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Acta Neuropathologica
Published in: Acta Neuropathologica 6/2014

Open Access 01-12-2014 | Original Paper

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

Authors: 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. Rutka, Michael D. Taylor, Uri Tabori, Cynthia Hawkins

Published in: Acta Neuropathologica | Issue 6/2014

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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.
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Metadata
Title
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells
Authors
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. Rutka
Michael D. Taylor
Uri Tabori
Cynthia Hawkins
Publication date
01-12-2014
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 6/2014
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-014-1327-6

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