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Molecular targeting of polo-like kinase 1 (PLK1) for the treatment of brain tumours

University of British Columbia

Brain cancer is a disease that is difficult to treat and has a high mortality rate. Two of the major challenges facing current treatments are disease relapse and drug resistance. Disease relapse may be attributable to brain tumour initiating cells (BTICs), which are multi-potent stem-like cells endowed with the ability to self-renew and generate differentiated cells that form the bulk of a tumour. BTICs are notably resistant to conventional chemotherapy and radiation and may therefore survive treatments, repopulate new tumours and cause disease relapse. Failure to respond to Temozolomide (TMZ), a DNA alkylating agent used as a front-line therapy for glioma, is frequently observed in glioma patients with O⁶-methylguanine-DNA methyltransferase over-expression. Furthermore, despite being largely ineffective in the pediatric population, TMZ is routinely used in clinic due to the lack of therapeutic agents that cross the blood-brain-barrier. There is an imperative need to seek alternative therapeutic strategies to address these issues. In the studies described herein, we identified polo-like kinase 1 (PLK1) as a novel molecular target for the treatment of the most common malignant brain tumours in adults and children, glioblastoma multiforme (GBM) and medulloblastoma (MB), respectively. In our studies, PLK1 is highly expressed in GBM and MB cultured cell lines, tumour tissues and patient-derived primary isolates but not in the normal brain cells including astrocytes, neurons and human neural stem cells. Targeting PLK1 by siRNA or the small molecule inhibitor BI2536 suppressed cell growth and induced cell cycle arrest accompanied by apoptosis in both GBM and MB. Of note, PLK1 inhibition had the unique capacity of obliterating GBM and MB BTICs, as well as TMZ-resistant GBM cells. To further the study, we demonstrated that BI2536 delayed disease progression and prolonged the survival of mice bearing orthotopic GBM or MB brain tumours. In addition, we established the prognostic importance of PLK1 as an independent marker for patient survival in both GBM and MB, lending further support to targeting this kinase in brain cancer treatment.  

Text

2013-08-15

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/44820

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/