TY - JOUR
T1 - Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells
AU - Barszczyk, Mark
AU - Buczkowicz, Pawel
AU - Castelo-Branco, Pedro
AU - Mack, Stephen C.
AU - Ramaswamy, Vijay
AU - Mangerel, Joshua
AU - Agnihotri, Sameer
AU - Remke, Marc
AU - Golbourn, Brian
AU - Pajovic, Sanja
AU - Elizabeth, Cynthia
AU - Yu, Man
AU - Luu, Betty
AU - Morrison, Andrew
AU - Adamski, Jennifer
AU - Nethery-Brokx, Kathleen
AU - Li, Xiao Nan
AU - Van Meter, Timothy
AU - Dirks, Peter B.
AU - Rutka, James T.
AU - Taylor, Michael D.
AU - Tabori, Uri
AU - Hawkins, Cynthia
N1 - Publisher Copyright:
© 2014, The Author(s).
PY - 2014/12
Y1 - 2014/12
N2 - 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.
AB - 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.
KW - Ependymoma
KW - Imetelstat
KW - TRAP
KW - Telomerase
KW - Telomerase inhibition
UR - http://www.scopus.com/inward/record.url?scp=84939890243&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84939890243&partnerID=8YFLogxK
U2 - 10.1007/s00401-014-1327-6
DO - 10.1007/s00401-014-1327-6
M3 - Article
C2 - 25120190
AN - SCOPUS:84939890243
SN - 0001-6322
VL - 128
SP - 863
EP - 877
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 6
ER -
