Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells

Mark Barszczyk, Pawel Buczkowicz, Pedro Castelo-Branco, Stephen C. Mack, Vijay Ramaswamy, Joshua Mangerel, Sameer Agnihotri, Marc Remke, Brian Golbourn, Sanja Pajovic, Cynthia Elizabeth, Man Yu, Betty Luu, Andrew Morrison, Jennifer Adamski, Kathleen Nethery-Brokx, Xiao Nan Li, Timothy Van Meter, Peter B. Dirks, James T. RutkaMichael D. Taylor, Uri Tabori, Cynthia Hawkins*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.

Original languageEnglish (US)
Pages (from-to)863-877
Number of pages15
JournalActa Neuropathologica
Volume128
Issue number6
DOIs
StatePublished - Dec 2014

Keywords

  • Ependymoma
  • Imetelstat
  • TRAP
  • Telomerase
  • Telomerase inhibition

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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