implications for future clinical consideration of CSF-1R inhibitors, and for other therapies that target the TME in cancer.

描述（由申请人提供）：高级别胶质瘤，也称为多形性胶质母细胞瘤（GBM），是最常见和侵袭性最强的成人原发性脑肿瘤。GBM患者对目前的治疗方法，包括手术、放疗和替莫唑胺化疗反应最小。大多数患者在诊断后14个月内死亡，强调迫切需要新的治疗方法来对抗这种疾病。基于不同的基因表达特征，GBM可分为几个分子亚型，包括前源性、神经性、间充质和经典亚型。在这些亚型中，前膜GBM在年轻患者中尤其具有侵袭性，大多数直接针对该亚型肿瘤细胞的治疗方法都失败了。