Browsing by Author "McKenzie, Brienne Alexandra"

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    Myxoma Virus Treatment for Brain Tumour Initiating Cells: Interrogating and Enhancing Myxoma-Mediated Cell Death
    (2012-12-20) McKenzie, Brienne Alexandra; Forsyth, Peter; Kurz, Ebba
    Brain tumour initiating cells (BTICs) are stem-like cells hypothesized to mediate recurrence in high-grade gliomas. Preclinical success has been demonstrated in treating patient-derived BTICs with oncolytic virotherapy, using replication-competent viruses to target and kill malignant cells. Myxoma virus (MyxV) is an oncolytic candidate, which is highly effective in conventional glioma models, but only modestly effective in BTICs. The objective of this study was to improve MyxV efficacy in BTICs in vitro, combining chemotherapeutics and virotherapy. Using a pharmacoviral screen, eleven compounds that enhance MyxV-mediated cell death were identified. A lead compound, axitinib, was validated in multiple BTIC models. It was demonstrated that a virally encoded protein, M011L, prevents MyxV-induced apoptosis in BTICs, and M011L disruption was shown to greatly improve MyxV-mediated cell death through apoptosis induction. These studies have elucidated multiple strategies for improving MyxV efficacy in a preclinical glioma model, with implications for the future clinical development of MyxV.