Inhibition of Polo-like Kinase 4 as Therapy for Glioblastoma Primary Brain Tumors

Glioblastoma (GBM) is an aggressive disease known to be almost universally fatal with 5% survivors. Current therapeutic measures for GBM are broadly ineffective; therefore development of novel treatment options is of paramount importance. Polo-like kinase (PLK)-4 is a centriole protein essential for regulating cell division and it has been reported that PLK proteins are uniquely overexpressed in 80% of tumors. PLK-4 overexpression is not observed in normal cells, making this protein an ideal and selective drug target. In this study a PLK-4 inhibitor, developed previously, was tested for its effect on GBM cells in culture. This PLK-4 inhibitor blocks mitotic division by allowing DNA replication to continue in the absence of cytokinesis, impeding proliferation and leading to cell death. We hypothesize that this PLK-4 inhibitor can be used as a therapeutic agent to treat glioblastoma by exploiting mitotic arrest to promote cell death. The first study was an in silico assay which revealed a -9.2kcal/mol binding affinity of the drug to the protein target. For the rest of the molecular studies, different primary tumor cell lines developed from patients with glioblastoma were incubated with the drug in culture. We measured cellular viability over time and found that 80% of the tested cell lines were sensitive to at least 20nM of the drug. Furthermore, flow cytometry analysis revealed that more than 50% of cells from each cell line tested became polyploidy. We also explored the synergistic effects between with the PLK-4 inhibitor drug and a DNA damaging agent and found possible potentiation. Our data suggests that this specific PLK-4 inhibitor is a promising therapeutic agent that can effectively inhibit proliferation of GBM.