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Developing therapeutic strategies to elicit metabolic synthetic lethality in glioblastoma

制定治疗策略以引发胶质母细胞瘤代谢合成致死率

基本信息

批准号：
10303047
负责人：
Prakash Chinnaiyan
金额：
$ 33.35万
依托单位：
WILLIAM BEAUMONT HOSPITAL RESEARCH INST
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：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303047
关键词：
Acylation Automobile Driving Cell Death Cell Proliferation Cells Chemicals Clinical Complex Coupling Cues DNA Sequence Alteration Data Development Ecology Energy-Generating Resources Enzymes Event Fatty Acids Genetic Transcription Genomics Glioblastoma Gliomagenesis Glucose Glycolysis Heterogeneity Histone Deacetylase Inhibitor Investigation Laboratory Study Link Malignant Neoplasms Mediator of activation protein Mesenchymal Mesenchymal Differentiation Metabolic Metabolic Pathway Metabolism Methods Modeling Molecular Mutation Nutrient Oxides PTEN gene Patients Phenotype Play Pre-Clinical Model Process Proliferating Receptor Protein-Tyrosine Kinases Research Design Resistance Role Secondary to Series Source Stress Testing Therapeutic Toxic effect Tumor-Derived aggressive therapy base beta-Hydroxybutyrate cancer therapy clinically relevant combinatorial deprivation design fatty acid metabolism fatty acid-transport protein in vivo lipid metabolism metabolic phenotype metabolomics new therapeutic target novel novel therapeutics programs translational potential treatment strategy tumor tumor metabolism tumor microenvironment uptake vector

项目摘要

ABSTRACT Glioblastoma (GBM) continues to be an invariably fatal malignancy with limited treatment options. Our laboratory studies tumor metabolism and its potential to serve as a novel therapeutic target. Through a series of investigations, our group has identified that the diverse tumor ecology implicit in this malignancy contributes to considerable intratumoral metabolic heterogeneity and dynamic metabolic reprogramming, allowing GBM cells to adapt and proliferate under diverse, microenvironmental stresses. Specifically, through integrative cross-platform analyses coupling metabolomics with genomics in patient-derived tumors, we identified enhanced fatty acid oxidization (FAO) as a metabolic node in GBM driven by a transcriptional program designed to import and utilize fatty acids from the tumor microenvironment. This metabolic phenotype was specific to the mesenchymal subtype in GBM and recapitulated in preclinical models. Functional analyses uncovered specific roles these fatty acids play in gliomagenesis, which are dependent upon nutrient availability. In a state of glucose deprivation, mesenchymal GBM cells utilize these exogenous fatty acids to serve as a vital, alternate source of ATP, whereas in nutrient favorable conditions, the intermediary metabolism of FAO acts as a metabolic cue to drive a transcriptional program supporting cellular proliferation and mesenchymal differentiation. Accordingly, inhibiting FAO in standard, nutrient rich conditions led to decreased proliferation, however, robust energetic stress and non-apoptotic cell death was observed in mesenchymal GBM cells in the context of glucose deprivation. In this application, we propose to extend these promising findings by defining molecular mechanisms governing enhanced FAO in GBM (Aim 1), delineating the multiple roles FAO may play in gliomagenesis in the context of this tumor’s diverse tumor ecology (Aim 2), and evaluate the translational potential for eliciting metabolic synthetic lethality in GBM through energetic stress (Aim 3).

摘要