The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin

Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causin...

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Autores: Ordóñez JL, Amaral AT, Carcaboso AM, Herrero-Martín D, Del Carmen García-Macías M, Sevillano V, Alonso D, Pascual-Pasto G, San-Segundo L, Vilà-Ubach M, Rodrigues T, Fraile S, Teodosio C, Mayo-Iscar A, Aracil M, Galmarini CM, Tirado OM, Mora J, de Álava E
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p7990
Acceso en línea:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=7990
Access Level:acceso abierto
Palabra clave:ewing sarcoma
PARP inhibitor
trabectedin
DNA damage
PDX models
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spelling The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedinOrdóñez JLAmaral ATCarcaboso AMHerrero-Martín DDel Carmen García-Macías MSevillano VAlonso DPascual-Pasto GSan-Segundo LVilà-Ubach MRodrigues TFraile STeodosio CMayo-Iscar AAracil MGalmarini CMTirado OMMora Jde Álava Eewing sarcomaPARP inhibitortrabectedinDNA damagePDX modelsRecent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced.H2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.IMPACT JOURNALS LLC2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=7990OncotargetISSN: 19492553reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p79902026-05-27T12:37:41Z
dc.title.none.fl_str_mv The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
title The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
spellingShingle The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
Ordóñez JL
ewing sarcoma
PARP inhibitor
trabectedin
DNA damage
PDX models
title_short The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
title_full The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
title_fullStr The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
title_full_unstemmed The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
title_sort The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin
dc.creator.none.fl_str_mv Ordóñez JL
Amaral AT
Carcaboso AM
Herrero-Martín D
Del Carmen García-Macías M
Sevillano V
Alonso D
Pascual-Pasto G
San-Segundo L
Vilà-Ubach M
Rodrigues T
Fraile S
Teodosio C
Mayo-Iscar A
Aracil M
Galmarini CM
Tirado OM
Mora J
de Álava E
author Ordóñez JL
author_facet Ordóñez JL
Amaral AT
Carcaboso AM
Herrero-Martín D
Del Carmen García-Macías M
Sevillano V
Alonso D
Pascual-Pasto G
San-Segundo L
Vilà-Ubach M
Rodrigues T
Fraile S
Teodosio C
Mayo-Iscar A
Aracil M
Galmarini CM
Tirado OM
Mora J
de Álava E
author_role author
author2 Amaral AT
Carcaboso AM
Herrero-Martín D
Del Carmen García-Macías M
Sevillano V
Alonso D
Pascual-Pasto G
San-Segundo L
Vilà-Ubach M
Rodrigues T
Fraile S
Teodosio C
Mayo-Iscar A
Aracil M
Galmarini CM
Tirado OM
Mora J
de Álava E
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ewing sarcoma
PARP inhibitor
trabectedin
DNA damage
PDX models
topic ewing sarcoma
PARP inhibitor
trabectedin
DNA damage
PDX models
description Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced.H2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=7990
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=7990
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv IMPACT JOURNALS LLC
publisher.none.fl_str_mv IMPACT JOURNALS LLC
dc.source.none.fl_str_mv Oncotarget
ISSN: 19492553
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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