Targeting HER2 with T-DM1, an Antibody Cytotoxic Drug Conjugate, Is Effective in 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.

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.

J Urol. 2015 Jun 3. pii: S0022-5347(15)04105-1. doi: 10.1016/j.juro.2015.05.087. [Epub ahead of print]

Hayashi T1, Seiler R1, Oo HZ1, Jäger W1, Moskalev I1, Awrey S1, Dejima T1, Todenhöfer T1, Li N1, Fazli L1, Matsubara A1, Black PC2.

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.