Biologic consequence and therapeuticimplications of cysteine catabolism in glioblastoma

 描述(申请人提供)：胶质母细胞瘤(GBM)仍然是一种致命的恶性肿瘤。为了确定新的分子靶点，已建立的了解这些侵袭性肿瘤生物学的方法在很大程度上是基于基因的。不幸的是，这种水平的理解所提供的临床成果是有限的，主要是基于与肿瘤发生相关的信号网络的复杂性，以及无法描绘出实际推动单个肿瘤生长的关键“功能”信号通路。虽然癌症可以获得广泛的遗传和/或表观遗传修饰，但他们可以使用的代谢策略数量有限。我们研究的基本假设是：(1)在胶质瘤的发生过程中需要激活特定的代谢程序，以及(2)这些途径是有针对性的。最近，我们使用包含&gt；2000标准的代谢组文库，用液、气相色谱(LC/GC)和串联质谱仪(MS)对大约70个胶质瘤进行了全球代谢组分析，以努力确定GBM使用的独特代谢程序。一项关键发现是确定了代谢中间产物半胱氨酸亚磺酸(CsA)在GBM中的积聚，与II级胶质瘤相比，CsA是相对积聚最高的代谢物。这代表了在癌症生物学的背景下首次鉴定这种代谢物。我们继续优化分析方法以量化组织中CsA的水平，证实在患者来源的肿瘤和GBM细胞系中这一代谢信号轴被激活，并确定其在适应低氧中的作用。在拟议的研究中，我们现在试图使用基于通量的研究来验证这个代谢节点，并确定它作为GBM新的分子靶点的潜力。

 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.