We and others have identified a PI3-kinase modulated epigenetic regulation of a HOX gene cluster to be associated with resistance to alkylating agent chemotherapy and poor clinical outcome in both paediatric and adult glioblastoma. This process is thought to be mediated via phosphorylation of EZH2, a member of the Polycomb repressive complex (PRC) with intrinsic histone methyltransferaseactivity that is also important for stem cell maintenance. It is not clear whether these prognostic and predictive associations are due to direct oncogenic actions of the HOX genes, or due to effects on the self-renewal capacity of brain tumour initiating cells. We propose to investigate the mechanisms of drug resistance and gliomagenesis mediated via this signaling pathway, using an iterative molecular cell biology approach on paediatric and adult glioblastoma cell lines and primary neurosphere cultures. We will also utilise novel PI3-kinase/Akt and histone methyltransferase inhibitors developed within The Institute to both deconvolute the signaling mechanisms involved, as well as test the most promising strategies for therapeutic intervention using orthotopic models of the disease. This project will provide a training in a range of techniques including cell and molecular biology, molecular pathology and molecular pharmacology.