Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses

Oncolytic adenoviruses are promising anticancer agents due to their ability to self-amplify at the tumor mass. However, tumor stroma imposes barriers difficult to overcome by these agents. Transgene expression is a valuable strategy to counteract these limitations and to enhance antitumor activity....

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Autores: Rojas, Juan José, Guedán Carrió, Sònia, Searle, Peter F., Martinez Quintanilla, Jordi, Gil Hoyos, Raúl, Alcayaga Miranda, Francisca, Cascallò, Manel, Alemany Bonastre, Ramon
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2010
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/173558
Acceso en línea:https://hdl.handle.net/2445/173558
Access Level:acceso abierto
Palabra clave:Adenovirus
Tumors
Adenoviruses
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spelling Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic AdenovirusesRojas, Juan JoséGuedán Carrió, SòniaSearle, Peter F.Martinez Quintanilla, JordiGil Hoyos, RaúlAlcayaga Miranda, FranciscaCascallò, ManelAlemany Bonastre, RamonAdenovirusTumorsAdenovirusesTumorsOncolytic adenoviruses are promising anticancer agents due to their ability to self-amplify at the tumor mass. However, tumor stroma imposes barriers difficult to overcome by these agents. Transgene expression is a valuable strategy to counteract these limitations and to enhance antitumor activity. For this purpose, the genetic backbone in which the transgene is inserted should be optimized to render transgene expression compatible with the adenovirus replication cycle and to keep genome size within the encapsidation size limit. In order to design a potent and selective oncolytic adenovirus that keeps intact all the viral functions with minimal increase in genome size, we inserted palindromic E2F-binding sites into the endogenous E1A promoter. The insertion of these sites controlling E1A-Δ24 results in a low systemic toxicity profile in mice. Importantly, the E2F-binding sites also increased the cytotoxicity and the systemic antitumor activity relative to wild-type adenovirus in all cancer models tested. The low toxicity and the increased potency results in improved antitumor efficacy after systemic injection and increased survival of mice carrying tumors. Furthermore, the constrained genome size of this backbone allows an efficient and potent expression of transgenes, indicating that this virus holds promise for overcoming the limitations of oncolytic adenoviral therapy.Cell Press2010info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/173558Articles publicats en revistes (Patologia i Terapèutica Experimental)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/mt.2010.173Molecular Therapy, 2010, vol. 18, num. 11, p. 1960-1971https://doi.org/10.1038/mt.2010.173cc-by-nc-nd (c) The American Society of Gene and Cell Therapy, 2010http://creativecommons.org/licenses/by-nc-nd/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1735582026-05-27T06:46:51Z
dc.title.none.fl_str_mv Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses
title Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses
spellingShingle Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses
Rojas, Juan José
Adenovirus
Tumors
Adenoviruses
Tumors
title_short Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses
title_full Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses
title_fullStr Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses
title_full_unstemmed Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses
title_sort Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses
dc.creator.none.fl_str_mv Rojas, Juan José
Guedán Carrió, Sònia
Searle, Peter F.
Martinez Quintanilla, Jordi
Gil Hoyos, Raúl
Alcayaga Miranda, Francisca
Cascallò, Manel
Alemany Bonastre, Ramon
author Rojas, Juan José
author_facet Rojas, Juan José
Guedán Carrió, Sònia
Searle, Peter F.
Martinez Quintanilla, Jordi
Gil Hoyos, Raúl
Alcayaga Miranda, Francisca
Cascallò, Manel
Alemany Bonastre, Ramon
author_role author
author2 Guedán Carrió, Sònia
Searle, Peter F.
Martinez Quintanilla, Jordi
Gil Hoyos, Raúl
Alcayaga Miranda, Francisca
Cascallò, Manel
Alemany Bonastre, Ramon
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Adenovirus
Tumors
Adenoviruses
Tumors
topic Adenovirus
Tumors
Adenoviruses
Tumors
description Oncolytic adenoviruses are promising anticancer agents due to their ability to self-amplify at the tumor mass. However, tumor stroma imposes barriers difficult to overcome by these agents. Transgene expression is a valuable strategy to counteract these limitations and to enhance antitumor activity. For this purpose, the genetic backbone in which the transgene is inserted should be optimized to render transgene expression compatible with the adenovirus replication cycle and to keep genome size within the encapsidation size limit. In order to design a potent and selective oncolytic adenovirus that keeps intact all the viral functions with minimal increase in genome size, we inserted palindromic E2F-binding sites into the endogenous E1A promoter. The insertion of these sites controlling E1A-Δ24 results in a low systemic toxicity profile in mice. Importantly, the E2F-binding sites also increased the cytotoxicity and the systemic antitumor activity relative to wild-type adenovirus in all cancer models tested. The low toxicity and the increased potency results in improved antitumor efficacy after systemic injection and increased survival of mice carrying tumors. Furthermore, the constrained genome size of this backbone allows an efficient and potent expression of transgenes, indicating that this virus holds promise for overcoming the limitations of oncolytic adenoviral therapy.
publishDate 2010
dc.date.none.fl_str_mv 2010
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://hdl.handle.net/2445/173558
url https://hdl.handle.net/2445/173558
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/mt.2010.173
Molecular Therapy, 2010, vol. 18, num. 11, p. 1960-1971
https://doi.org/10.1038/mt.2010.173
dc.rights.none.fl_str_mv cc-by-nc-nd (c) The American Society of Gene and Cell Therapy, 2010
http://creativecommons.org/licenses/by-nc-nd/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) The American Society of Gene and Cell Therapy, 2010
http://creativecommons.org/licenses/by-nc-nd/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv Articles publicats en revistes (Patologia i Terapèutica Experimental)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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