A therapeutic strategy for malignant mesothelioma with reconstituting tumor suppressor pathways which were defective due to the characteristic genetic deletion

• Project/Area Number: 16K09598
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: Shingyoji Masato 千葉県がんセンター(研究所), 呼吸器内科, 部長 (60450433)
• Co-Investigator(Kenkyū-buntansha): 田川 雅敏 千葉県がんセンター(研究所), がん治療開発グループ, 部長 (20171572)
• Research Collaborator: TAGAWA masatoshi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 悪性中皮腫 / p53経路 / Hippo経路 / 細胞障害活性 / アデノウイルス / MDM2阻害剤 / MDM2 / FAK / 低分子G蛋白 / AMPK-mTOR / 細胞死 / MDM4 / NF2 / Rb蛋白 / Mdm2 / Mdm4 / ユビキチン化 / 遺伝子 / トランスレーショナルリサーチ / バイオテクノロジー

Outline of Final Research Achievements

Clinical specimens from malignant mesothelioma patients showed two characteristic genetic abnormalities, a defect in the INK4A/ARF region and several types of gene mutations mapped in the Hippo pathway, which consequently induced a functional loss of the p53 pathway, and up-regulation of pRb and Hippo pathways. These genetic changes can be therapeutic targets for mesothelioma treatments. We then took an approach to reconstitute the p53 pathway, which suppressed pRb functions accordingly, and to inhibit effectors of the augmented Hippo pathway. Enhanced expression of endogenous or exogenous p53 and inhibition of down-stream signaling of the Hippo pathways achieved growth suppressive effects in mesothelioma and a combination of activated p53 and inhibited Hippo pathway produced synergistic cytotoxic effects to mesothelioma.

Academic Significance and Societal Importance of the Research Achievements

悪性中皮腫は今後とも本邦で増加する疾患であり、その治療は難しく、また多くの場合早期診断も容易ではなく、極めて予後不良の疾患である。さらにアスベスト（石綿）の消費は新興国を中心に継続しており、今後とも世界的レベルで患者数が増加する。そこで本研究では同疾患の特徴的な遺伝子変異に着目し、
それに起因する細胞増殖機構に基づいて、幾つかの薬剤による細胞傷害効果を検討した。その結果複数の経路を薬物で制御することによって、当該疾患の治療法が開発できる可能性を示した。

Research Products

• [Journal Article] Heat shock protein 90 inhibitors augment endogenous wild-type p53 expression but down-regulate the adenovirally-induced expression by inhibiting a proteasome activity (2018)
  • Author(s): Chai Kuan、Ning Xuerao、Nguyen Thao Thi Thanh、Zhong Boya、Morinaga Takao、Li Zhihan、Shingyoji Masato、Tada Yuji、Tatsumi Koichiro、Shimada Hideaki、Hiroshima Kenzo、Yamaguchi Naoto、Tagawa Masatoshi
  • Journal Title: Oncotarget Volume: 9 Issue: 40 Pages: 26130-26143
  • DOI: 10.18632/oncotarget.25452
  • Peer Reviewed / Open Access
• [Journal Article] Metformin produces growth inhibitory effects in combination with nutlin-3a on malignant mesothelioma through a cross-talk between mTOR and p53 pathways (2017)
  • Author(s): Shimazu Kengo、Tada Yuji、Morinaga Takao、Shingyoji Masato、Sekine Ikuo、Shimada Hideaki、Hiroshima Kenzo、Namiki Takao、Tatsumi Koichiro、Tagawa Masatoshi
  • Journal Title: BMC Cancer Volume: 17 Issue: 1 Pages: 309-309
  • DOI: 10.1186/s12885-017-3300-y
  • NAID: 120007129116
  • Peer Reviewed / Open Access
• [Journal Article] Augmented expression of cardiac ankyrin repeat protein is induced by pemetrexed and a possible marker for the pemetrexed resistance in mesothelioma cells (2017)
  • Author(s): Qin Yiyang、Sekine Ikuo、Fan Mengmeng、Takiguchi Yuichi、Tada Yuji、Shingyoji Masato、Hanazono Michiko、Yamaguchi Naoto、Tagawa Masatoshi
  • Journal Title: Cancer Cell International Volume: 17 Issue: 1 Pages: 120-120
  • DOI: 10.1186/s12935-017-0493-8
  • NAID: 120007134581
  • Peer Reviewed / Open Access
• [Journal Article] Combination of a third generation bisphosphonate and replication-competent adenoviruses augments the cytotoxicity on mesothelioma (2016)
  • Author(s): Jiang, Y., Zhong, B., Kawamura, K., Morinaga, T., Shingyoji, M., Sekine, I., Tada, Y., Tatsumi, K., Shimada, H., Hiroshima, K. and Tagawa, M.
  • Journal Title: BMC Cancer Volume: 16 Issue: 1 Pages: 455-455
  • DOI: 10.1186/s12885-016-2483-y
  • NAID: 120007129538
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 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] An inhibitor for the MDM2-p53 Interaction Produces Synergistic Cytotoxicity with Oncolytic Adenoviruses on Mesothelioma with Wild-type p53 Genotype (2017)
  • Author(s): Masatoshi Tagawa, Thao Thi Thanh Nguyen, Takao Morinaga, Boya Zhong, Michiko Hanazono, Shuji Kubo, Masato Shingyoji, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima
  • Organizer: 20th annual meeting of American Society of Gene and Cell Therapy
  • Int'l Joint Research
• [Presentation] A MDM2 inhibitor augments cytotoxicity of oncolytic adenoviruses defective of E1B 55kDa molecules through enhancing DNA damages and apoptosis in mesothelioma (2017)
  • Author(s): Masatoshi Tagawa, Thao Thi Thanh Nguyen, Takao Morinaga, Boya Zhong, Michiko Hanazono, Shuji Kubo, Masato Shingyoji, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima
  • Organizer: 23rd annual meeting of Japan Society of Gene Therapy
• [Presentation] Enhanced expression of endogenous p53 contributes to E1B55-defective adenoviruses-induced cell death of mesothelioma deleted in the INK4a/ARF region (2016)
  • Author(s): Yuji Tada, Thi Thanh Thao Nguyen, Shuji Kubo, Masato Shingyoji, Ikuo Sekine, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima, Masatoshi Tagawa
  • Organizer: Tenth international meeting on replicating oncolytic virus therapeutics
  • Place of Presentation: Vancouver（Canada）
  • Year and Date: 2016-10-01
  • Int'l Joint Research
• [Presentation] Combination of nutlin-3a and HSP90 inhibitors produces synergistic cytotoxicity on mesothelioma with the wild-type p53 (2016)
  • Author(s): Masatoshi Tagawa, Shinya Okamoto, Takao Morinaga, Masato Shingyoji, Ikuo Sekine, Toshio Suzuki, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima
  • Organizer: The 13th international conference of the international mesothelioma interested group
  • Place of Presentation: Birmingham（UK）
  • Year and Date: 2016-05-01
  • Int'l Joint Research