Glioblastoma is the most common and most malignant form of primary brain tumour. It affects both children and adults and remains virtually incurable. As a result, it is a leading cause of cancer-related deaths and more effective therapeutic strategies are urgently needed. Herein, I propose to use an innovative methodology combining high-throughput drug screening, pathway analysis and functional genomics to simultaneously develop new treatment modalities and identify novel therapeutic targets / biomarkers for glioblastoma. Using high-throughput screening based on drug repositioning principles, I will first identify already approved drugs that can increase the efficacy of conventional and targeted therapies for glioblastoma. Taking advantage of the first-class and clinically-relevant models of glioblastoma available in the host institution, I will then evaluate the therapeutic potential of the hit compounds in vivo. In parallel, using pathway analysis tools and the known targets of the hit compounds, I will generate a list of genes potentially involved in treatment resistance in glioblastoma. The significance of these genes will then be validated using RNA interference-based high-throughput screening. Finally, the patho-physiological role of the key genes identified and validated by this approach will be investigated by functional genomics and their prognostic and/or predictive value will be evaluated using the unique collection of clinically-annotated samples from glioblastoma patients available in the host institution. Overall, this research project will lead to the identification and pre-clinical validation of innovative treatment combinations for glioblastoma, and the discovery of novel therapeutic targets and biomarkers to be used in future clinical trials. It will thus increase our understanding of the biology and resistance to therapy of glioblastoma and has the potential to significantly impact on clinical practice and patient outcome.