title: Targeting HER2 with T-DM1, an Antibody Cytotoxic Drug Conjugate, is Effective in HER2 Over Expressing Bladder Cancer.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Tetsutaro
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: 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.
authors.forename: Roland
authors.initials: R
authors.lastname: Seiler
authors.affiliation: 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.
authors.forename: Htoo Zarni
authors.initials: HZ
authors.lastname: Oo
authors.affiliation: 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.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jäger
authors.affiliation: 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.
authors.forename: Igor
authors.initials: I
authors.lastname: Moskalev
authors.affiliation: 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.
authors.forename: Shannon
authors.initials: S
authors.lastname: Awrey
authors.affiliation: 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.
authors.forename: Takashi
authors.initials: T
authors.lastname: Dejima
authors.affiliation: 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.
authors.forename: Tilman
authors.initials: T
authors.lastname: Todenhöfer
authors.affiliation: 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.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: 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.
authors.forename: Akio
authors.initials: A
authors.lastname: Matsubara
authors.affiliation: 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.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Black
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008453:Maytansine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000187:drug effects*; D000068878:Trastuzumab / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: ERBB2 protein; apoptosis; cytotoxins; human; trastuzumab; urinary bladder neoplasms