Our previous work has identified four neurodevelopmental transcription factors as master regulators of a stem-like state in glioblastoma. Our network model currently contains ~50 nodes that are both transcriptional targets and protein partners of these factors. Our lab is designing guide RNA (gRNA) for the CRISPR/CAS9 genome-editing technology to generate functional knock-out of these regulators. We are evaluating the effect of genome-editing with both in vitro (self-renewal, differentiation, viability) and in vivo (orthotopic tumor-propagation) assays. When applicable (e.g. chromatin regulators) the genome-wide positioning of functionally relevant proteins is mapped and their druggability assessed. We use computational analytical tools to integrate our findings. The information will be used to further establish a global model of regulatory networks that are critical to glioblastoma cells and assess novel therapeutic options.