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Introduction Hyperactivation of the PI3K signalling is common in cancers but the precise role of the pathway in glioma biology remains to be determined. Some understanding of PI3K signalling mechanisms in brain cancer comes from studies on neural stem/progenitor cells, where signals transmitted via the PI3K pathway cooperate with other intracellular pathways and downstream transcription factors to regulate critical cell functions. Material and methods To investigate the role for the PI3K pathway in glioma initiation and development, we generated a mouse model targeting the inducible expression of a PIK3CAH1047A oncogenic mutant and deletion of the PI3K negative regulator, PTEN, to neural stem/progenitor cells (NSPCs). Results and discussions Expression of a Pik3caH1047A was sufficient to generate tumours with oligodendroglial features but simultaneous loss of PTEN was required for the development of invasive, high-grade glioma. Pik3caH1047A-PTEN mutant NSPCs exhibited enhanced neurosphere formation which correlated with increased WNT signalling, while loss of CREB in Pik3ca-Pten tumours led to longer symptom-free survival in mice. Conclusion Taken together, our findings present a novel mouse model for glioma demonstrating that the PI3K pathway is important for initiation of tumourigenesis and that disruption of downstream CREB signalling attenuates tumour expansion. Recently developed experimental compounds which target CREB can inhibit tumour cell proliferation in vitro and in vivo therefore, co-targeting archetypal oncogenic pathways, including PI3K, MAPK and WNT, as well as transcription factors such as CREB, may prove to be effective therapeutic approaches for difficult to treat cancers, including high-grade glioma.