Aurora B Kinase Inhibition by AZD1152 Concomitant with Tumor Treating Fields Is Effective in the Treatment of Cultures from Primary and Recurrent Glioblastomas

Abstract

Tumor Treating Fields (TTFields) were incorporated into the treatment of glioblastoma, the most malignant brain tumor, after showing an effect on progression-free and overall survival in a phase III clinical trial. The combination of TTFields and an antimitotic drug might further improve this approach. Here, we tested the combination of TTFields with AZD1152, an Aurora B kinase inhibitor, in primary cultures of newly diagnosed (ndGBM) and recurrent glioblastoma (rGBM). AZD1152 concentration was titrated for each cell line and 5–30 nM were used alone or in addition to TTFields (1.6 V/cm RMS; 200 kHz) applied for 72 h using the inovitro™ system. Cell morphological changes were visualized by conventional and confocal laser microscopy. The cytotoxic effects were determined by cell viability assays. Primary cultures of ndGBM and rGBM varied in p53 mutational status; ploidy; EGFR expression and MGMT-promoter methylation status. Nevertheless; in all primary cultures; a significant cytotoxic effect was found following TTFields treatment alone and in all but one, a significant effect after treatment with AZD1152 alone was also observed. Moreover, in all primary cultures the combined treatment had the most pronounced cytotoxic effect in parallel with morphological changes. The combined treatment of TTFields and AZD1152 led to a significant reduction in the number of ndGBM and rGBM cells compared to each treatment alone. Further evaluation of this approach, which has to be considered as a proof of concept, is warranted, before entering into early clinical trials.

Aurora Kinase A Inhibition plus Tumor Treating Fields Suppress Glioma Cell Proliferation in a Cilium-Independent Manner

“…Since TTFields prolong patient survival, there are active searches for combinatorial drug targets, particularly those that interfere with tumor cell mitosis and cell survival mechanisms. Relevant to our study, an inhibitor of Aurora B kinase pathway, AZD1152 (Barasertib) displays both properties by disrupting mitosis and survival of newly diagnosed and recurrent GBM cells in vitro which is exacerbated by TTFields treatment (31). Our in vitro data suggest similar effects may be achievable by targeting Aurora A kinase pathway, a widely studied target across cancers (19, 37).…”

“…We grew adherent L0 and R24-3 cells in the presence of vehicle or AURKB inhibitor, AZD1152 (Barasertib). Given that as low as 5nM of AZD1152 significantly inhibited GBM cell proliferation in vitro (31), we used a range of 3-100nM of AZD1152 to examine GBM ciliogenesis 24hr after treatment. While we observed changes in nuclear size/morphology/number at all AZD1152 concentrations, we observed no effect of AZD1152 on the percent of ciliated GBM cells ( Suppl.…”

Theory and application of TTFields in newly diagnosed glioblastoma

“…This suggests that the combination of TTFields and aurora kinase inhibitor drugs can further improve antitumor efficacy. 73 …”

“…In an in vitro experiment, compared with either treatment alone, combination treatment with AZD1152 (an aurora B kinase inhibitor) and TTFields was found to significantly reduce the numbers of primary cultured ndGBM and rGBM cells. This suggests that the combination of TTFields and aurora kinase inhibitor drugs can further improve antitumor efficacy 73 …”