Novel oral mTORC1/2 inhibitor TAK-228 has synergistic antitumor effects when combined with paclitaxel or PI3Kα inhibitor TAK-117 in preclinical bladder cancer models

Advanced bladder cancer is associated with a poor prognosis and limited treatment options. The PI3K/AKT/mTOR pathway is frequently activated in this disease and can be a potential therapeutic target for treatment intervention. We studied the antitumor efficacy of a new targeted therapy, TAK-228 (ora...

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Autores: Hernández Prat, Anna, 1984-, Rodriguez-Vida, Alejo, Juanpere, Nuria, Arpí Llucià, Oriol, Menéndez, Silvia, Soria-Jiménez, Luis, Martínez, Alejandro, Iarchouk, Natalia, Rojo, Federico, Albanell Mestres, Joan, Brake, Rachael, Rovira Guerín, Ana, Bellmunt Molins, Joaquim, 1959-
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/43764
Acceso en línea:http://hdl.handle.net/10230/43764
http://dx.doi.org/10.1158/1541-7786.MCR-18-0923
Access Level:acceso abierto
Palabra clave:Bufeta--Càncer--Tractament
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spelling Novel oral mTORC1/2 inhibitor TAK-228 has synergistic antitumor effects when combined with paclitaxel or PI3Kα inhibitor TAK-117 in preclinical bladder cancer modelsHernández Prat, Anna, 1984-Rodriguez-Vida, AlejoJuanpere, NuriaArpí Llucià, OriolMenéndez, SilviaSoria-Jiménez, LuisMartínez, AlejandroIarchouk, NataliaRojo, FedericoAlbanell Mestres, JoanBrake, RachaelRovira Guerín, AnaBellmunt Molins, Joaquim, 1959-Bufeta--Càncer--TractamentAdvanced bladder cancer is associated with a poor prognosis and limited treatment options. The PI3K/AKT/mTOR pathway is frequently activated in this disease and can be a potential therapeutic target for treatment intervention. We studied the antitumor efficacy of a new targeted therapy, TAK-228 (oral mTORC1/2 inhibitor), in preclinical models of bladder cancer. We evaluated the effects of TAK-228 in combination with a PI3Kα inhibitor (TAK-117) or with chemotherapy (paclitaxel). We used six bladder cancer cell lines and in vivo xenografts models. TAK-228 strongly inhibited cell proliferation in vitro, and reduced tumor growth and angiogenesis in vivo. Three possible biomarkers of response to TAK-228 (basal levels of 4E-BP1, p-4E-BP1/4E-BP1 ratio, or eIF4E/4E-BP1 ratio) were identified. The combination of TAK-228 and TAK-117 had synergistic effects in vitro and in vivo. Furthermore, TAK-228 demonstrated greater efficiency when combined with paclitaxel. TAK-228 also showed ex vivo activity in tumor tissue from patients with treatment-naïve bladder cancer. TAK-228 is a promising investigational agent that induces a strong effect on cell proliferation, tumor growth, and angiogenesis in bladder cancer models. High synergistic effects were observed with TAK-228 combined with a PI3K inhibitor or with chemotherapy. These results are currently being investigated in a clinic trial of TAK-228 plus paclitaxel in patients with metastatic bladder cancer (NCT03745911). IMPLICATIONS: Strong synergistic effects were observed when combining TAK-228 with TAK-117 (a PI3Kα inhibitor) or with paclitaxel chemotherapy. A phase II study at our institution is currently evaluating the efficacy of TAK-228 combined with paclitaxel in patients with metastatic bladder cancer.American Association for Cancer Research (AACR)20202019info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/43764http://dx.doi.org/10.1158/1541-7786.MCR-18-0923reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésMolecular Cancer Research. 2019 Sep;17(9):1931-44© American Association for Cancer Research (AACR) http://dx.doi.org/10.1158/1541-7786.MCR-18-0923info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/437642026-06-12T07:21:37Z
dc.title.none.fl_str_mv Novel oral mTORC1/2 inhibitor TAK-228 has synergistic antitumor effects when combined with paclitaxel or PI3Kα inhibitor TAK-117 in preclinical bladder cancer models
title Novel oral mTORC1/2 inhibitor TAK-228 has synergistic antitumor effects when combined with paclitaxel or PI3Kα inhibitor TAK-117 in preclinical bladder cancer models
spellingShingle Novel oral mTORC1/2 inhibitor TAK-228 has synergistic antitumor effects when combined with paclitaxel or PI3Kα inhibitor TAK-117 in preclinical bladder cancer models
Hernández Prat, Anna, 1984-
Bufeta--Càncer--Tractament
title_short Novel oral mTORC1/2 inhibitor TAK-228 has synergistic antitumor effects when combined with paclitaxel or PI3Kα inhibitor TAK-117 in preclinical bladder cancer models
title_full Novel oral mTORC1/2 inhibitor TAK-228 has synergistic antitumor effects when combined with paclitaxel or PI3Kα inhibitor TAK-117 in preclinical bladder cancer models
title_fullStr Novel oral mTORC1/2 inhibitor TAK-228 has synergistic antitumor effects when combined with paclitaxel or PI3Kα inhibitor TAK-117 in preclinical bladder cancer models
title_full_unstemmed Novel oral mTORC1/2 inhibitor TAK-228 has synergistic antitumor effects when combined with paclitaxel or PI3Kα inhibitor TAK-117 in preclinical bladder cancer models
title_sort Novel oral mTORC1/2 inhibitor TAK-228 has synergistic antitumor effects when combined with paclitaxel or PI3Kα inhibitor TAK-117 in preclinical bladder cancer models
dc.creator.none.fl_str_mv Hernández Prat, Anna, 1984-
Rodriguez-Vida, Alejo
Juanpere, Nuria
Arpí Llucià, Oriol
Menéndez, Silvia
Soria-Jiménez, Luis
Martínez, Alejandro
Iarchouk, Natalia
Rojo, Federico
Albanell Mestres, Joan
Brake, Rachael
Rovira Guerín, Ana
Bellmunt Molins, Joaquim, 1959-
author Hernández Prat, Anna, 1984-
author_facet Hernández Prat, Anna, 1984-
Rodriguez-Vida, Alejo
Juanpere, Nuria
Arpí Llucià, Oriol
Menéndez, Silvia
Soria-Jiménez, Luis
Martínez, Alejandro
Iarchouk, Natalia
Rojo, Federico
Albanell Mestres, Joan
Brake, Rachael
Rovira Guerín, Ana
Bellmunt Molins, Joaquim, 1959-
author_role author
author2 Rodriguez-Vida, Alejo
Juanpere, Nuria
Arpí Llucià, Oriol
Menéndez, Silvia
Soria-Jiménez, Luis
Martínez, Alejandro
Iarchouk, Natalia
Rojo, Federico
Albanell Mestres, Joan
Brake, Rachael
Rovira Guerín, Ana
Bellmunt Molins, Joaquim, 1959-
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Bufeta--Càncer--Tractament
topic Bufeta--Càncer--Tractament
description Advanced bladder cancer is associated with a poor prognosis and limited treatment options. The PI3K/AKT/mTOR pathway is frequently activated in this disease and can be a potential therapeutic target for treatment intervention. We studied the antitumor efficacy of a new targeted therapy, TAK-228 (oral mTORC1/2 inhibitor), in preclinical models of bladder cancer. We evaluated the effects of TAK-228 in combination with a PI3Kα inhibitor (TAK-117) or with chemotherapy (paclitaxel). We used six bladder cancer cell lines and in vivo xenografts models. TAK-228 strongly inhibited cell proliferation in vitro, and reduced tumor growth and angiogenesis in vivo. Three possible biomarkers of response to TAK-228 (basal levels of 4E-BP1, p-4E-BP1/4E-BP1 ratio, or eIF4E/4E-BP1 ratio) were identified. The combination of TAK-228 and TAK-117 had synergistic effects in vitro and in vivo. Furthermore, TAK-228 demonstrated greater efficiency when combined with paclitaxel. TAK-228 also showed ex vivo activity in tumor tissue from patients with treatment-naïve bladder cancer. TAK-228 is a promising investigational agent that induces a strong effect on cell proliferation, tumor growth, and angiogenesis in bladder cancer models. High synergistic effects were observed with TAK-228 combined with a PI3K inhibitor or with chemotherapy. These results are currently being investigated in a clinic trial of TAK-228 plus paclitaxel in patients with metastatic bladder cancer (NCT03745911). IMPLICATIONS: Strong synergistic effects were observed when combining TAK-228 with TAK-117 (a PI3Kα inhibitor) or with paclitaxel chemotherapy. A phase II study at our institution is currently evaluating the efficacy of TAK-228 combined with paclitaxel in patients with metastatic bladder cancer.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/43764
http://dx.doi.org/10.1158/1541-7786.MCR-18-0923
url http://hdl.handle.net/10230/43764
http://dx.doi.org/10.1158/1541-7786.MCR-18-0923
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Molecular Cancer Research. 2019 Sep;17(9):1931-44
dc.rights.none.fl_str_mv © American Association for Cancer Research (AACR) http://dx.doi.org/10.1158/1541-7786.MCR-18-0923
info:eu-repo/semantics/openAccess
rights_invalid_str_mv © American Association for Cancer Research (AACR) http://dx.doi.org/10.1158/1541-7786.MCR-18-0923
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research (AACR)
publisher.none.fl_str_mv American Association for Cancer Research (AACR)
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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