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.

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.

• Authors: 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, Joaquim Bellmunt
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 17 Issue 9 Pg. 1931-1944 (09 2019) ISSN: 1557-3125 [Electronic] United States
• PMID: 31160383 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Benzoxazoles
• Imidazoles
• Morpholines
• Pyridines
• Pyrimidines
• serabelisib
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• sapanisertib
• Paclitaxel

Topics

• Administration, Oral
• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology)
• Benzoxazoles (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Synergism
• Humans
• Imidazoles (administration & dosage, pharmacology)
• Male
• Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors)
• Mechanistic Target of Rapamycin Complex 2 (antagonists & inhibitors)
• Mice
• Morpholines (administration & dosage, pharmacology)
• Paclitaxel (administration & dosage, pharmacology)
• Pyridines (administration & dosage, pharmacology)
• Pyrimidines (administration & dosage, pharmacology)
• Urinary Bladder Neoplasms (drug therapy, metabolism)
• Xenograft Model Antitumor Assays