Tetsutaro Hayashi1, Roland Seiler1, Htoo Zarni Oo1, Wolfgang Jäger1, Igor Moskalev1, Shannon Awrey1, Takashi Dejima1, Tilman Todenhöfer1, Na Li1, Ladan Fazli1, Akio Matsubara1, Peter C Black2. 1. Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia (TH, RS, HZO, WJ, IM, SA, TD, TT, NL, LF, PCB), Vancouver, British Columbia, Canada; Department of Urology, Institute of Biomedical and Health Science, Hiroshima University (TH), Hiroshima, Japan. 2. Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia (TH, RS, HZO, WJ, IM, SA, TD, TT, NL, LF, PCB), Vancouver, British Columbia, Canada; Department of Urology, Institute of Biomedical and Health Science, Hiroshima University (TH), Hiroshima, Japan. Electronic address: pblack@mail.ubc.ca.
Abstract
PURPOSE: Systemic therapy for advanced bladder cancer has not changed substantially in more than 2 decades and mortality rates remain high. The recognition of HER2 over expression in bladder cancer has made HER2 a promising therapeutic target. T-DM1, a new drug consisting of the HER2 antibody trastuzumab conjugated with a cytotoxic agent, has been shown in breast cancer to be superior to trastuzumab. We tested T-DM1 in preclinical models of bladder cancer. MATERIALS AND METHODS: We evaluated the effect of T-DM1 compared to trastuzumab in different in vitro and in vivo models of HER2 over expressing bladder cancer. RESULTS: RT4V6 was the highest HER2 expressing bladder cancer cell line and it showed higher growth inhibition with T-DM1 compared to trastuzumab. T-DM1 but not trastuzumab induced apoptosis of RT4V6 cells after G2/M arrest on cell cycle analysis. HER2 expression was higher in cell lines with acquired cisplatin resistance compared to the corresponding parental cell lines. Resistant cells showed higher sensitivity to T-DM1 by the induction of apoptosis. In addition, cells cultured in anchorage independent conditions increased HER2 expression compared to cells cultured in adherent conditions and T-DM1 significantly inhibited colony formation in soft agar compared to trastuzumab. In an orthotopic bladder cancer xenograft model tumor growth of cisplatin resistant RT112 was significantly inhibited by T-DM1 via the induction of apoptosis compared to treatment with control IgG or trastuzumab. CONCLUSIONS: T-DM1 has promising antitumor effects in preclinical models of HER2 over expressing bladder cancer.
PURPOSE: Systemic therapy for advanced bladder cancer has not changed substantially in more than 2 decades and mortality rates remain high. The recognition of HER2 over expression in bladder cancer has made HER2 a promising therapeutic target. T-DM1, a new drug consisting of the HER2 antibody trastuzumab conjugated with a cytotoxic agent, has been shown in breast cancer to be superior to trastuzumab. We tested T-DM1 in preclinical models of bladder cancer. MATERIALS AND METHODS: We evaluated the effect of T-DM1 compared to trastuzumab in different in vitro and in vivo models of HER2 over expressing bladder cancer. RESULTS: RT4V6 was the highest HER2 expressing bladder cancer cell line and it showed higher growth inhibition with T-DM1 compared to trastuzumab. T-DM1 but not trastuzumab induced apoptosis of RT4V6 cells after G2/M arrest on cell cycle analysis. HER2 expression was higher in cell lines with acquired cisplatin resistance compared to the corresponding parental cell lines. Resistant cells showed higher sensitivity to T-DM1 by the induction of apoptosis. In addition, cells cultured in anchorage independent conditions increased HER2 expression compared to cells cultured in adherent conditions and T-DM1 significantly inhibited colony formation in soft agar compared to trastuzumab. In an orthotopic bladder cancer xenograft model tumor growth of cisplatin resistant RT112 was significantly inhibited by T-DM1 via the induction of apoptosis compared to treatment with control IgG or trastuzumab. CONCLUSIONS:T-DM1 has promising antitumor effects in preclinical models of HER2 over expressing bladder cancer.
Authors: Francesco Soria; Marco Moschini; Andrea Haitel; Gregory J Wirth; Jose A Karam; Christopher G Wood; Morgan Rouprêt; Vitaly Margulis; Pierre I Karakiewicz; Alberto Briganti; Jay D Raman; Solene-Florence Kammerer-Jacquet; Romain Mathieu; Karim Bensalah; Yair Lotan; Mehmet Özsoy; Mesut Remzi; Kilian M Gust; Shahrokh F Shariat Journal: World J Urol Date: 2016-06-07 Impact factor: 4.226