Weiss, SamuelLuchman, H. ArteeJensen, Katharine2017-06-232017-06-2320172017Jensen, K. (2017). A Novel Combinatorial Strategy Targeting the EGFR and JAK2/STAT3 Pathways in GBM Brain Tumour Initiating Cells (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/24930http://hdl.handle.net/11023/3901Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary adult brain tumour with a median survival of only 15 months. Despite aggressive treatment, long-lasting tumour control cannot be achieved and disease recurrence is inevitable. Brain tumour initiating cells (BTICs) are postulated to be at the root of disease initiation and recurrence, suggesting that BTIC targeting therapies are crucial to establishing tumour control. Resistance of cancer cells to targeted therapies can occur through the activation of compensating signalling pathways. Using a BTIC model of GBM, we identified the activation of signal transducer and activator of transcription (STAT)3 as a compensation mechanism in response to epidermal growth factor receptor (EGFR) inhibition. We showed that concurrent inhibition of EGFR and STAT3 was highly effective in vitro, as it dramatically decreased BTIC viability and neurosphere formation. Combined inhibition of EGFR and STAT3 resulted in the attenuation of both oncogenic signalling pathways. In vivo, systemic administration of the EGFR inhibitor, afatinib, and the JAK2 inhibitor, pacritinib, demonstrated favourable pharmacokinetic and pharmacodynamic properties, displaying blood-brain barrier penetration and on-target activity in orthotopic BTIC xenografts. Overall, these data provide a promising strategy to overcome EGFR inhibitor resistance by targeting two oncogenic pathways in combination.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.NeuroscienceGlioblastoma multiformeCancerBrain Tumour Initiating CellsEGFRJAK2/STAT3Combinatorial StrategyMolecular Therapeuticsmaster thesis10.11575/PRISM/24930