Biologic consequence and therapeuticimplications of cysteine catabolism in glioblastoma

 描述（由申请人提供）：胶质母细胞瘤（GBM）仍然是一种致命的恶性肿瘤。用于理解这些侵袭性肿瘤的生物学以努力鉴定新的分子靶点的既定方法在很大程度上是基于基因型的。不幸的是，这种理解水平提供的临床收益有限，主要是基于与肿瘤发生相关的信号网络的复杂性质，以及无法描绘实际驱动个体肿瘤生长的关键“功能性”信号通路。虽然癌症可以获得各种各样的遗传和/或表观遗传修饰，但它们可以采用的代谢策略数量有限。我们研究的基本假设是：（1）在胶质瘤肿瘤发生过程中需要激活特定的代谢程序，（2）这些途径是可靶向的。我们最近在~70个胶质瘤中使用液相和气相色谱（LC/GC）结合串联质谱（MS）使用由>2000个标准品组成的代谢组学文库进行了全球代谢组学分析，以确定GBM使用的独特代谢程序。一个关键发现是鉴定了GBM中代谢中间体半胱氨酸亚磺酸（CSA）的蓄积，与II级胶质瘤相比，CSA是相对蓄积最高的代谢物。这代表了在癌症生物学背景下首次鉴定出这种代谢物。我们继续优化测定以定量组织中的CSA水平，证实了患者来源的肿瘤和GBM细胞系中该代谢信号传导轴的激活，并确定了其在适应缺氧中的作用。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，并确定其作为GBM中新分子靶点的潜力。

 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.