Biologic consequence and therapeuticimplications of cysteine catabolism in glioblastoma

胶质母细胞瘤中半胱氨酸分解代谢的生物学后果和治疗意义

基本信息

批准号：
9266514
负责人：
Prakash Chinnaiyan
金额：
$ 22.8万
依托单位：
WILLIAM BEAUMONT HOSPITAL RESEARCH INST
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：
2016-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9266514
关键词：
Attenuated Automobile Driving Biological Biological Assay Biological Models Biology Brain Neoplasms Cancer Biology Catabolism Cell Line Cell Survival Cells Clinical Complex Coupled Cysteine Cysteine Metabolism Pathway Cysteine dioxygenase Cystine Data Set Development Enzymes Epigenetic Process Evaluation Gas Chromatography Genetic Genotype Glioblastoma Glioma Glucose Glutathione Growth Hypoxia In Vitro Individual Investigation Label Libraries Liquid substance Malignant Neoplasms Mass Spectrum Analysis Mediating Metabolic Metabolic Activation Metabolic Pathway Metabolism Mitochondria Modeling Modification Molecular Target Monitor Nature Pathway interactions Patients Phenotype Play Pre-Clinical Model Research Role Signal Pathway Signal Transduction Stress Testing Therapeutic Intervention Tissues Tumor Biology Tumor-Derived Warburg Effect attenuation base cysteine sulfinic acid extracellular in vivo insight knock-down metabolomics novel programs public health relevance small hairpin RNA tandem mass spectrometry therapeutic target tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma (GBM) continues to be an invariably fatal malignancy. The established approach for understanding the biology of these aggressive tumors in an effort to identify novel molecular targets has largely been genotype based. Unfortunately, clinical gains offered by this level of understanding have been limited, largely based on the complex nature of signaling networks associated with tumorigenesis and the inability to delineate the key "functional" signaling pathways actually driving growth in an individual tumor. While cancers have access to a wide variety of genetic and/or epigenetic modifications, there are a limited number of metabolic strategies that they can employ. The underlying hypotheses of our research are that (1) activation of specific metabolic programs are required during glioma tumorigenesis, and (2) these pathways are targetable. We recently performed global metabolomic profiling in ~70 gliomas with liquid and gas chromatography (LC/GC) coupled with tandem mass-spectrometry (MS) using a metabolomic library consisting of >2000 standards in an effort to identify unique metabolic programs utilized by GBM. A key discovery was the identification of the accumulation of the metabolic intermediate cysteine sulfinic acid (CSA) in GBM, which ranked as the metabolite with the highest relative accumulation when compared to Grade II glioma. This represents the first identification of this metabolite in the context of cancer biology. We went on to optimize assays to quantify CSA levels in tissue, confirmed activation of this metabolic signaling axis in both patient derived tumors and GBM cell lines, and established its role in adapting to hypoxia. In the proposed study, we now seek to validate this metabolic node using flux-based studies and determine its potential to serve as a novel molecular target in GBM.

描述（由适用提供）：胶质母细胞瘤（GBM）仍然是致命的恶性肿瘤。理解这些侵略性肿瘤的生物学的既定方法，以鉴定新的分子靶标，这在很大程度上基于基因型。不幸的是，这种理解水平所提供的临床收益受到限制，这主要基于与肿瘤发生相关的信号网络的复杂性质以及无法描述实际驱动单个肿瘤生长的关键“功能”信号通路。尽管癌症可以使用多种遗传和/或表观遗传修饰，但它们可以采用有限的代谢策略。我们研究的基本假设是（1）在神经胶质瘤肿瘤发生过程中需要激活特定的代谢程序，并且（2）这些途径是可定位的。最近，我们使用由> 2000标准组成的代谢组库中的液体和气相色谱法（LC/GC）以及串联质量 - 光谱法（MS）进行了〜70个神经膜瘤的全局代谢组分析，并进行了串联质量质谱法（MS），以识别GBM使用的独特代谢程序。一个关键的发现是鉴定了GBM中代谢中间半胱氨酸硫酸（CSA）的积累，与II级胶质瘤相比，该代谢物是具有最高相对积累的代谢物。这代表了使用基于通量的研究对该代谢节点的首次识别，并确定了其作为GBM中新型分子靶标的潜力。