EXTH-75. THE AURORA KINASE A INHIBITOR ALISERTIB IS SYNERGISTIC WITH IRINOTECAN AND CARBOPLATIN AGAINST GLIOBLASTOMA CELLS

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2018-11, Vol.20 (suppl_6), p.vi101-vi101
• Main Authors: Burton, Eric, Zumbar, Cory, King, Paul, Sak, Muge, Usubalieva, Aisulu, Li, Xiaohui, Mifsud, Caroline, McElroy, Joseph, Lehman, Norman
• Format: Article
• Language: English
• Subjects: Abstracts
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noy148.422

Abstract INTRODUCTION Alisertib is a selective AURKA inhibitor currently in clinical trial for recurrent glioblastoma. We have previously shown that alisertib potently inhibits growth of glioblastoma cells in vitro and in vivo. As effective chemotherapeutic approaches for refractory glioblastoma may require a combination of agents, we tested the efficacy of alisertib to potentiate the effects of carboplatin and irinotecan. METHODS The ability of alisertib to potentiate the growth inhibitory effects of these agents was assessed by using colony formation assays with cultured glioblastoma cells. RESULTS Alisertib potentiated the anti-proliferative action of both irinotecan and carboplatin in these assays. This effect was often synergistic, including against glioblastoma tumor stem-like cells (neurospheres), as demonstrated by Chou-Talalay and Bliss analyses. We then compared O6-methylguanine DNA methyltransferase (MGMT) expression levels of each cell line by western blotting, and found that high MGMT expression correlated with more pronounced potentiation of carboplatin’s growth inhibitory effects by alisertib, while low MGMT expression correlated with stronger potentiation of irinotecan by alisertib. This suggests that MGMT expression levels may be predictive of patient response to these drug combinations, however additional studies are required to confirm this possibility. CONCLUSIONS Since clinical experience with alisertib, carboplatin and irinotecan as single agents already exists, these findings may provide rationale for the design of clinical trials for their use in combination treatment regimens.