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Bit older article,MP28-14 TARGETING HER2 WITH TRASTUZUMAB-DM1 (T-DM1) IN HER2-OVEREXPRESSING BLADDER CANCER Tetsutaro Hayashi*, Wolfgang Jaeger, Igor Moskalev, Shannon Awrey, Na Li, Ladan Fazli, Vancouver, Canada; Wataru Yasui, Akio Matsubara, Hiroshima, Japan; Peter Black, Vancouver, Canada INTRODUCTION AND OBJECTIVES: Human epidermal growth factor receptor-2 (HER2) is involved in proliferation, cell survival and metastasis, and remains an attractive therapeutic target in bladder cancer. Although trastuzumab has failed to show any significant benefit in early phase clinical trials, some of this may be due to poor drug potency. T-DM1 (Genentech Inc., South San Francisco, CA) is a new drug consisting of trastuzumab conjugated with a cytotoxic agent, DM1 (derivative of maytansine 1). It has been proven effective even in breast cancer patients refractory to trastuzumab. The objective of this study was to establish the pre-clinical proof of principle for targeting HER2 with T-DM1 in bladder cancer. METHODS: HER2 expression was analyzed in bladder tumors by immunohistochemistry (IHC) using the same scoring criteria as breast cancer. Bladder cancer cell lines including several with acquired resistance to cisplatin (CDDP-R) were screened for expression of HER2 by Western blot and quantitative RT-PCR. The growth-inhibitory effect was compared between trastuzumab and T-DM1 by proliferation assay and fluorescence activated cell sorting (FACS). In vivo effects were evaluated in an orthotopic bladder cancer xenograft model with bioluminescence imaging. RESULTS: HER2 overexpression (2+ and 3+ staining) was observed in 59 of 159 (37%) bladder cancer patients treated by radical cystectomy and was correlated with higher histological grade and advanced stage. In 12 bladder cancer cell lines, RT4V6 showed highest HER2 expression and showed 24% higher growth inhibition with 1mg/ml T-DM1 compared to trastuzumab. FACS analysis revealed T-DM1, but not trastuzumab, induced apoptosis of RT4V6 cells after G2/M cell cycle arrest (1mg/ml). We confirmed HER2 expression to be three to ten times higher in of CDDP-R cell lines compared to the parental cell lines. RT112 CDDP-R and T24 CDDP-R cell lines showed higher sensitivity for T-DM1 at the concentration of 0.1mg/ml and 1mg/ml than parental cell lines (p<0.05, p<0.01). In vivo growth of RT112 CDDP-R xenografts was inhibited by T-DM1 compared to treatment with either a control IgG or trastuzumab. IHC of the xenografts revealed that T-DM1 induced apoptosis and diminished Ki67 positive cells compared to the same controls. CONCLUSIONS: Our results demonstrate that T-DM1 has promising anti-tumor effects in pre-clinical models of HER2-overexpressing bladder cancer. Targeting HER2 with T-DM1 warrants further clinical investigations, especially in patients with HER2 alterations or cisplatin resistance. Source of Funding: none http://www.jurology.com/article/S0022-5347(14)00921-5/pdf One would think with positive results in backpocket, some agency would be conducting a clinical trial trying to bring to market a drug for patients that fail to respond to trastuzumab and/or cisplatin, then again, one would be WRONG! http://www.croh-online.com/article/S1040-8428(15)30026-3/fulltext Maybe ONE DAY I-SPY2 will present t-dm1/perjeta findings! |
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