The IGF axis as a mediator of treatment resistance in glioblastoma multiforme
Despite multimodality treatment with surgery, ionising radiation (IR) and chemotherapy, the outlook for patients with glioblastoma multiforme (GBM) is extremely poor. The unfavorable prognosis is linked to activation of DNA repair and cell signaling pathways, driving chemo/radio-resistance. GBMs express insulin-like growth factor receptors (IGF-1Rs) that mediate cell survival and invasion, and contribute in other tumour types to therapy resistance. Our recent data indicate that IGF-1R is overexpressed in paediatric GBM (pGBM) and associates with adverse survival. Furthermore we have initial evidence that pGBM cells are sensitised to IR by IGF-1R blockade. This project will investigate the hypothesis that IGFs drive treatment resistance in pGBM. Using genetic and pharmacological approaches the student will test effects of IGF blockade on pGBM resistance to IR and targeted agents. Depending on initial findings, subsequent directions may include investigation of the molecular basis of sensitisation, use of genome editing to explore the mutational context for response or resistance to IGF blockade, and in vivo assessment and imaging of novel IGF inhibitory agents in combination with IR or selected targeted drugs. The project will provide training in a wide range of research methods, and will contribute to evaluation of IGF-1R as a treatment target in pGBM.