Open AccessT‐DM1, a novel antibody–drug conjugate, is highly effective against primary HER2 overexpressing uterine serous carcinoma in vitro and in vivo
Author(s) -
English Diana P.,
Bellone Stefania,
Schwab Carlton L.,
Bortolomai Ileana,
Bonazzoli Elena,
Cocco Emiliano,
Buza Natalia,
Hui Pei,
Lopez Salvatore,
Ratner Elena,
Silasi DanArin,
Azodi Masoud,
Schwartz Peter E.,
Rutherford Thomas J.,
Santin Alessandro D.
Publication year - 2014
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.274
Subject(s) - in vivo , flow cytometry , cancer research , antibody , apoptosis , trastuzumab , microbiology and biotechnology , serous fluid , biology , antibody drug conjugate , immunohistochemistry , chemistry , medicine , pathology , monoclonal antibody , immunology , cancer , biochemistry , breast cancer
Amplification of c‐erbB2 has been reported in over 30% of uterine serous carcinoma ( USC ) and found to confer poor survival because of high proliferation and increased resistance to therapy. In this study, we evaluated for the first time Trastuzumab emtansine ( T‐DM1 ), a novel antibody–drug conjugate, against multiple epidermal growth factor receptor‐2 ( HER 2)‐positive USC cells in vitro followed by developing a supportive in vivo model. Fifteen primary USC cell lines were assessed by immunohistochemistry ( IHC ) and flow cytometry for HER 2 protein expression. C‐erbB2 gene amplification was evaluated using fluorescent in situ hybridization. Sensitivity to T‐ DM 1 and trastuzumab (T)‐induced antibody‐dependent cell‐mediated cytotoxicity was evaluated in 5‐h chromium release assays. T‐ DM 1 and T cytostatic and apoptotic activities were evaluated using flow‐cytometry‐based proliferation assays. In vivo activity of T‐ DM 1 versus T in USC xenografts in SCID mice was also evaluated. High levels of HER 2 protein overexpression and HER 2 gene amplification were detected in 33% of USC cell lines. T‐ DM 1 was considerably more effective than trastuzumab in inhibiting cell proliferation and in causing apoptosis ( P = 0.004) of USC showing HER 2 overexpression. Importantly, T‐ DM 1 was highly active at reducing tumor formation in vivo in USC xenografts overexpressing HER 2 ( P = 0.04) and mice treated with TDM ‐1 had significantly longer survival when compared to T‐treated mice and control mice ( P ≤ 0.0001). T‐ DM 1 shows promising antitumor effect in HER 2‐positive USC cell lines and USC xenografts and its activity is significantly higher when compared to T. T‐ DM 1 may represent a novel treatment option for HER 2‐positive USC patients with disease refractory to trastuzumab and traditional chemotherapy.