ArticleActa neuropathologica2014
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells.
Article in Acta neuropathologica, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 37 citations in OpenAlex.
- A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study.Journal of neuro-oncology · 2016Trial
- The Role of Glia Telomere Dysfunction in the Pathogenesis of Central Nervous System Diseases.Molecular neurobiology · 2024Review
- The biology of ependymomas and emerging novel therapies.Nature reviews. Cancer · 2022Review
- How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?Biomolecules · 2021Review
- Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma.Acta neuropathologica communications · 2020Article
- Molecular Mechanism of Telomere Length Dynamics and Its Prognostic Value in Pediatric Cancers.Journal of the National Cancer Institute · 2020Article
- YAP1/TAZ drives ependymoma-like tumour formation in mice.Nature communications · 2020Article
- Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma.Journal of experimental & clinical cancer research : CR · 2020Review
- Intracranial ependymomas: molecular insights and translation to treatment.Brain pathology (Zurich, Switzerland) · 2020Review
- Telomere Maintenance in Pediatric Cancer.International journal of molecular sciences · 2019Review
- Patient-Derived Orthotopic Xenograft Models of Pediatric Brain Tumors: In a Mature Phase or Still in Its Infancy?Frontiers in oncology · 2019Review
- Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner.Cancer cell · 2018Article
- Telomerase activation in posterior fossa group A ependymomas is associated with dismal prognosis and chromosome 1q gain.Neuro-oncology · 2017Article
- H3 K27M mutations are extremely rare in posterior fossa group A ependymoma.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2017Article
- The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants.Acta neuropathologica · 2017Article
- Review
- Vaccination strategies for neuro-oncology.Neuro-oncology · 2015Review
- Posterior fossa ependymoma: current insights.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2015Review
- Perifosine as a potential novel anti-telomerase therapy.Oncotarget · 2015Article
- Pathology, Molecular Genetics, and Epigenetics of Diffuse Intrinsic Pontine Glioma.Frontiers in oncology · 2015Review
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Authors and funding
23 authors at 5 institutions in 3 countries.
Funding
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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Registered trials
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