title: A clinical protocol to inhibit the HGF/c-Met pathway for malignant mesothelioma with an intrapleural injection of adenoviruses expressing the NK4 gene.
abstract: BACKGROUND
  The hepatocyte growth factor (HGF)/c-Met signal pathway is up-regulated in human mesothelioma and suppression of the HGF/c-Met signaling with a competitive inhibitor, NK4 homologous to HGF in the structure, produced anti-tumor effects to mesothelioma in a preclinical study. Mesothelioma is highly resistant to a number of chemotherapeutic agents but distant metastasis to extra-thoracic organs is relatively infrequent until the late stage.
  
  
  METHODS
  We planned to conduct a clinical study of gene therapy with adenoviruses expressing the NK4 gene (Ad-NK4) to control the local tumor growth. The study is designed to inject Ad-NK4 into the intrapleural cavity with a dose escalation manner from 10(10) to 10(12) virus particles per patient and to examine safety and possible clinical benefits. The clinical investigation is a first-in-human trial to use the NK4 gene and to block the HGF/c-Met pathway with gene medicine. We conducted in vivo animal experiments to examine the safety level as one of the preclinical studies, and showed that Ad DNA administered in the pleural cavity was detected in many parenchymal organs. Biochemical and pathological analyses showed that liver damages were the major adverse effects with little toxicity to other organs. These studies firstly demonstrated biodistribution and transgene expression after an intrapleural injection of Ad vectors in an animal study, which contrasts with an intravenous injection showing relatively rapid clearance of Ad-NK4.
  
  
  CONCLUSIONS
  The clinical study can also provide information regarding production of NK4 protein and antibody against NK4, and inhibition levels of the HGF/c-Met pathway by detecting dephosphorylation of c-Met in mesothelioma cells. These data will be crucial to judge whether local production of NK4 molecules can be an anti-cancer strategy.
  
  
  BACKGROUND
  UMIN clinical trials registry, Japan. Register ID: UMIN15771.
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.affiliation: Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hiroshima
authors.affiliation: Department of Surgery, School of Medicine, Toho University, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Kobe University Graduate School of Health Science, Kobe, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Morishita
authors.affiliation: Kobe University Graduate School of Health Science, Kobe, Japan ; Divison of Translational Research for Biologics, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan ; Division of Urology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Shirakawa
authors.affiliation: Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Division of Respirology, Chiba Cancer Center, Chiba, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Shingyoji
authors.affiliation: Department of Medical Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Sekine
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717 Japan ; Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tagawa
keywords: Adenovirus; HGF; Mesothelioma; NK4; c-Met