Telomerase Inhibition as a Novel Therapy for Pediatric Ependymoma

Authors

  • Vincent C.H. Wong,

    1. Divisions of Pathology and
    2. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
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  • Andrew Morrison,

    1. Divisions of Pathology and
    2. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
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  • Uri Tabori,

    1. Haematology-Oncology and
    2. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
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  • Cynthia E. Hawkins

    Corresponding author
    1. Divisions of Pathology and
    2. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
      Cynthia Hawkins, MD, PhD, Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8 (E-mail: cynthia.hawkins@sickkids.ca)
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Cynthia Hawkins, MD, PhD, Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8 (E-mail: cynthia.hawkins@sickkids.ca)

Abstract

Ependymomas are the third most common pediatric brain tumor with an overall survival of ∼50%. Recently, we showed that telomerase [human telomerase reverse transcriptase (hTERT)] expression is a predictor of poor outcome in pediatric ependymoma. Thus, we hypothesized that ependymomas with functional telomerase may behave more aggressively and that these patients may benefit from anti-telomerase therapy. To address our hypothesis, we investigated the effect of telomerase inhibition on primary ependymoma cells harvested at the time of surgery, as no animal models or established cell lines are readily available for this tumor. The cells were characterized for glial fibrillary acidic protein (GFAP) and hTERT expression, initial telomere length and telomerase activity. They were then subjected to telomerase inhibition (MST-312, 1 µM) and tested for effects on cell viability (MTT assay), proliferation (MIB-1), apoptosis (cleaved caspase 3) and DNA damage (γH2AX). After 72 h of telomerase inhibition, primary ependymoma cells showed a significant decrease in cell number (P < 0.001), accompanied by increased DNA damage (γH2AX expression) (P < 0.01) and decreased proliferative index (MIB-1) (P < 0.01). Half showed an increase in apoptosis (cleaved caspase 3). These data suggest that telomerase inhibition may be an effective adjuvant therapy in pediatric ependymoma, potentially inducing tumor growth arrest in the short term, independent of telomere shortening.

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