Title: Telomestatin impairs glioma stem cell survival and growth through the disruption of telomeric G-quadruplex and inhibition of the proto-oncogene, c-Myb

Background: Glioma stem cells (GSCs) are a critical therapeutic target of glioblastoma multiforme (GBM). Methods: The effects of a G-quadruplex ligand, telomestatin (TMS), were evaluated using patient-derived GSCs, non-stem tumor cells (non-GSCs), and normal fetal neural precursors in vitro and in vivo. The molecular targets of TMS were determined by immunofluorescence in situ hybridization (iFISH) and cDNA microarray. The data was then validated by in vitro and in vivo functional assays, as well as by immunohistochemistry against 90 clinical samples. Results: TMS impaired the maintenance of GSC stem cell-state by inducing apoptosis in vitro and in vivo. The migration potential of GSCs was also impaired by TMS treatment. In contrast, both normal neural precursors and non-GSCs were relatively resistant to TMS. Treatment of GSC-derived mouse intracranial tumors reduced tumor sizes in vivo without a noticeable cell death in normal brains. iFISH revealed both telomeric and non-telomeric DNA damage by TMS in GSCs but not in non-GSCs. cDNA microarray identified a proto-oncogene, c-Myb, as a novel molecular target of TMS in GSCs and pharmacodynamic analysis in TMS-treated tumor-bearing mouse brains demonstrated a reduction Research. on April 14, 2017. © 2012 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on January 9, 2012; DOI: 10.1158/1078-0432.CCR-11-1795