P08.41 Development of a novel TERT-targeting therapy for glioblastomas

Abstract

Introduction: Approximately 60–80% of GBM harbour mutations in the promoter region of TERT that leads to its upregulation, making it the most common single genetic abnormalities in GBM. TERT, a reverse-transcriptase subunit of telomerase, has been an attractive candidate for therapy target because of their observed upregulation in a wide variety of cancers, including GBMs, a phenomenon that presumably helps maintain telomeres for their indefinite proliferation. However, no targeted therapy against telomerase has been successful so far, possibly because telomerase inhibition may not be necessarily expected to immediately suppress proliferation when telomere has already been elongated. It has been reported recently that TERT has an RNA-dependent RNA polymerase (RdRP) activity independent of its function at telomeres. The TERT-RdRP activity appears to be involved in controlling cell cycle and maintenance of stem cell phenotype, suggesting that TERT may be directly targeted to suppress tumour cell proliferation. Through drug screening, we have previously identified eribulin as a specific inhibitor for RdRP activity of TERT. Eribulin does not affect the telomerase activity at the concentration to inhibit the RdRP activity. In order to develop a novel TERT-targeted therapy against GBM, we investigated the anti-tumour efficacy of eribulin in cultured and xenografted GBM cells.