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

• 批准号: 9883336
• 负责人: Prakash Chinnaiyan
• 金额: $ 34.16万
• 依托单位: WILLIAM BEAUMONT HOSPITAL RESEARCH INST
• 依托单位国家: 美国
• 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/9883336
• 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; treatment strategy; tumor; tumor metabolism; tumor microenvironment; uptake; vector

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 胶质母细胞瘤（GBM）仍然是一种总是致命的恶性肿瘤，治疗选择有限。我们 实验室研究肿瘤代谢及其作为新的治疗靶点的潜力。通过一系列 我们的研究小组已经确定，这种恶性肿瘤中隐含的多种肿瘤生态有助于 相当大的肿瘤内代谢异质性和动态代谢重编程， 细胞在不同的微环境压力下适应和增殖。具体而言，通过整合 在患者源性肿瘤中，通过将代谢组学与基因组学相结合的跨平台分析，我们发现 增强的脂肪酸氧化（FAO）作为GBM中由转录程序驱动的代谢节点 旨在从肿瘤微环境中导入和利用脂肪酸。这种代谢表型是 特异于GBM中的间充质亚型，并在临床前模型中重现。功能分析 揭示了这些脂肪酸在神经胶质瘤发生中的特殊作用，这取决于营养素 空房的在葡萄糖剥夺的状态下，间充质GBM细胞利用这些外源性脂肪酸， 作为一个重要的，替代来源的ATP，而在营养有利的条件下，中间代谢， 作为一种代谢线索，驱动支持细胞增殖的转录程序， 间充质分化因此，在标准、营养丰富的条件下抑制FAO会导致减少 然而，在间充质细胞中观察到强烈的能量应激和非凋亡性细胞死亡。 GBM细胞在葡萄糖剥夺的背景下。在这个应用中，我们建议扩展这些有前途的 通过定义增强粮农组织在GBM（目标1）的分子机制， FAO在胶质瘤的多种肿瘤生态背景下可能在胶质瘤发生中发挥的作用（目的2），并评估 通过能量应激引发GBM代谢合成致死的转化潜力（目的3）。