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

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 +/- A 11 vs 64 +/- A 18 %; p = 0.03) and overall survival (58 +/- A 12 vs 83 +/- A 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.Canadian Institutes of Health Research [MOP 82727]info:eu-repo/semantics/publishedVersio

Clinical and Biological Studies of the Alternative Lengthening of Telomeres in Paediatric Brain Tumours

Certain cancers maintain telomeres using the alternative lengthening of telomeres (ALT), which is associated with mutations to specific genes in several cancers. ALT has not been characterized in paediatric brain tumours (PBTs).We hypothesized that ALT is present in PBTs, is associated with mutations to ALT-associated genes, and impacts survival.517 PBTs and 163 control tumours were screened for ALT using the c-circle assay.ALT was found in high grade PBTs of mesenchymal/neuroepithelial tissue origin characterized by a high incidence of mutant TP53. ALT was associated with TP53 (p = 7.32x10-8) and ATRX (p = 5.23x10-4) mutations. ALT abrogated poor survival in TP53 mutant paediatric malignant gliomas (p = 0.03). Association with improved survival approached significance in TP53 mutant choroid plexus carcinoma (p = 0.07).ALT is found in PBTs harboring somatic TP53 mutations, and impacts survival. Stratification using ALT is important for the management of these cancers in children.M.Sc