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Polo-like kinase 1 as a prognostic and therapeutic target in high-grade brain tumors

University of British Columbia

High-grade brain tumors have some of the highest rates of cancer-related death. Occurring predominately in adults, patients with glioblastoma (GBM) are not expected to survive longer than two years. Similarly, medulloblastoma (MB) is the most commonly occurring malignant brain tumor in children and, although these cases have a much better probability of survival, the severe impact of high-intensity treatment often causes long-term negative side effects. Unfortunately, high-grade brain tumors are frequently resistant to standard treatments like temozolomide (TMZ). Further, the development of new drugs is hindered by the blood-brain barrier and the astronomical cost of drug discovery and clinical evaluation. The immediate need for new treatment options encouraged our approach of querying compounds that have previously been tested in clinical trials. Herein, we found that TMZ resistant GBM cells express high levels of the mitotic kinase, Polo-Like Kinase 1 (PLK1) and that TMZ resistance can be overcome using PLK1 kinase inhibitors, such as BI-2536. An assessment of off-patent drugs revealed that the anti-alcoholism treatment, disulfiram (DSF), also had efficacy in eliminating PLK1-high cells and this work proposes DSF can be repurposed for cancer treatment. The importance of PLK1 was further investigated in a retrospective study of MB patient samples that were assessed with the NanoString nCounter system. Cases with high PLK1 expression were more likely to relapse and had worse overall survival. This work suggests that stratification of these high-risk cases can identify patients that may benefit from PLK1 inhibitors, which cause G2/M arrest and apoptosis. Notably, both DSF and BI-2536 treatment had no negative growth effects on normal brain cells. Finally, translationally controlled tumor protein (TCTP) is a substrate of PLK1 that is used as a marker of kinase activity. An exploration of the clinical and mechanistic impact of TCTP demonstrated a striking association with the sonic hedgehog (SHH) MB subtype, as well, as establishing its role in cancer cell proliferation. In conclusion, the studies outlined in this thesis encourage the investigation of PLK1 as a therapeutic target in high-grade brain tumors and emphasizes the potential benefit of fighting cancer with repurposed drugs.

Text

2015-08-18

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/54512

Experimental Medicine

University of British Columbia

UBCV

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