A Novel Combinatorial Strategy Targeting the EGFR and JAK2/STAT3 Pathways in GBM Brain Tumour Initiating Cells

Simple item page
atmire.migration.oldid5704
dc.contributor.advisorWeiss, Samuel
dc.contributor.advisorLuchman, H. Artee
dc.contributor.authorJensen, Katharine
dc.contributor.committeememberGrewal, Savraj
dc.contributor.committeememberMahoney, Douglas
dc.contributor.committeememberNarendran, Aru
dc.date.accessioned2017-06-23T18:42:44Z
dc.date.available2017-06-23T18:42:44Z
dc.date.issued2017
dc.date.submitted2017en
dc.description.abstractGlioblastoma 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.en_US
dc.identifier.citationJensen, 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/24930en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/24930
dc.identifier.urihttp://hdl.handle.net/11023/3901
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity 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.
dc.subjectNeuroscience
dc.subject.otherGlioblastoma multiforme
dc.subject.otherCancer
dc.subject.otherBrain Tumour Initiating Cells
dc.subject.otherEGFR
dc.subject.otherJAK2/STAT3
dc.subject.otherCombinatorial Strategy
dc.subject.otherMolecular Therapeutics
dc.titleA Novel Combinatorial Strategy Targeting the EGFR and JAK2/STAT3 Pathways in GBM Brain Tumour Initiating Cells
dc.typemaster thesis
thesis.degree.disciplineNeuroscience
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameMaster of Science (MSc)
ucalgary.item.requestcopytrue
Files
Collections
Open Theses and Dissertations