Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma

[eng] Constitutive activation of the chemokine receptor CXCR4 is associated with tumor progression, invasion and resistance to treatment. Overexpression of CXCR4 in diffuse large B-cell lymphoma (DLBCL) confers a reduced prognosis. However, the biological relevance of this receptor in DLBCL progress...

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Detalles Bibliográficos
Autor: Recasens Zorzo, Clara
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/126313
Acceso en línea:https://hdl.handle.net/2445/126313
http://hdl.handle.net/10803/663897
Access Level:acceso abierto
Palabra clave:Oncologia
Hematologia
Limfomes
Desenvolupament de medicaments
Oncology
Hematology
Lymphomas
Drug development
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spelling Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphomaRecasens Zorzo, ClaraOncologiaHematologiaLimfomesDesenvolupament de medicamentsOncologyHematologyLymphomasDrug development[eng] Constitutive activation of the chemokine receptor CXCR4 is associated with tumor progression, invasion and resistance to treatment. Overexpression of CXCR4 in diffuse large B-cell lymphoma (DLBCL) confers a reduced prognosis. However, the biological relevance of this receptor in DLBCL progression remains underexplored. In this thesis, the new CXCR4 inhibitor IQS-01.01 has been preclinicaly evaluated in in vitro and in vivo models of DLBCL. It has been concluded that 1) inhibition of CXCR4 presents antitumor properties in DLBCL, 2) that IQS-01.01RS holds better pharmacological properties than the reference CXCR4 inhibitor, AMD3100 3) that treatment with IQS- 01.01RS reduces the levels of the oncogene MYC and 4) that the combinantion of IQS- 01.01RS with the BET-bromodomain inhibitor, CPI203, is synergistic in DLBCL. The results of this doctoral thesis unravel a cooperation between CXCR4 and MYC in DLBCL, and indicate that CXCR4 inhibition in combination with inhibition of MYC is a promising novel therapeutic approach in DLBCL.[spa] La activación constitutiva del receptor de quemocinas CXCR4 está asociada a la progresión tumoral, invasión y resistencia al tratamiento. En el linfoma difuso de células grandes (LDCG) la sobreexpresión de CXCR4 concede un peor pronóstico, pero la relevancia biológica de este receptor no se ha estudiado en profundidad. En esta tesis se ha evaluado un nuevo inhibidor de CXCR4 (IQS-01.01) en modelos preclínicos de LDCG. Usando tanto modelos in vitro como in vivo de LDCG se ha concluido 1) que la inhibición de CXCR4 en LDCG tiene un efecto antitumoral, 2) que IQS-01.01RS tiene mayores propiedades farmacológicas que el inhibidor de referencia, AMD3100 3) que el tratamiento con IQS-01.01RS reduce los niveles del oncogén MYC y 4) que la combinación de IQS-01.01 RS con el inhibido de BET, CPI203, confiere un efecto antitumoral sinérgico. Los resultados de esta tesis doctoral ponen en evidencia una cooperación entre MYC y CXCR4 en LDCG e indican que la inhibición de CXCR4 en combinación con un inhibidor de MYC es una terapia prometedora contra el LDCG.Universitat de BarcelonaRoué, GaëlPérez Galán, PatriciaUniversitat de Barcelona. Facultat de Medicina2018info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/126313http://hdl.handle.net/10803/663897Tesis Doctorals - Facultat - Medicinareponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaIngléscc-by-nc-nd, (c) Recasens, 2018http://creativecommons.org/licenses/by-nc-nd/3.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1263132026-05-27T06:46:51Z
dc.title.none.fl_str_mv Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma
title Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma
spellingShingle Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma
Recasens Zorzo, Clara
Oncologia
Hematologia
Limfomes
Desenvolupament de medicaments
Oncology
Hematology
Lymphomas
Drug development
title_short Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma
title_full Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma
title_fullStr Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma
title_full_unstemmed Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma
title_sort Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma
dc.creator.none.fl_str_mv Recasens Zorzo, Clara
author Recasens Zorzo, Clara
author_facet Recasens Zorzo, Clara
author_role author
dc.contributor.none.fl_str_mv Roué, Gaël
Pérez Galán, Patricia
Universitat de Barcelona. Facultat de Medicina
dc.subject.none.fl_str_mv Oncologia
Hematologia
Limfomes
Desenvolupament de medicaments
Oncology
Hematology
Lymphomas
Drug development
topic Oncologia
Hematologia
Limfomes
Desenvolupament de medicaments
Oncology
Hematology
Lymphomas
Drug development
description [eng] Constitutive activation of the chemokine receptor CXCR4 is associated with tumor progression, invasion and resistance to treatment. Overexpression of CXCR4 in diffuse large B-cell lymphoma (DLBCL) confers a reduced prognosis. However, the biological relevance of this receptor in DLBCL progression remains underexplored. In this thesis, the new CXCR4 inhibitor IQS-01.01 has been preclinicaly evaluated in in vitro and in vivo models of DLBCL. It has been concluded that 1) inhibition of CXCR4 presents antitumor properties in DLBCL, 2) that IQS-01.01RS holds better pharmacological properties than the reference CXCR4 inhibitor, AMD3100 3) that treatment with IQS- 01.01RS reduces the levels of the oncogene MYC and 4) that the combinantion of IQS- 01.01RS with the BET-bromodomain inhibitor, CPI203, is synergistic in DLBCL. The results of this doctoral thesis unravel a cooperation between CXCR4 and MYC in DLBCL, and indicate that CXCR4 inhibition in combination with inhibition of MYC is a promising novel therapeutic approach in DLBCL.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/126313
http://hdl.handle.net/10803/663897
url https://hdl.handle.net/2445/126313
http://hdl.handle.net/10803/663897
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv cc-by-nc-nd, (c) Recasens, 2018
http://creativecommons.org/licenses/by-nc-nd/3.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd, (c) Recasens, 2018
http://creativecommons.org/licenses/by-nc-nd/3.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Facultat - Medicina
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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score 15,301629

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