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Biguanide Sensitivity of Glioma Stem Cells

胶质瘤干细胞的双胍敏感性

基本信息

批准号：
10057268
负责人：
Biplab Dasgupta
金额：
$ 34.14万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057268
关键词：
Address Adult Biguanides Binding Sites Biochemical Biological Assay Brain Neoplasms CREB1 gene CRISPR/Cas technology Cell Culture Techniques Cell Line Cells ChIP-seq Clinic Collaborations Complex Core Facility DNA Binding Data Dose Elements Environment Enzymes Fatty Acids Genes Genetic Genetic Transcription Glioblastoma Glioma Glucose Glycolysis Goals Human In Vitro Lentivirus LoxP-flanked allele Luciferases Malignant Neoplasms Mass Spectrum Analysis Messenger RNA Metformin Methods Michigan Mitochondria Modeling Molecular Molecular Analysis Mus Myocardium Nutrient Pharmaceutical Preparations Pharmacology Study Phosphopeptides Phosphorylation Phosphotransferases Physiological Plasma Production Reagent Resistance Role Skeletal Muscle Stress System Testing The Cancer Genome Atlas Therapeutic Time Tissues Transcript Tumor Tissue Universities adenylate kinase brain tissue cancer cell cancer clinical trial druggable target enolase experimental study hypoxia inducible factor 1 improved in vivo interest knock-down metabolomics mouse model neoplastic cell novel novel therapeutics oxidation patient derived xenograft model pre-clinical programs sensor single cell proteins stem cell model stem cells tool transcription factor transcriptomics tumor tumor growth tumorigenesis

项目摘要

The biguanide metformin that inhibits mitochondrial complex I activity is now in over 200 oncology clinical trials. In this proposal we will determine how to enhance cancer cell sensitivity towards metformin therapy. There are two principal modes of cellular energy production – glycolysis and mitochondrial oxidation of glycose and fatty acids. Metformin inhibits mitochondrial energy production. Therefore, when switched to a low glucose medium (that reduces glycolysis), cancer cells become sensitized to metformin. Physiological glucose concentration in tissues is however significantly lower compared to that used in most cell culture studies and glucose concentration is even lower in tumor tissues. At this physiological range of glucose, cancer cells maintain high glycolytic rate and genes that regulate cancer cell glycolysis may resist biguanide action by upregulating compensatory glycolysis when mitochondria is inhibited. Therefore, identification and inhibition of such genes may enhance cancer cell liability towards biguanides. Despite promise in other cancers, our data shows that glioma stem cells (GSCs) are resistant to biguanides at physiological glucose. We discovered that the cellular energy sensor AMP kinase (AMPK) that augments glycolysis during stress in cardiac and skeletal muscle is co-opted by GSCs for optimal glycolysis. We propose to test the mechanisms by which AMPK regulates glycolysis in GSCs in vitro and in vivo. Through dose escalation pharmacological studies in mice we will determine maximum tolerated metformin dose in brain tumor-bearing mice, quantitate metformin plasma levels, and metformin concentrations attained in normal brain and tumor tissue. We will test if genetic inhibition of AMPK in GSCs reduces glycolysis, suppress proliferation and tumor growth and improves metformin sensitivity.

抑制线粒体复合物I活性的双胍二甲双胍目前在200多个国家上市。肿瘤临床试验在这项提案中，我们将确定如何增强癌细胞对二甲双胍治疗。细胞能量产生有两种主要模式-糖酵解和线粒体葡萄糖和脂肪酸的氧化。代谢酶抑制线粒体能量产生。所以当转换到低葡萄糖培养基（减少糖酵解），癌细胞变得对二甲双胍敏感。然而，组织中的生理葡萄糖浓度显著低于大多数细胞中使用的葡萄糖浓度。培养研究和肿瘤组织中的葡萄糖浓度甚至更低。在葡萄糖的生理范围内，癌细胞保持高糖酵解速率，调节癌细胞糖酵解的基因可能抵抗双胍当线粒体受到抑制时，通过上调代偿性糖酵解发挥作用。因此，识别和这些基因的抑制可增强癌细胞对双胍的易感性。尽管承诺在其他我们的数据显示，神经胶质瘤干细胞（GSC）在生理葡萄糖下对双胍类药物具有抗性。我们发现，细胞能量传感器AMP激酶（AMPK）在应激过程中增加糖酵解，心肌和骨骼肌被GSC选择用于最佳的糖酵解。我们建议测试的机制， AMPK在体外和体内调节GSC中的糖酵解。通过药理学剂量递增在小鼠中的研究中，我们将确定携带脑肿瘤的小鼠中二甲双胍的最大耐受剂量，定量二甲双胍血浆水平和在正常脑和肿瘤组织中获得的二甲双胍浓度。我们将测试如果GSC中AMPK的遗传抑制减少糖酵解，抑制增殖和肿瘤生长，提高二甲双胍敏感性。