Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model

// Yuuki Ohara 1 , Shan Hwu Chew 1 , Nobuaki Misawa 1 , Shenqi Wang 1 , Daiki Somiya 1 , Kae Nakamura 2 , Hiroaki Kajiyama 2 , Fumitaka Kikkawa 2 , Yuta Tsuyuki 3 , Li Jiang 1 , Kyoko Yamashita 1 , Yoshitaka Sekido 4 , Kenneth E. Lipson 5 and Shinya Toyokuni 1, 6 1 Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan 2 Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan 3 Department of Pathology and Laboratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan 4 Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan 5 FibroGen, Inc., San Francisco, CA 94158, USA 6 Sydney Medical School, The University of Sydney, Sydney 2006, Australia Correspondence to: Shinya Toyokuni, email: toyokuni@med.nagoya-u.ac.jp Keywords: connective tissue growth factor (CTGF); malignant mesothelioma; molecular target therapy; FG-3019 (pamrevlumab); tumor microenvironment Received: October 31, 2017 Accepted: March 09, 2018 Published: April 06, 2018 ABSTRACT Malignant mesothelioma is an aggressive neoplasm with no particularly effective treatments. We previously reported that overexpression of connective tissue growth factor (CTGF/CCN2) promotes mesothelioma growth, thus suggesting it as a novel molecular target. A human monoclonal antibody that antagonizes CTGF (FG-3019, pamrevlumab) attenuates malignant properties of different kinds of human cancers and is currently under clinical trial for the treatment of pancreatic cancer. This study reports the effects of FG-3019 on human mesothelioma in vitro and in vivo . We analyzed the effects of FG-3019 on the proliferation, apoptosis, migration/invasion, adhesion and anchorage-independent growth in three human mesothelioma cell lines, among which ACC-MESO-4 was most efficiently blocked with FG-3019 and was chosen for in vivo experiments. We also evaluated the coexistent effects of fibroblasts on mesothelioma in vitro , which are also known to produce CTGF in various pathologic situations. Coexistent fibroblasts in transwell systems remarkably promoted the proliferation and migration/invasion of mesothelioma cells. In orthotopic nude mice model, FG-3019 significantly inhibited mesothelioma growth. Histological analyses revealed that FG-3019 not only inhibited the proliferation but also induced apoptosis in both mesothelioma cells and fibroblasts. Our data suggest that FG-3019 antibody therapy could be a novel additional choice for the treatment of mesothelioma.