Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.1/11219 |
Resumo: | 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. |
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Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cellsTert promoter mutationsIntracranial ependymomaMultifactorial analysisTherapeutic targetHighly recurrentGrowth arrestBrain-tumorsStem-cellsChildhoodExpressionPediatric 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]SpringerSapientiaBarszczyk, MarkBuczkowicz, PawelCastelo-Branco, PedroMack, Stephen C.Ramaswamy, VijayMangerel, JoshuaAgnihotri, SameerRemke, MarcGolbourn, BrianPajovic, SanjaElizabeth, CynthiaYu, ManLuu, BettyMorrison, AndrewAdamski, JenniferNethery-Brokx, KathleenLi, Xiao-NanVan Meter, TimothyDirks, Peter B.Rutka, James T.Taylor, Michael D.Tabori, UriHawkins, Cynthia2018-12-07T14:52:48Z2014-122014-12-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/11219eng0001-632210.1007/s00401-014-1327-6info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-24T10:22:59Zoai:sapientia.ualg.pt:10400.1/11219Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:02:43.666192Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells |
title |
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells |
spellingShingle |
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells Barszczyk, Mark Tert promoter mutations Intracranial ependymoma Multifactorial analysis Therapeutic target Highly recurrent Growth arrest Brain-tumors Stem-cells Childhood Expression |
title_short |
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells |
title_full |
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells |
title_fullStr |
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells |
title_full_unstemmed |
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells |
title_sort |
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells |
author |
Barszczyk, Mark |
author_facet |
Barszczyk, Mark Buczkowicz, Pawel Castelo-Branco, Pedro Mack, Stephen C. Ramaswamy, Vijay Mangerel, Joshua Agnihotri, Sameer Remke, Marc Golbourn, Brian Pajovic, Sanja Elizabeth, Cynthia Yu, Man Luu, Betty Morrison, Andrew Adamski, Jennifer Nethery-Brokx, Kathleen Li, Xiao-Nan Van Meter, Timothy Dirks, Peter B. Rutka, James T. Taylor, Michael D. Tabori, Uri Hawkins, Cynthia |
author_role |
author |
author2 |
Buczkowicz, Pawel Castelo-Branco, Pedro Mack, Stephen C. Ramaswamy, Vijay Mangerel, Joshua Agnihotri, Sameer Remke, Marc Golbourn, Brian Pajovic, Sanja Elizabeth, Cynthia Yu, Man Luu, Betty Morrison, Andrew Adamski, Jennifer Nethery-Brokx, Kathleen Li, Xiao-Nan Van Meter, Timothy Dirks, Peter B. Rutka, James T. Taylor, Michael D. Tabori, Uri Hawkins, Cynthia |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Sapientia |
dc.contributor.author.fl_str_mv |
Barszczyk, Mark Buczkowicz, Pawel Castelo-Branco, Pedro Mack, Stephen C. Ramaswamy, Vijay Mangerel, Joshua Agnihotri, Sameer Remke, Marc Golbourn, Brian Pajovic, Sanja Elizabeth, Cynthia Yu, Man Luu, Betty Morrison, Andrew Adamski, Jennifer Nethery-Brokx, Kathleen Li, Xiao-Nan Van Meter, Timothy Dirks, Peter B. Rutka, James T. Taylor, Michael D. Tabori, Uri Hawkins, Cynthia |
dc.subject.por.fl_str_mv |
Tert promoter mutations Intracranial ependymoma Multifactorial analysis Therapeutic target Highly recurrent Growth arrest Brain-tumors Stem-cells Childhood Expression |
topic |
Tert promoter mutations Intracranial ependymoma Multifactorial analysis Therapeutic target Highly recurrent Growth arrest Brain-tumors Stem-cells Childhood Expression |
description |
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. |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014-12 2014-12-01T00:00:00Z 2018-12-07T14:52:48Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.1/11219 |
url |
http://hdl.handle.net/10400.1/11219 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
0001-6322 10.1007/s00401-014-1327-6 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Springer |
publisher.none.fl_str_mv |
Springer |
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reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799133261663830016 |