Glypican-1 targeted antibody-based therapy induces preclinical antitumor activity against esophageal squamous cell carcinoma

// Emi Harada 1, * , Satoshi Serada 1, * , Minoru Fujimoto 1 , Yusuke Takahashi 1 , Tsuyoshi Takahashi 2 , Hisashi Hara 2 , Rie Nakatsuka 2 , Takahito Sugase 2 , Takahiko Nishigaki 2 , Yurina Saito 2 , Kosuke Hiramatsu 1 , Satoshi Nojima 3 , Risa Mitsuo 1 , Tomoharu Ohkawara 1 , Eiichi Morii 3 , Masaki Mori 2 , Yuichiro Doki 2 , Yasufumi Kaneda 4 , Tetsuji Naka 1 1 Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan 2 Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan 3 Department of Pathology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan 4 Division of Gene Therapy Science, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan * These authors contributed equally to this work and share first authorship Correspondence to: Satoshi Serada, email: serada@nibiohn.go.jp Tetsuji Naka, email: tnaka@nibiohn.go.jp Keywords: esophageal squamous cell carcinoma, glypican-1 Received: August 17, 2016 Accepted: February 15, 2017 Published: March 01, 2017 ABSTRACT Esophageal squamous cell carcinoma (ESCC) has a poor prognosis despite the development of multimodal therapy. Expression of glypican-1 (GPC1) has been reported to be elevated in a subset of patients with ESCC and associated with chemoresistance. This study aimed to determine the association of GPC1 with ESCC growth and potential usefulness of the GPC1 targeted therapy by monoclonal antibody (mAb) in ESCC. Expression of GPC1 was higher in ESCC tumor tissues than in adjacent non-tumoral tissues and normal tissues. Knockdown of GPC1 decreased growth of ESCC cells and induced apoptosis via inhibition of EGFR, AKT and p44/42-MAPK signaling pathways in vitro . Anti-GPC1 mAb strongly inhibited tumor growth via antibody-dependent cellular cytotoxicity dependent and independent manner in GPC1-positive ESCC xenograft models. Anti-GPC1 mAb also inhibited tumor growth of GPC1 positive ESCC patients derived tumor xenograft models. Furthermore, anti-GPC1 mAb showed a significant tumor growth inhibition with decreased angiogenesis compared with IgG treated controls in ESCC xenografted mice. Treatment with anti-GPC1 mAb was not toxic in mice. Anti-GPC1 mAb may have a potent anti-tumor effect and represent a novel treatment option for patients with GPC1-positive ESCC.