Molecular Mechanisms of Tumour Resistance Laboratory
Approximately 2000 Australians are expected to be diagnosed with brain cancer and about 1500 Australians will die this year. The most severe form of brain cancer, Glioblastoma (also known as GBM or grade IV astrocytoma) is the most common primary tumour of the central nervous system and is classified as one of the most aggressive. Surgery to remove the bulk of the tumour followed by standard treatment of radiotherapy and chemotherapy (mainly using the chemotherapeutic temozolomide) is the usual treatment regimen used for these patients. However, the residual tumour cells unable to be removed by surgery are often resistant to this treatment leading to rapid tumour reccurence and an overall poor survival rate of less than 15 months post surgery.
Therefore, there is a urgent need to further understand the critical molecular mediators of tumour recurrence and tumour resistance to therapy and more importantly overcome this resistance with novel therapeutics. Our laboratory particularly focuses on both these critical questions. This project will definitively analysis the molecular systems that mediate resistance to the current therapeutics used to treat glioblastoma utilising primary and established glioblastoma cell lines, genetic and patient-derived xenograft animal models and patient tumour tissue. Specifically, we will use a combination of large scale genome wide and phospho-proteomic analysis, cell and molecular biology based studies and bio-informatics approaches to achieve this goal. Furthermore, our laboratory will identify novel agents that can overcome this resistance isolating agents that are effective in the treatment of glioblastoma patients. Overall, this project is expected to yield important novel biomarkers for resistance to current therapeutic agents used clinically for the treatment of glioblastoma.
Ms Lucia Paradiso, Research Assistant,
Prof Andrew Scott (Olivia Newton John Cancer Research Centre – Austin Hospital branch).
Dr Hui Gan (Olivia Newton John Cancer Research Centre – Austin Hospital branch).
Dr Leonie Quinn (University of Melbourne, Dept of Anatomy, Parkville)
Dr Theo Mantamadiotis (University of Melbourne, Dept of Pathology, Parkville)
2016 – 2019Victorian Cancer Agency Mid-career Research Fellowship “Overcoming Resistance to Epidermal Growth Factor Receptor Targeted Therapy” ($559,088).
2015 – 2016Cure Brain Cancer Foundation “Circulating microRNA as a biomarker in brain cancer” Morokoff, A.M., Drummond, K., Luwor, R.B., ($200,000).
1. Areeb, Z., Stylli, S.S., Ware, T.M.B., Harris, N.C., Shukla, L., Shayan, R., Paradiso, L., Li, B., Morokoff, A.P. Kaye, A.H. and Luwor, R.B. Inhibition of Glioblastoma Cell Proliferation, Migration and Invasion by the Proteasome Antagonist Carfilzomib. (Med Oncol 2016 May;33(5):53).
2. Ching, J., Amiridis, S., Stylli, S.S., Bjorksten, A.R., Zheng, T., Paradiso, L., Luwor, R.B., Morokoff, A., O'Brien, T.J. and Kaye, A.H. The Peroxisome Proliferator Activated Receptor Gamma agonist Pioglitazone modulates functional expression of the glutamate transporter Excitatory Amino Acid Transporter 2 (EAAT2) in human glioblastoma cells. Oncotarget 2015 Aug 28;6(25):21301-14.
3. Areeb, Z., Stylli, S.S., Koldej, R., Ritchie, D.S., Siegal, T., Morokoff, A.P., Kaye, A.H. and Luwor, R.B. Micro RNA as Potential Biomarkers in Glioblastoma, J Neuro-Oncol 2015 Nov;125(2):237-48
.4. Luwor, R.B., Stylli, S.S. and Kaye, A.H. The Role of Stat3 in Glioblastoma Multiforme. J Clin Neurosci., 20(7): 907-11, 2013.
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