Glioblastoma is the most common and aggressive malignant brain tumor with an invariably poor prognosis of less than 15 months. Glioblastoma is virtually incurable due to high drug resistance and relapse after radiotherapy or chemotherapy, which highlights the urgent need for more intensive research and novel glioblastoma therapeutics.
Recent studies suggest that relapse is due to glioblastoma initiating cells (GICs), which represent the current target for glioblastoma therapy. However, identification of GIC targets for drug discovery is limited by challenges of isolation, purification and characterization of GICs. Our knowledge of gene abnormality from glioblastoma case studies allow us to hypothesize that a model of GICs could be derived from pluripotent stem cells engineered with appropriate mutations involved in PI3K pathway. The aims of this study are to develop a mouse iPSC-derived GIC model, and to use it to investigate protein phosphorylation, in particular, downstream of PI3K signaling, as well as to screen therapeutics.
Cell tissue, from floxed Pik3caH1047R/PTEN engineered mice, was used as a source of induced pluripotent stem cells (iPSC) by applying recently optimized Cre-excisable Dox-inducible Polycistronic OKSM Lentivirus system. These iPSCs are being used to derive neural stem (NS) cells and then the GIC model is activated by inducing expressing of Cre-recombinase to excise the floxed PTEN and activate expression of Pik3caH1047R. Then, our objective is to use the established mouse GIC model combined with proteomics techniques to identify phosphorylated proteins downstream of PI3K signaling in order to screen potential therapeutics.
At present our GIC model is being established and optimized. Mutated NS cells exhibit more rapid growth, suggesting that they represent a good model for study of PI3K signaling for potential therapeutic targets. This iPS-derived GIC model is a promising model to investigate basic glioblastoma research and to reveal new targets for suppression of GIC activity.