Medium-chain acyl-coenzyme A dehydrogenase as an essential feeder of glioblastoma multiforme

中链酰基辅酶 A 脱氢酶作为多形性胶质母细胞瘤的重要饲养者

基本信息

批准号：
10335175
负责人：
Giulio Francesco Draetta
金额：
$ 35.73万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335175
关键词：
Acute Astrocytoma Belief Bioenergetics Biological Models Cancer Center Cell Energetics Cells Clinical DNA Methylation DNA Repair Data Dependence Derivation procedure Development Disease Drug Targeting Enzymes Epidermal Growth Factor Receptor Epigenetic Process FLT3 gene Fermentation Fibroblast Growth Factor Receptors Frequencies Genes Genetic Genetic Diseases Genetic Transcription Genomics Glioblastoma Glioma Gliomagenesis Glucose Glycolysis Goals Grant Heterogeneity Histones Human Human Genetics In Vitro Inter-tumoral heterogeneity Knockout Mice Knowledge Lesion Libraries Life Light Lipids Malignant Glioma Malignant Neoplasms Metabolic Metabolic Pathway Metabolism Mission Mitochondria Modeling Mosaicism Mutation Oncogenic Outcome Oxygen Pathway Analysis Pathway interactions Patient-Focused Outcomes Patients Production Radiation Radiation therapy Recurrence Research Resistance Role Signal Pathway TP53 gene Tamoxifen The Cancer Genome Atlas Therapeutic Therapeutic Intervention Tissue Sample Toxic effect Translating United States National Institutes of Health Up-Regulation Ursidae Family Validation Warburg Effect acyl-CoA dehydrogenase aerobic glycolysis base cancer cell clinical practice dietary enzyme pathway fatty acid oxidation gene product glioma cell line glucose metabolism human disease improved improved outcome in vivo in vivo Model innovation knock-down lipid metabolism mitochondrial metabolism mouse model nerve stem cell new therapeutic target novel novel strategies overexpression oxidation patient population programs screening searchable database small hairpin RNA standard of care stem cell model stem cells targeted treatment temozolomide transcriptomics translational impact treatment response tumor tumor heterogeneity tumor progression

项目摘要

Summary Glioblastoma (GBM) is among the deadliest human cancers with a median survival of 15 to 19 months. Over 90% of patients treated with the current standard of care, concomitant temozolomide and radiotherapy, show tumor progression while on treatment. Consequently, recurrence is inevitable and the optimal management re- mains unclear. There is an urgent need to develop strategies for improving treatment options for GBM. GBM is among the most comprehensively genomically characterized tumors, which has confirmed extensive inter- tumoral heterogeneity. These studies have identified genetic lesions that provide a rationale for targeted treat- ments, but to date, the accumulated genetic characterization of GBMs has failed to significantly impact clinical practice and patient outcomes. In addition, extensive intratumoral heterogeneity in GBM is documented as bears functional relevance, influencing response to therapy. This includes varied metabolic adaptations that have been documented in GBM. The clear dependency of GBM on altered metabolic programs and an evolving under- standing of metabolic functional heterogeneity and adaptation in cancer prompted an unbiased screen for gene products that feed essential metabolic pathways in GBM. This identified Medium-chain Acyl-CoA Dehydrogen- ase (MCAD) as candidate feeder of GBM. The long-term goal of this research is identify novel therapeutic targets for the treatment of GBM. The overall objective is to evaluate the oncogenic mechanism of MCAD in GBM to determine whether this dependency represents a therapeutic opportunity, either directly through targeted inhibi- tion of MCAD, or indirectly by targeting the cancer-relevant pathways it regulates. The central hypothesis is that the essential activities of MCAD in GBM influence lipid metabolism, energy production, and/or epigenetic repro- gramming. The rationale for focusing on MCAD is based on the strong emergence of ACADM and other acyl- CoA dehydrogenases from the screening that uniquely employed low-passage, patient-derived glioma spheres (GSCs) in vivo to interrogate an shRNA library targeting 330 metabolism genes, convincing in vitro and in vivo validation of the dependence of GBM models on MCAD, and a very high frequency of elevated MCAD expression in human disease. The specific aims are to (i) elucidate the MCAD mechanism of action, (ii) evaluate the effect of MCAD on epigenetic reprogramming of cells, and (iii) evaluate tumor impact and tolerability of acute MCAD expression. This grant is significant because a deep understanding of the cancer-essential mechanism(s) of MCAD in GBM may illuminate a new molecule or pathway to target that may improve outcomes for patients with this deadly disease. It is anticipated that the research may be of high translational relevance if it is determined that effects of MCAD targeting may synergize with standard-of-care and/or targeted therapies that perturb DNA repair. The research is innovative because targeting lipid degradation enzymes represents a novel approach for a potential cancer therapeutic.

概括胶质母细胞瘤（GBM）是最致命的人类癌症之一，中位生存期为15到19个月。超过 90％的患者接受了当前护理标准，伴随替莫唑胺和放射疗法的患者治疗时肿瘤进展。因此，复发是不可避免的，最佳管理重新电源不清楚。迫切需要制定改善GBM治疗选择的策略。 GBM是在基因组最全面的肿瘤中，它已经证实了广泛的间隔肿瘤异质性。这些研究已经确定了遗传病变，这些病变为有针对性的治疗提供了理由 MENTS，但迄今为止，GBM的累积遗传表征未能显着影响临床练习和患者的结果。此外，GBM中广泛的肿瘤内异质性记录为熊功能相关性，影响对治疗的反应。这包括多种代谢适应记录在GBM中。 GBM对改变的代谢程序的明显依赖性以及不断发展的不足代谢功能异质性和癌症适应性的站立促使基因无偏见为GBM提供基本代谢途径的产品。这确定了中链酰基-COA脱氢 ASE（MCAD）作为GBM的候选喂食器。这项研究的长期目标是确定新颖的治疗靶标用于治疗GBM。总体目的是评估MCAD在GBM中的致癌机制确定这种依赖性是否代表治疗机会，直接通过靶向抑制 MCAD或通过靶向与癌症相关的途径的间接态度。中心假设是 MCAD在GBM中的基本活动会影响脂质代谢，能量产生和/或表观遗传学再生语法。专注于MCAD的理由是基于Acadm和其他酰基的强烈出现 COA脱氢酶来自筛查，该筛查使用了独特的低通量，患者衍生的神经胶质瘤球（GSC）在体内询问针对330个代谢基因的shRNA库，令人信服的体外和体内 GBM模型对MCAD的依赖性的验证以及MCAD表达升高的频率很高在人类疾病中。具体目的是（i）阐明MCAD作用机理，（ii）评估效果 MCAD对细胞的表观遗传重编程，（iii）评估急性MCAD的肿瘤影响和耐受性表达。这项赠款是重要的，因为对癌症必不可少的机制有深入的了解 GBM中的MCAD可能会阐明一种新的分子或目标途径，该途径可能会改善这种致命的疾病。预计如果确定研究可能具有很高的转化相关性 MCAD靶向的影响可能与扰动DNA的护理标准和/或靶向疗法协同作用维修。该研究具有创新性，因为靶向脂质降解酶代表了一种新颖的方法潜在的癌症治疗。