EXTH-33. COMPREHENSIVE TARGETING OF NOVEL MASTER REGULATORS OF CANCER STEM CELLS TO TREAT GLIOBLASTOMA – IN VIVO STUDY. (5th November 2018)

• Record Type: Journal Article
• Authors: Deng, Changwang; Sebastian, Mathew; Le, Son; Jin, Dan; Chen, Dongjiang; Thomas, Nagheme; Tran, David
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi92
• Page End: vi92
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.382
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Glioblastoma (GBM) is the most prevalent and aggressive brain cancer in adults. GBM is enriched with glioma stemlike cells (GSCs) that contribute to tumor initiation and treatment resistance and thus a natural focus for therapeutic development. However, targeting GSCs has been a challenge because of the dearth of knowledge of master regulators specific to GSCs and not to normal brain cells. Therefore systematic elucidation of the GSC specific core regulatory program will improve our understanding of GSC biology and provide an opportunity to develop novel GSC specific therapy with maximal efficacy and minimal toxicity. To accomplish these objectives, we have recently developed two innovative computational platforms, GeneRep and nSCORE and experimentally validated them in several published datasets. With this platforms, a cluster of 6 interrelated master subnetworks emerged, which were functionally grouped into the stemness and cancer pathways, some of which are known Olig and Myc factors. By enforcing the expression of this cluster in normal Human Astrocytes, we were able to reprogram these normal cells into GSC-like cells as measured by the neurosphere formation and in vivo tumorigenesis assays, confirming the contribution of this cluster for the GSC development. Furthermore, this cluster was present and functioned cooperatively to maintain GSCs in patient derived GSC lines. Functionally blockage individually or two of them by shRNA significantly reduces neurosphere formation and promotes cell death. Intracranial Injection of those gene-modified-GSCs into NSG mouse, dramatically double the mouse survival time. Most promising, preliminary data shows that in vivo tumor growth could be inhibited by either modulation of gene expression or via cancer vaccine. Our data establish a novel set of genes controlling GSCs survival and provide a compelling rationale for its therapeutic targeting to reduce tumor growth.