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: 10057400
• 负责人: Prakash Chinnaiyan
• 金额: $ 33.68万
• 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/10057400
• 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)仍然是一种致命的恶性肿瘤，治疗选择有限。我们的 实验室研究肿瘤新陈代谢及其作为新的治疗靶点的潜力。通过一系列 通过研究，我们的小组已经发现，这种恶性肿瘤隐含的不同的肿瘤生态对 到相当大的瘤内代谢异质性和动态代谢重新编程，允许GBM 细胞在不同的微环境压力下适应和增殖。具体地说，通过整合 跨平台分析结合代谢组学和基因组学在患者来源的肿瘤中，我们发现 增强脂肪酸氧化(FAO)作为GBM中转录程序驱动的代谢节点 旨在从肿瘤微环境中进口和利用脂肪酸。这种代谢表型是 特异于GBM中的间质亚型，并在临床前模型中概括。功能分析 已发现这些脂肪酸在神经胶质瘤形成中扮演的特定角色，这依赖于营养 可用性。在缺糖状态下，间充质GBM细胞利用这些外源脂肪酸 作为ATP的重要替代来源，而在营养条件有利的情况下，中间代谢 作为新陈代谢信号，驱动转录程序支持细胞增殖和 间充质分化。因此，抑制粮农组织在标准的、营养丰富的条件下导致下降 然而，在间质中观察到了增殖、强烈的能量应激和非凋亡性细胞死亡。 缺糖背景下的基底膜细胞。在本应用程序中，我们建议扩展这些有希望的 通过定义在GBM(目标1)中管理加强粮农组织的分子机制的发现，描绘了多重 粮农组织在该肿瘤不同的肿瘤生态背景下可能在胶质瘤发生中发挥的作用(目标2)，并进行评估 通过能量应激诱导GBM代谢合成致死性的翻译潜力(目标3)。