title: Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells.
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.
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Barszczyk
authors.forename: Pawel
authors.initials: P
authors.lastname: Buczkowicz
authors.forename: Pedro
authors.initials: P
authors.lastname: Castelo-Branco
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Mack
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.forename: Joshua
authors.initials: J
authors.lastname: Mangerel
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Brian
authors.initials: B
authors.lastname: Golbourn
authors.forename: Sanja
authors.initials: S
authors.lastname: Pajovic
authors.forename: Cynthia
authors.initials: C
authors.lastname: Elizabeth
authors.forename: Man
authors.initials: M
authors.lastname: Yu
authors.forename: Betty
authors.initials: B
authors.lastname: Luu
authors.forename: Andrew
authors.initials: A
authors.lastname: Morrison
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adamski
authors.forename: Kathleen
authors.initials: K
authors.lastname: Nethery-Brokx
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
authors.forename: Timothy
authors.initials: T
authors.lastname: Van Meter
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dirks
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002675:Child, Preschool; D015331:Cohort Studies; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004806:Ependymoma / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000201:enzymology; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009841:Oligonucleotides; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000187:drug effects / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D019098:Telomerase; C519562:imetelstat