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HDAC inhibitors reverse the Warburg Effect and Elicit Metabolic Vulnerabilities in Model Systems of Glioblastoma

HDAC 抑制剂逆转 Warburg 效应并引发胶质母细胞瘤模型系统中的代谢脆弱性

基本信息

批准号：
10649574
负责人：
MARKUS D SIEGELIN
金额：
$ 40.5万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649574
关键词：
Acute Adult Animals Apoptosis Autophagocytosis Binding Biological Models Brain Neoplasms Carbon Isotopes Cell Respiration Cells Cellular Metabolic Process ChIP-seq Clinical Combined Modality Therapy Coupled Dependence Diagnosis Digestion Disease Disease Progression Down-Regulation Energy Metabolism Enhancers Enzymes Epigenetic Process FDA approved Gene set enrichment analysis Genes Genetic Glioblastoma Glioma Glucose Glycolysis Goals HDAC1 gene Histone Deacetylase Histone Deacetylase Inhibitor Histones In Vitro Induction of Apoptosis Life Expectancy Link Lipids Lysosomes Malignant Neoplasms Malignant neoplasm of brain Mediating Metabolic Metabolism Mitochondria Molecular Multiple Myeloma Mus Nonesterified Fatty Acids Oxidative Phosphorylation Oxygen Pathway interactions Patients Pharmaceutical Preparations Predisposition Primary Brain Neoplasms Process Production Prognosis Promoter Regions Research Role Signal Transduction Testing Therapeutic Therapeutic Intervention Time Translations United States Vorinostat Warburg Effect aerobic glycolysis antitumor effect c-myc Genes combat etomoxir experimental study extracellular fatty acid oxidation in vivo in vivo Model inhibitor innovation molecular subtypes neoplastic cell novel novel therapeutic intervention oxidation patient derived xenograft model pharmacologic pre-clinical programs public health relevance resistance mechanism stable isotope standard of care stem temozolomide therapy resistant transcription factor transcriptome translational potential treatment strategy tumor tumor metabolism

项目摘要

Glioblastoma multiforme (GBM) is the most common primary brain tumor with about 8500 cases diagnosed each year in the United States. Within a time frame of roughly one year almost all patients succumb to this detrimental disease despite treatment. Therefore, novel, ideally tumor specific approaches are necessary to combat these tumors. Akin to other malignancies, GBMs depend on aerobic glycolysis, meaning that paradoxically glucose is metabolized to lactate in the presence of an abundance of molecular oxygen (Warburg-effect). Based on a chromatin immunoprecipitation sequencing and transcriptome analysis, we found that HDAC-inhibition through panobinostat, vorinostat and FK228 results in reprogramming of metabolism in stem-like and established GBM cells, which is orchestrated in part by the modulation of three key transcription factors. This leads to a significant reduction of glycolysis (reversal of the Warburg effect) with lower overall ATP levels. HDAC treated GBM cells reactivate oxidative phosphorylation (OXPHOS). Consistently, interference with mitochondrial translation or ATP production enhanced apoptosis in stem-like glioma and patient derived xenograft (PDX) cells. To fuel OXPHOS, HDAC treated glioblastoma cells increased the levels of transporters and enzymes related to fatty acid oxidation (FAO) and pharmacological inhibition of FAO by the clinically validated compound, Etomoxir, synergistically induced apoptosis in PDX, stem-like and established glioblastoma cells in vitro as well as in PDX models in vivo. Overall, this research will enhance our understanding about the treatment of brain tumors and may potentially allow us to formulate a novel treatment strategy for glioblastomas and other gliomas.

多形性胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，美国每年确诊8500例。在一段时间内，一年后，几乎所有的病人都死于这种有害的疾病，尽管进行了治疗。因此，新的，理想的肿瘤特异性方法是必要的，以打击这些肿瘤的与其他恶性肿瘤相似，GBM依赖于有氧糖酵解，这意味着矛盾的是，葡萄糖在存在大量分子氧（Warburg效应）。基于染色质免疫沉淀通过测序和转录组分析，我们发现通过帕比司他、伏立诺他和FK228导致干细胞样代谢的重编程，并建立GBM细胞，这部分是由三个关键的调节协调，转录因子这导致糖酵解的显著减少（糖酵解的逆转）。瓦尔堡效应），总体ATP水平较低。HDAC处理的GBM细胞重新激活氧化磷酸化（OXPHOS）。一致，干扰线粒体翻译或ATP产生增强干细胞样胶质瘤和患者的细胞凋亡衍生的异种移植（PDX）细胞。为了给OXPHOS提供燃料，HDAC处理的胶质母细胞瘤细胞增加与脂肪酸氧化有关的转运蛋白和酶的水平（粮农组织）以及通过临床验证的化合物，依托莫西，协同诱导PDX、干细胞样和已建立的胶质母细胞瘤细胞凋亡，体外以及体内PDX模型。总的来说，这项研究将提高我们的了解脑肿瘤的治疗，并可能使我们能够为胶质母细胞瘤和其他胶质瘤制定新的治疗策略。