The therapeutic strategies with augmented replications of oncolytic adenoviruses for malignant mesothelioma

• Project/Area Number: 18K15937
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: MORINAGA Takao 千葉県がんセンター(研究所), がん治療開発グループ, 研究員 (30757000)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 腫瘍融解性アデノウイルス / 細胞周期 / がん代謝 / 脂質合成酵素 / アデノウイルス / 遺伝子治療 / 悪性中皮腫 / p53 / 代謝

Outline of Final Research Achievements

Malignant mesothelioma is a cancer with poor prognosis and a novel strategy to cure this cancer is needed urgently. We examined whether combinations of oncolytic adenoviruses harboring a genetic region that is specifically activated in tumors instead of the authentic promoter region for the essential gene E1 and small compounds had stronger cytotoxicity and greater replications in mesothelioma cells compared to single use of the virus. We found in this study methods to increase the viral replication and cytotoxicity specifically in p53-deficient tumor cells or in tumor cells expressing a greater level of a specific lipid synthesis enzyme than normal cells. Our findings may lead to a novel stronger and tumor specific therapeutic strategy with oncolytic adenoviruses.

Academic Significance and Societal Importance of the Research Achievements

ウイルスの遺伝子工学的改変技術は、ウイルス治療の進化に貢献してきた。腫瘍選択的に感染し腫瘍細胞内で増殖するウイルスは、根治の難しいがんに対して有効な治療選択の一つとなっている。一方で、遺伝子工学的にウイルスを改変するだけでは、患者ごとに最適な治療法を提供することはできない。本研究では、ウイルスの生物学的特性を応用し、腫瘍の遺伝的背景に合わせて低分子化合物の組み合わせを変えることで、より柔軟なウイルス治療に応用できることを示唆している。

Research Products

• [Journal Article] AMPK activation induced in pemetrexed-treated cells is associated with development of drug resistance independently of target enzyme expression (2019)
  • Author(s): Qin, Y. Sekine, I. Hanazono, M. Morinaga, T. Fan, M. Takiguchi, Y. Tada, Y. Shingyoji, M. Yamaguchi, N. Tagawa, M.
  • Journal Title: Mol Oncol. Volume: 13 Issue: 6 Pages: 1419-1432
  • DOI: 10.1002/1878-0261.12496
  • Peer Reviewed / Open Access
• [Journal Article] A p53-stabilizing agent, CP-31398, induces p21 expression with increased G2/M phase through the YY1 transcription factor in esophageal carcinoma defective of the p53 pathway. (2019)
  • Author(s): Boya Zhong, Masato Shingyoji, Michiko Hanazono, Thao Thi Thanh Nguyen, Takao Morinaga, Yuji Tada, Kenzo Hiroshima, Hideaki Shimada, Masatoshi Tagawa
  • Journal Title: Am. J. Cancer Res. Volume: 9 Pages: 79-93
  • Peer Reviewed / Open Access
• [Journal Article] A p53-stabilizing agent, CP-31398, induces p21 expression with increased G2/M phase through the YY1 transcription factor in esophageal carcinoma defective of the p53 pathway (2019)
  • Author(s): Zhong, B., Shingyoji, M., Hanazono, M., Nguyen, T.T.T., Morinaga, T., Tada, Y., Hiroshima, K., Shimada, H., Tagawa, M.
  • Journal Title: Am. J. Cancer Res. Volume: 9 Pages: 79-93
  • Peer Reviewed / Open Access
• [Journal Article] Multi-panel assay of serum autoantibodies in colorectal cancer (2018)
  • Author(s): Ushigome Mitsunori、Nabeya Yoshihiro、Soda Hiroaki、Takiguchi Nobuhiro、Kuwajima Akiko、Tagawa Masatoshi、Matsushita Kazuyuki、Koike Junichi、Funahashi Kimihiko、Shimada Hideaki
  • Journal Title: International Journal of Clinical Oncology Volume: 23 Issue: 5 Pages: 917-923
  • DOI: 10.1007/s10147-018-1278-3
  • Peer Reviewed / Open Access
• [Journal Article] Role of membrane cholesterol levels in activation of Lyn upon cell detachment (2018)
  • Author(s): Morinaga, T., Yamaguchi, N., Nakayama, Y., Tagawa, M. and Yamaguchi, N.
  • Journal Title: Int. J. Mol. Sci. Volume: 19 Issue: 6 Pages: 1811-1811
  • DOI: 10.3390/ijms19061811
  • Peer Reviewed / Open Access
• [Presentation] An inhibitor for the lipid synthetic pathway increased oncolytic adenoviral replications in mesothelioma (2019)
  • Author(s): Takao Morinaga, Shuji Kubo, Masato Shingyoji, Yuji Tada, Hideaki Shimada, Kenzo Hiroshima, Masatoshi Tagawa
  • Organizer: 第25回 日本遺伝子細胞治療学会学術集会
• [Presentation] Downregulation of the lipid synthetic pathway increased oncolytic adenoviral replications in mesothelioma. (2019)
  • Author(s): 盛永 敬郎, 久保 秀司, 関根 郁夫, 多田 裕司, 島田 英昭
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Cytotoxicity of oncolytic adenoviruses against p53-deficient cells was enhanced by a wee1 kinase inhibitor. (2019)
  • Author(s): Takao Morinaga, Masatoshi Tagawa
  • Organizer: APCGCT 2019
  • Int'l Joint Research
• [Presentation] An MDM2 inhibitor achieves synergistic cytotoxicity with oncolytic adenoviruses on mesothelioma with the wild-type p53 gene (2018)
  • Author(s): Masatoshi Tagawa, Thao Thi Thanh Nguyen, Takao Morinaga, Masato Shingyoji, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima
  • Organizer: The 14th international conference of the international mesothelioma interested group
  • Int'l Joint Research
• [Presentation] Inhibition of the HGF/c-Met for mesothelioma with an intra-pleural injection of the NK4 gene-expressing adenoviral vectors (2018)
  • Author(s): Yuji Tada, Takao Morinaga, Ikuo Sekine, Toshio Suzuki, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima, Masatoshi Tagawa
  • Organizer: The 14th international conference of the international mesothelioma interested group
  • Int'l Joint Research
• [Presentation] Cytotoxicity of Replication-Competent Adenoviruses Defective of E1B55kDa Molecules Is Irrelevant to P53 Expression, but Increases with a P53-Augmenting MDM2 Inhibitor through DNA Damages and Enhanced Viral Propagations in Mesothelioma with the Wild-Type P53 Genotype (2018)
  • Author(s): Thao Thi Thanh Nguyen, Takao Morinaga, Boya Zhong, Shuji Kubo, Masato Shingyoji, Yuji Tada, Yuichi Takiguchi, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima, Masatoshi Tagawa
  • Organizer: 21st annual meeting of American Society of Gene and Cell Therapy
  • Int'l Joint Research
• [Presentation] A phase1 clinical trial of inhibiting the HGF/c-Met pathway for malignant pleural mesothelioma with NK4 gene-expressing adenoviral vectors (2018)
  • Author(s): Yuji Tada, Takao Morinaga, Hideaki Shimada, Kenzo Hiroshima, Masatoshi Tagawa
  • Organizer: 24th annual meeting of Japan Society of Gene Therapy
• [Presentation] A Wee1 kinase inhibitor augments apoptosis and replications of adenoviruses in p53-deficient tumor cells (2018)
  • Author(s): Takao Morinaga, Thao Thi Thanh Nguyen, Boya Zhong, Shuji Kubo, Masato Shingyoji, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima, Masatoshi Tagawa
  • Organizer: 24th annual meeting of Japan Society of Gene Therapy
• [Presentation] Inhibitors for the MDM2-p53 interaction increase a DNA damage signal and augment replications of oncolytic adenoviruses in mesothelioma with the wild-type p53 genotype (2018)
  • Author(s): Masatoshi Tagawa, Thao Thi Thanh Nguyen, Takao Morinaga, Boya Zhong, Michiko Hanazono, Masato Shingyoji, Shuji Kubo, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima
  • Organizer: 24th annual meeting of Japan Society of Gene Therapy
• [Presentation] Inhibition of the HGF/c-Met for mesothelioma with an intra-pleural injection of the NK4 gene-expressing adenoviral vectors (2018)
  • Author(s): Yuji. Tada, Takao Morinaga, Ikuo Sekine, Toshio Suzuki, Iwao Shimomura, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima, Masatoshi Tagawa
  • Organizer: International Association for the Study of Lung Cancer 19th World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] Wee1 阻害薬はp53欠損細胞における腫瘍融解性アデノウイルスの複製と感染を増強する (2018)
  • Author(s): 盛永敬郎、グエン タオ、鐘博雅、久保秀司、関根郁夫、多田裕司、巽浩一郎、島田英昭、廣島健三、田川雅敏
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 核酸合成酵素非依存的なペメトレキセート耐性はAICARTを介したAMPKの活性化に関与している (2018)
  • Author(s): 鐘博雅、関根郁夫、滝口裕一、グエン タオ、盛永敬郎、多田裕司、山口直人、田川雅敏
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] MDM2阻害剤による内因性p53発現上昇は、転写調節因子NF1発現を上昇させ腫瘍融解性ウイルスの増殖を増強させる (2018)
  • Author(s): グエン タオ、盛永敬郎、鐘博雅、久保秀司、多田裕司、巽浩一郎、島田英昭、廣島健三、田川雅敏
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] HSP90阻害剤は内因性p53発現を上昇させるが外因性p53発現をプロテアソーム活性で抑制する (2018)
  • Author(s): 田川雅敏、盛永敬郎、鐘博雅、Nguyen Thi Thanh Thao、久保秀司、多田裕司、巽浩一郎、島田英昭、廣島健三、山口直人
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 胸膜中皮腫を対象としたNK4遺伝子発現ベクター胸腔内投与の第1相臨床試験 (2018)
  • Author(s): 多田裕司、盛永敬郎、鈴木敏夫、下村巌、石綿司、由佐俊和、島田英昭、廣島健三、滝口裕一、関根郁夫、巽浩一郎、田川雅敏
  • Organizer: 第25回石綿・中皮腫研究会
• [Presentation] 切除不能胸膜中皮腫に対しNK4遺伝子発現アデノウィルスベクター胸腔内投与の安全性を確認する臨床試験 (2018)
  • Author(s): 多田裕司、盛永敬郎、鈴木敏夫、下村巌、由佐俊和、島田英昭、廣島健三、滝口裕一、巽浩一郎、田川雅敏
  • Organizer: 第５９回日本肺癌学会学術集会
• [Presentation] Wee1 kinase inhibitor increased cytotoxicity of oncolytic adenoviruses in p53-deficient cells (2018)
  • Author(s): T. Morinaga, N.T. Thao, Z. Boya, M. Tagawa
  • Organizer: American Society for Cell Biology
  • Int'l Joint Research
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