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Molecular Cancer Research
Molecular Cancer Research

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Signal Transduction and Functional Imaging

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

Anna Hernández-Prat, Alejo Rodriguez-Vida, Nuria Juanpere-Rodero, Oriol Arpi, Silvia Menéndez, Luis Soria-Jiménez, Alejandro Martínez, Natalia Iarchouk, Federico Rojo, Joan Albanell, Rachael Brake, Ana Rovira and Joaquim Bellmunt
Anna Hernández-Prat
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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Alejo Rodriguez-Vida
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.Medical Oncology Department, Hospital del Mar-CIBERONC, Barcelona, Spain.
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Nuria Juanpere-Rodero
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.Pathology Department, Hospital del Mar-CIBERONC, Barcelona, Spain.Medical School, Universitat Pompeu Fabra (UPF), Barcelona, Spain.
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  • ORCID record for Nuria Juanpere-Rodero
Oriol Arpi
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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Silvia Menéndez
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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Luis Soria-Jiménez
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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Alejandro Martínez
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.Medical Oncology Department, Hospital del Mar-CIBERONC, Barcelona, Spain.
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Natalia Iarchouk
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Federico Rojo
Pathology Department, IIS-Fundación Jimenez Diaz, Madrid, Spain.
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Joan Albanell
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.Medical Oncology Department, Hospital del Mar-CIBERONC, Barcelona, Spain.Medical School, Universitat Pompeu Fabra (UPF), Barcelona, Spain.
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Rachael Brake
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts.
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Ana Rovira
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.Medical Oncology Department, Hospital del Mar-CIBERONC, Barcelona, Spain.
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Joaquim Bellmunt
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.Medical Oncology Department, Hospital del Mar-CIBERONC, Barcelona, Spain.Dana-Farber/HCC, Harvard Medical School, Boston, Massachusetts.
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  • For correspondence: jbellmunt@imim.cat
DOI: 10.1158/1541-7786.MCR-18-0923 Published September 2019
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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.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2019;17:1931–44

  • Received August 31, 2018.
  • Revision received March 14, 2019.
  • Accepted May 28, 2019.
  • Published first June 3, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Research: 17 (9)
September 2019
Volume 17, Issue 9
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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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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
Anna Hernández-Prat, Alejo Rodriguez-Vida, Nuria Juanpere-Rodero, Oriol Arpi, Silvia Menéndez, Luis Soria-Jiménez, Alejandro Martínez, Natalia Iarchouk, Federico Rojo, Joan Albanell, Rachael Brake, Ana Rovira and Joaquim Bellmunt
Mol Cancer Res September 1 2019 (17) (9) 1931-1944; DOI: 10.1158/1541-7786.MCR-18-0923

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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
Anna Hernández-Prat, Alejo Rodriguez-Vida, Nuria Juanpere-Rodero, Oriol Arpi, Silvia Menéndez, Luis Soria-Jiménez, Alejandro Martínez, Natalia Iarchouk, Federico Rojo, Joan Albanell, Rachael Brake, Ana Rovira and Joaquim Bellmunt
Mol Cancer Res September 1 2019 (17) (9) 1931-1944; DOI: 10.1158/1541-7786.MCR-18-0923
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Molecular Cancer Research
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