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Functional genomic analysis of glioblastoma multiforme through short interfering RNA screening: A paradigm for therapeutic development

机译:通过短时干扰RNA筛选对多种胶质母细胞瘤的功能基因组学分析:治疗开发的范例

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摘要

Glioblastoma multiforme (GBM) is a high-grade brain malignancy arising from astrocytes. Despite aggressive surgical approaches, optimized radiation therapy regimens, and the application of cytotoxic chemotherapies, the median survival of patients with GBM from time of diagnosis remains less than 15 months, having changed little in decades. Approaches that target genes and biological pathways responsible for tumorigenesis or potentiate the activity of current therapeutic modalities could improve treatment efficacy. In this regard, several genomic and proteomic strategies promise to impact significantly on the drug discovery process. High-throughput genome-wide screening with short interfering RNA (siRNA) is one strategy for systematically exploring possible therapeutically relevant targets in GBM. Statistical methods and protein-protein interaction network databases can also be applied to the screening data to explore the genes and pathways that underlie the pathological basis and development of GBM. In this study, we highlight several genome-wide siRNA screens and implement these experimental concepts in the T98G GBM cell line to uncover the genes and pathways that regulate GBM cell death and survival. These studies will ultimately influence the development of a new avenue of neurosurgical therapy by placing the drug discovery process in the context of the entire biological system.
机译:多形胶质母细胞瘤(GBM)是星形胶质细胞引起的高级脑恶性肿瘤。尽管采取了积极的外科手术方法,优化的放射治疗方案以及细胞毒性化学疗法的应用,GBM患者自诊断开始的中位生存期仍不到15个月,几十年来几乎没有变化。靶向负责肿瘤发生的基因和生物学途径或增强当前治疗方式的活性的方法可以提高治疗效果。在这方面,几种基因组和蛋白质组学策略有望显着影响药物发现过程。使用短干扰RNA(siRNA)进行高通量全基因组筛选是系统探索GBM中可能的治疗相关靶标的一种策略。统计方法和蛋白质-蛋白质相互作用网络数据库也可以用于筛选数据,以探索构成GBM病理基础和发展的基因和途径。在这项研究中,我们重点介绍了几个全基因组的siRNA筛选,并在T98G GBM细胞系中实施了这些实验性概念,以揭示调节GBM细胞死亡和存活的基因和途径。这些研究将把药物发现过程置于整个生物系统的范围内,最终将影响神经外科治疗新途径的发展。

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