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Tada Y, Hiroshima K, Shimada H, et al. A clinical protocol to inhibit the HGF/c-Met pathway for malignant mesothelioma with an intrapleural injection of adenoviruses expressing the NK4 gene. Springerplus. 2015;4:358doi: 10.1186/s40064-015-1123-3.
Tada, Y., Hiroshima, K., Shimada, H., Morishita, N., Shirakawa, T., Matsumoto, K., Shingyoji, M., Sekine, I., Tatsumi, K., & Tagawa, M. (2015). A clinical protocol to inhibit the HGF/c-Met pathway for malignant mesothelioma with an intrapleural injection of adenoviruses expressing the NK4 gene. SpringerPlus, 4358. https://doi.org/10.1186/s40064-015-1123-3
Tada, Yuji, et al. "A clinical protocol to inhibit the HGF/c-Met pathway for malignant mesothelioma with an intrapleural injection of adenoviruses expressing the NK4 gene." SpringerPlus vol. 4 (2015): 358. doi: https://doi.org/10.1186/s40064-015-1123-3
Tada Y, Hiroshima K, Shimada H, Morishita N, Shirakawa T, Matsumoto K, Shingyoji M, Sekine I, Tatsumi K, Tagawa M. A clinical protocol to inhibit the HGF/c-Met pathway for malignant mesothelioma with an intrapleural injection of adenoviruses expressing the NK4 gene. Springerplus. 2015 Jul 16;4:358. doi: 10.1186/s40064-015-1123-3. eCollection 2015. PMID: 26191485; PMCID: PMC4503710.
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Springerplus. 2015 Jul 16;4:358. doi: 10.1186/s40064-015-1123-3. eCollection 2015.

A clinical protocol to inhibit the HGF/c-Met pathway for malignant mesothelioma with an intrapleural injection of adenoviruses expressing the NK4 gene.

SpringerPlus

Yuji Tada, Kenzo Hiroshima, Hideaki Shimada, Naoya Morishita, Toshiro Shirakawa, Kunio Matsumoto, Masato Shingyoji, Ikuo Sekine, Koichiro Tatsumi, Masatoshi Tagawa

Affiliations

  1. Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  2. Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.
  3. Department of Surgery, School of Medicine, Toho University, Tokyo, Japan.
  4. Kobe University Graduate School of Health Science, Kobe, Japan.
  5. 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.
  6. Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
  7. Division of Respirology, Chiba Cancer Center, Chiba, Japan.
  8. Department of Medical Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
  9. 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.

PMID: 26191485 PMCID: PMC4503710 DOI: 10.1186/s40064-015-1123-3

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/DESIGN: 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.

DISCUSSION: 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.

TRIAL REGISTRATION: UMIN clinical trials registry, Japan. Register ID: UMIN15771.

Keywords: Adenovirus; HGF; Mesothelioma; NK4; c-Met

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