10159- SPDR-4 A RUNX1 SWITCH-OFF APPROACH INHIBITS THE PIF1-P21 AXIS, ONE OF THE MECHANISMS OF GLIOBLASTOMA MALIGNANCY MAINTENANCE

Abstract BACKGROUND Glioblastoma is a high-grade brain tumor and Long-term survival is difficult even with multidisciplinary treatment, necessitating the development of novel therapeutic approaches. Although the transcription factor RUNX1 has been implicated in the maintenance of glioblastoma malignancy, its role is still unclear. We have previously demonstrated that administration of a new drug that inhibits transcription of the RUNX family, chlorambucil-conjugated PI polyamide (Chb-M’, co-developed by Kamikubo and Sugiyama), or RUNX1 knockdown, results in cell growth inhibition in glioblastoma cell lines and that the RUNX1-BIRC5-p21 axis is implicated. METHODS AND RESULTS Since RUNX1 is a transcription factor associated with multiple gene transcription, we performed microarray experiments using Chb-M’. Since PIF1 association was suggested, chromatin immunoprecipitation and reporter assay were performed, and these showed that RUNX1 directly regulates PIF1. The RUNX1-PIF1-p21 pathway was also found to be involved in the mechanism of glioblastoma malignancy maintenance, as RUNX1 knockdown decreased PIF1 and PIF1 knockdown suppressed cell proliferation and increased p21. Chb-M’ administration in mice glioblastoma model clearly reduced tumor size and prolonged survival compared to controls. In addition, FITC-binding Chb-M’ was administered to mice, and FITC selectively accumulated in tumors, indicating that Chb-M’ was shown to have tumor-specific effects. DISCUSSION AND CONCLUSION Chb-M’ has been shown to exert its antitumor effect via the PIF1/p21 axis, and Chb-M’ acts in vivo in a tumor-specific manner, making it a potential new therapeutic agent for glioblastoma. Furthermore, Chb-N’, which has higher cellular affinity than Chb-M’, has been developed and is currently under preclinical investigation.