OS01.5 Development of TERT-targeting therapy using eribulin mesylate in mouse glioblastoma model

Abstract

INTRODUCTION: Despite of recent extensive genome analysis, no effective molecular targeting therapy has been successfully developed in patients with glioblastomas (GBMs). Approximately 60-80% of GBM harbour mutations in the promoter region of telomerase reverse transcriptase (TERT) that leads to upregulation of its protein production, making it the most common single genetic abnormalities in GBM. TERT has been an attractive candidate for molecular targeting therapy because of their observed upregulation in a wide variety of cancers, including GBMs, a phenomenon that presumably helps maintain telomeres for their indefinite proliferation. It has been reported recently that TERT has an RNA-dependent RNA polymerase (RdRP) activity, with which TERT is involved in maintenance of stem cell phenotype and mitotic progression. We have previously identified eribulin as a specific inhibitor of RdRP activity of TERT through drug screening and shown that eribulin suppressed growth of ovarian cancers with high TERT expression. In order to validate an efficacy of eribulin as a novel TERT-targeting therapy against GBM, we investigated the anti-tumor effect of eribulin in cultured cell and mouse brain tumor model using GBM cell lines. METHODS: The TERT promoter status was examined in 20 glioma cell lines. Seven cell lines were subjected to in vitro cytotoxicity assay. U87MG cells were either subcutaneously or intracranially transplanted in athymic mice. Tissue or plasma concentration of eribulin was measured by LC-MS/ MS. RESULTS: All GBM cell lines tested that harboured TERT promoter mutations including U87MG, U251MG, U118MG as well as several patient-derived glioblastoma sphere culture cells were highly sensitive to eribulin, IC50 below 1nM. Intraperitoneal administration of eribulin completely suppressed the growth of U87MG subcutaneous tumors in athymic mice, and the RdRP activities in treated tumors were significantly decreased in a dose-dependent manner. In U87MG brain tumor model, a high concentration of eribulin was detected in the brain tumour tissues as early as 15 minutes after intravenous injection of eribulin, which remained stable even 24 hours later when the plasma concentration of eribulin became undetectable. Finally, intraperitoneal administration of eribulin significantly prolonged the survival of mice with intracranially transplanted U87MG xenograft (p<0.001). CONCLUSION: Our results showed that eribulin efficiently transfers into brain tumour tissues and has a strong anti-tumour effect against GBM cells through inhibition of RdRP activity. Eribulin thus appears to be a promising novel TERT-targeting therapeutic agent against GBM. A clinical trial is being scheduled.