Abstract 695: Synergistic antitumor effects of polo like kinase inhibitor volasertib in combination with ionizing radiation in glioblastoma Conference Paper uri icon


  • Abstract Despite the availability of hundreds of drugs, there is little data on the efficacy of these agents in the extremely heterogeneous populations of tumor cells observed in glioblastoma. In this study, a high-throughput compound-screening (HTS) assay was used to identify drug sensitivities of a panel of 15 glioblastoma stem cell (GSC) lines, which are representative of the classic the cancer genome atlas (TCGA) molecular subtypes, to 21 compounds in Published Protein Kinase Inhibitor Set (PKSI). This HTS screen identified sensitivity of GSCs to inhibition of polo like kinase-1 (PLK-1), a key regulator of mitosis. Given that PLK-1 is often overexpressed in a broad spectrum of cancers, and with highest expression levels being correlated with poor prognosis in several cancer types as well, we further verified the HTS result with the second-generation PLK1 inhibitor volasertib as a single agent or in combination with ionizing radiation in GSCs. Efficacy of volasertib was analyzed by Cell-Titer Glo 5 days after treatment. Morphological and molecular changes were approached by immunoblotting and flow cytometry after volasertib treatment, and in combination with ionizing radiation at 2 Gy. In vitro studies showed that volasertib inhibited cell viability with an IC50 ranging from 44.3nM to 4.36M. Volasertib induced G2/M arrest accompanied by high levels of PLK-1, Aurora B and phosphor-histone 3 and prominent cleaved poly ADP ribose polymerase (PARP) in a dose- and time-dependent manner. Colony formation assay demonstrated that volasertib and ionizing radiation had synergistic effects on colony formation inhibition, suggesting that GSCs arrested in M phase by volasertib are more sensitive to ironizing radiation. The promising in vitro results of volasertib in GSCs led to further investigate the drug efficacy in intracranial xenograft models by volasertib alone, and in combination with radiation. Taken together, our results reinforce the potential therapeutic candidate of volasertib as a single agent and in combination with ionizing radiation in glioblastoma. Citation Format: Jianwen Dong, Nghi Nguyen, Ravesanker Ezhilarasan, Shaofang Wu, Yuji Piao, Soon Young Park, Ningyi Tiao, Clifford Stephan, Erik P. Sulman, John F. de Groot. Synergistic antitumor effects of polo like kinase inhibitor volasertib in combination with ionizing radiation in glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 695. doi:10.1158/1538-7445.AM2015-695

name of conference

  • Experimental and Molecular Therapeutics

published proceedings

  • Cancer Research

author list (cited authors)

  • Dong, J., Nguyen, N., Ezhilarasan, R., Wu, S., Piao, Y., Park, S. Y., ... de Groot, J. F.

citation count

  • 0

complete list of authors

  • Dong, Jianwen||Nguyen, Nghi||Ezhilarasan, Ravesanker||Wu, Shaofang||Piao, Yuji||Park, Soon Young||Tiao, Ningyi||Stephan, Clifford||Sulman, Erik P||de Groot, John F

publication date

  • January 2015