Abstract 3302: The effects of the g-quadruplex ligand telomestatin to human brain tumor stem cell survival and growth

Abstract

Abstract Glioblastoma multiforme (GBM) is the leading cause of death among primary brain tumors in adults and the current therapies have only palliative effect on prognosis of patients. Recently, stem cell-like cells in GBM (brain tumor stem-like cells; BTSC) have gained substantial attention as a potential therapeutic target. Hallmarks of BTSC include their self-renewal capacity and highly migratory potential. In this study, we demonstrate that treatment of patient-derived BTSC with a G-quadruplex ligand, telomestatin (TMS), inhibits BTSC self-renewal and maintenance of their stem cell state, and induces their apoptosis in vitro and in vivo. In contrast, both normal precursors and non-stem tumor cells from the matched samples are relatively resistant to TMS treatment. Treatment with a lower dose of TMS specifically inhibits BTSC migration into normal brain. Immunofluorescence in situ hybridization with TMS-treated GBM cells displays both telomeric and non-telomeric DNA damage in BTSC but not in non-stem tumor cells. cDNA microarray analysis identifies a proto-oncogene, c-Myb, as a target of TMS in BTSC, and the pharmacodynamic analysis with TMS-treated tumor-bearing mouse brains demonstrates reduction of c-Myb expression in tumors. An elevated c-Myb expression is found in surgical specimens of GBM compared to normal brain tissues. Lastly, TMS treatment of BTSC-derived mouse intracranial tumors reduces tumor sizes in vivo without any noticeable apoptotic cells in the normal brain, and a combined treatment of TMS with radiation or temozolomide results in additive inhibitory effects on GBM sphere growth in vitro. Collectively, these data indicate a potential avenue toward BTSC-directed therapeutic strategy using TMS via telomeric DNA damage and inhibition of c-Myb, which may offer a novel therapeutic approach for GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3302. doi:10.1158/1538-7445.AM2011-3302