Functional genomic analysis of glioblastoma multiforme through short interfering RNA screening: a paradigm for therapeutic development.
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.
Thaker
Nikhil G
NG
University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, USA. thakerng@umdnj.edu
Zhang
Fang
F
McDonald
Peter R
PR
Shun
Tong Ying
TY
Lazo
John S
JS
Pollack
Ian F
IF
D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics*; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D055808:Drug Discovery / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D005820:Genetic Testing / Q000379:methods; D055106:Genome-Wide Association Study / Q000379:methods; D023281:Genomics / Q000379:methods*; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D010597:Pharmacogenetics / Q000379:methods; D025941:Protein Interaction Mapping; D040901:Proteomics / Q000379:methods; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use
D034741:RNA, Small Interfering