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The Role of Vascular Endothelial Glutaminase in Tumor Vessel Normalization and Response to Therapy

血管内皮谷氨酰胺酶在肿瘤血管正常化和治疗反应中的作用

基本信息

批准号：
10239085
负责人：
Verra Ngwa
金额：
$ 3.32万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10239085
关键词：
4T1 6-Phosphofructo-2-kinase Amino Acids Area Biology Blood Vessels Blood flow Breast Cancer Patient Caliber Cancer Biology Cell Death Cell Line Cell Proliferation Cells Clinical Critical Thinking Development Drug Delivery Systems Endothelial Cells Endothelium Enzymes Fructose-2,6-bisphosphatase Future Generations Genetically Engineered Mouse Glucose Glutaminase Glutamine Glycolysis Goals Growth Hypoxia Immune checkpoint inhibitor Immunologics Immunophenotyping Immunotherapy International Knock-out Knockout Mice Knowledge Laboratories Learning Leukocytes Malignant Neoplasms Measures Metabolic Metabolism Methods Modeling Molecular Mus Neoplasm Metastasis Neoplasms in Vascular Tissue Nutrient Oxygen Pathway interactions Patient-Focused Outcomes Patients Perfusion Pericytes Proliferating Publishing Reporting Research Research Personnel Retina Role Stress Structural defect Tamoxifen Technology Testing Therapeutic Tissues Training Tumor Tissue Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Vascular Endothelial Cell Vascular Endothelium aerobic glycolysis aggressive breast cancer base blood vessel development cancer immunotherapy cancer subtypes career cell motility chemotherapy experience improved improved outcome insight interest malignant breast neoplasm migration mouse model neoplastic cell nutrition promoter recombinase-mediated cassette exchange repaired response skills success trait translational impact treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor immunology tumor progression wasting

项目摘要

Project Summary/Abstract Tumor blood vessels provide nutrition and oxygen and eliminate waste from tumor tissue. However, tumor-associated vessels are dysfunctional and structurally abnormal. They are often leaky and tortuous with chaotic blood flow, resulting in decreased drug delivery and reduced infiltration of immune cells. Complete blockade of tumor blood vessel formation has resulted in hypoxia, nutrient stress, and increased tumor cell motility and metastasis. A new concept to repair abnormal tumor vasculature, known as tumor vessel normalization, has been investigated to improve tumor vessel perfusion and oxygenation, reduce metastasis and increase efficacy of cancer immunotherapy. Several mechanisms, including inhibition of aerobic glycolysis in endothelium, have been shown to improve tumor vessel normalization. In addition to glycolysis, glutamine metabolism is required for proliferation and migration of ECs. Although glutamine metabolism is well studied in the context of cancer, its role in tumor vascular endothelial cells (TEC) is poorly understood. Using endothelium-specific glutaminase knockout mouse model and TNBC/basal-like cell lines, I propose to fill this gap by investigating the role of vascular endothelial glutaminase in tumor vessel normalization, tumor growth, metastasis, and response to therapy. To achieve this goal, I will first assess tumor vasculature for pericytes, tortuosity, diameter, perfusion, and leakiness, as well as tumor infiltrating lymphocytes, following GLS deletion from endothelial cells (Aim 1). Furthermore, I will use murine tumor models in the context of GLS knockout in TEC and assess tumor growth, metastasis, and response to both chemotherapy and immunotherapy (Aim 2). The success of this project will provide translational impact in the treatment of aggressive breast cancer TNBC or other cancers and will give me the knowledge and experience in the scientific method to launch my career as an independent investigator.

项目总结/文摘