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

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  • dc.contributor.author Hernández Prat, Anna, 1984-
  • dc.contributor.author Rodriguez-Vida, Alejo
  • dc.contributor.author Juanpere, Nuria
  • dc.contributor.author Arpí Llucià, Oriol
  • dc.contributor.author Menéndez, Silvia
  • dc.contributor.author Soria-Jiménez, Luis
  • dc.contributor.author Martínez, Alejandro
  • dc.contributor.author Iarchouk, Natalia
  • dc.contributor.author Rojo, Federico
  • dc.contributor.author Albanell Mestres, Joan
  • dc.contributor.author Brake, Rachael
  • dc.contributor.author Rovira Guerín, Ana
  • dc.contributor.author Bellmunt Molins, Joaquim, 1959-
  • dc.date.accessioned 2020-03-03T08:27:21Z
  • dc.date.issued 2019
  • dc.description.abstract 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.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Hernández-Prat A, Rodriguez-Vida A, Juanpere-Rodero N, Arpi O, Menéndez S, Soria-Jiménez L et al. 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. Mol Cancer Res. 2019 Sep;17(9):1931-44. DOI: 10.1158/1541-7786.MCR-18-0923
  • dc.identifier.doi http://dx.doi.org/10.1158/1541-7786.MCR-18-0923
  • dc.identifier.issn 1541-7786
  • dc.identifier.uri http://hdl.handle.net/10230/43764
  • dc.language.iso eng
  • dc.publisher American Association for Cancer Research (AACR)
  • dc.relation.ispartof Molecular Cancer Research. 2019 Sep;17(9):1931-44
  • dc.rights © American Association for Cancer Research (AACR) http://dx.doi.org/10.1158/1541-7786.MCR-18-0923
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.subject.other Bufeta--Càncer--Tractament
  • dc.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
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/acceptedVersion