Epithelial-mesenchymal transition targeted therapy for malignant pleural mesothelioma

• Project/Area Number: 17K09647
• 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 University
• Principal Investigator: Takiguchi Yuichi 千葉大学, 医学部附属病院, 教授 (30272321)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 中皮腫 / 悪性中皮腫 / 悪性胸膜中皮腫 / ペメトレキセド / 薬剤耐性 / 上皮間葉移行 / 胸膜中皮腫 / 薬物耐性 / 神経内分泌がん / 上皮間葉転換 / 分子標的治療

Outline of Final Research Achievements

Pemetrexed-resistant 4 human malignant mesothelioma cell lines were established, and the underlying mechanism was elucidated. Drug resistance was shown associated with increased expression of CARP, ADRB2, PAI1, ITGB3, ADAMTS5 and IGFBP3. By modulating these gene expression, CARP was proven to be a key molecule for pemetrexed-resistance of mesothelioma cells, and would be a good biomarker for chem-resistance. In relation to the main experiments, pirfenidon, an anti-fibrosing agent, was proven to prevent TGF and IGF-induced epithelial-mesenchymal transition.

Academic Significance and Societal Importance of the Research Achievements

悪性胸膜中皮腫は環境・産業衛生に関連した重要な疾患であるが、有効な治療薬が限られており予後の厳しい難治性疾患であり、その治療法の開発は急務である。ペメトレキセドは中皮腫に対して有効性を示す数少ない抗腫瘍薬ほひとつではあるが、初回耐性、獲得耐性が問題となる。本研究では主に獲得耐性機序を明らかにし、その関連シグナル伝達経路を合わせて解明することにより、ペメトレキセド耐性の克服、新たなバイオマーカーの開発を可能とするものであり、この疾患のunmet needの解決に貢献するものと思われる。

Research Products

• [Journal Article] Simultaneous chylous ascites and chylothorax during ramucirumab plus docetaxel chemotherapy in a patient with non-small lung cell cancer (2019)
  • Author(s): Arai, M. Maruta, S. Fan, M. M. Imai, C. Tawada, A. Takiguchi, Y.
  • Journal Title: Int Cancer Conf J Volume: 8 Issue: 3 Pages: 114-117
  • DOI: 10.1007/s13691-019-00366-6
  • Peer Reviewed
• [Journal Article] Long-Term Prognosis of Patients with Obscure Gastrointestinal Bleeding: A Retrospective Cohort Study (2019)
  • Author(s): Arai, M. Matsumura, T. Ohta, Y. Kiyono, S. Hayashi, M. Taida, T. Saito, K. Okimoto, K. Maruoka, D. Nakagawa, T. Katsuno, T. Kato, N. Takiguchi, Y.
  • Journal Title: Digestion Volume: - Issue: 1 Pages: 1-11
  • DOI: 10.1159/000493854
  • Peer Reviewed / Open Access
• [Journal Article] Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site (2019)
  • Author(s): Hayashi Hidetoshi、Kurata Takayasu、Takiguchi Yuichi、Arai Makoto、Takeda Koji、Akiyoshi Kohei、Matsumoto Koji、Onoe Takuma、Mukai Hirofumi、Matsubara Nobuaki、Minami Hironobu、Toyoda Masanori、Onozawa Yusuke、Ono Akira、Fujita Yoshihiko、Sakai Kazuko、et al.
  • Journal Title: Journal of Clinical Oncology Volume: 37 Issue: 7 Pages: 570-579
  • DOI: 10.1200/jco.18.00771
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intracardiac Tumors With Extracardiac Extension Diagnosed by Endoscopic Ultrasound With Bronchoscope-Guided Fine-Needle Aspiration (2019)
  • Author(s): Inage Terunaga、Nakajima Takahiro、Sata Yuki、Fujiwara Taiki、Iwasawa Syunichiro、Takiguchi Yuichi、Nakatani Yukio、Yoshino Ichiro
  • Journal Title: The Annals of Thoracic Surgery Volume: 107 Issue: 1 Pages: e5-e7
  • DOI: 10.1016/j.athoracsur.2018.05.046
  • Peer Reviewed / Open Access
• [Journal Article] Phase II trial of S-1 plus cisplatin combined with bevacizumab for advanced non-squamous non-small cell lung cancer (TCOG LC-1202) (2019)
  • Author(s): Miyanaga, A. （途中9名省略）Takiguchi, Y. Gemma, A.
  • Journal Title: Jpn J Clin Oncol Volume: 49 Issue: 8 Pages: 749-754
  • DOI: 10.1093/jjco/hyz064
  • Peer Reviewed
• [Journal Article] A Repeated Biopsy by EBUS-TBNA Contributed to the Selection of an Appropriate Therapeutic Regimen for a Lung Cancer Patient (2019)
  • Author(s): Naito, J. Toyoda, T. Nakajima, T. Fujiwara, T. Iwasawa, S. Suzuki, H. Takiguchi, Y. Yoshino, I.
  • Journal Title: J Bronchology Interv Pulmonol Volume: 26 Issue: 2 Pages: 129-131
  • DOI: 10.1097/lbr.0000000000000571
  • Peer Reviewed
• [Journal Article] Multicenter study of zoledronic acid administration in non-small-cell lung cancer patients with bone metastasis: Thoracic Oncology Research Group (TORG) 1017. (2019)
  • Author(s): Nakahara Y, Hosomi Y, Shibuya M, Mitsufuji H, Katagiri M, Naoki K, Soejima K, Nogami N, Nagase S, Nishikawa M, Minato K, Takiguchi Y, Seki N, Yamada K, Seto T, Okamoto H.
  • Journal Title: Mol Clin Oncol Volume: 11 Pages: 349-353
  • DOI: 10.3892/mco.2019.1903
  • Peer Reviewed / Open Access
• [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] Resveratrol Targets Urokinase-Type Plasminogen Activator Receptor Expression to Overcome Cetuximab-Resistance in Oral Squamous Cell Carcinoma (2019)
  • Author(s): Uzawa, K. （途中17名省略）Takiguchi, Y. Yamauchi, M. Tanzawa, H.
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 12179-12179
  • DOI: 10.1038/s41598-019-48717-w
  • Peer Reviewed
• [Journal Article] Growth suppression of human oral cancer cells by candidate agents for cetuximab-side effects (2019)
  • Author(s): Uzawa, K. （途中9名省略）Takiguchi, Y. Tanzawa, H.
  • Journal Title: Exp Cell Res Volume: 376 Issue: 2 Pages: 210-220
  • DOI: 10.1016/j.yexcr.2019.01.016
  • Peer Reviewed
• [Journal Article] Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line treatment for stage IV squamous non-small cell lung cancer: A phase 1b and randomized, open-label, multicenter, phase 2 trial in Japan (2019)
  • Author(s): Watanabe, S. （途中6名省略）Takiguchi, Y. （途中13名省略）Tamura, T.
  • Journal Title: Lung Cancer Volume: 129 Pages: 55-62
  • DOI: 10.1016/j.lungcan.2019.01.005
  • Peer Reviewed
• [Journal Article] Inhibition of Gli leads to antitumor growth and enhancement of cisplatin-induced cytotoxicity in large cell neuroendocrine carcinoma of the lung (2018)
  • Author(s): Ishiwata Tsukasa、Iwasawa Shunichiro、Ebata Takahiro、Fan Mengmeng、Tada Yuji、Tatsumi Koichiro、Takiguchi Yuichi
  • Journal Title: Oncology Reports Volume: 39 Pages: 1148-1154
  • DOI: 10.3892/or.2018.6183
  • Peer Reviewed
• [Journal Article] Anamorelin (ONO-7643) for the treatment of patients with non-small cell lung cancer and cachexia: Results from a randomized, double-blind, placebo-controlled, multicenter study of Japanese patients (ONO-7643-04) (2018)
  • Author(s): Katakami Nobuyuki、Uchino Junji、Yokoyama Takuma、Naito Tateaki、Kondo Masashi、Yamada Kouzo、Kitajima Hiromoto、Yoshimori Kozo、Sato Kazuhiro、Saito Hiroshi、Aoe Keisuke、Tsuji Tetsuya、Takiguchi Yuichi、Takayama Koichi、Komura Naoyuki、Takiguchi Toru、Eguchi Kenji
  • Journal Title: Cancer Volume: 124 Issue: 3 Pages: 606-616
  • DOI: 10.1002/cncr.31128
  • Peer Reviewed
• [Journal Article] Prognostic impact of presumed breast or ovarian cancer among patients with unfavorable-subset cancer of unknown primary site (2018)
  • Author(s): Kodaira Makoto、Yonemori Kan、Shimoi Tatsunori、Yoshida Akihiko、Yoshida Masayuki、Kitano Atsuko、Shimomura Akihiko、Yunokawa Mayu、Shimizu Chikako、Takiguchi Yuichi、Fujiwara Yasuhiro、Tamura Kenji
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 176-176
  • DOI: 10.1186/s12885-018-4092-4
  • Peer Reviewed
• [Journal Article] A Randomized Phase III Study Comparing Carboplatin With Nab-Paclitaxel Versus Docetaxel for Elderly Patients With Squamous-Cell Lung Cancer: Study Protocol (2018)
  • Author(s): Kogure Yoshihito、Saka Hideo、Takiguchi Yuichi、Atagi Shinji、Kurata Takayasu、Ebi Noriyuki、Inoue Akira、Kubota Kaoru、Takenoyama Mitsuhiro、Seto Takashi、Kada Akiko、Yamanaka Takeharu、Ando Masahiko、Yamamoto Nobuyuki、Gemma Akihiko、Ichinose Yukito
  • Journal Title: Clinical Lung Cancer Volume: 19 Issue: 5 Pages: e711-e715
  • DOI: 10.1016/j.cllc.2018.05.005
  • Peer Reviewed
• [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] Mefenamic acid enhances anticancer drug sensitivity via inhibition of aldo-keto reductase 1C enzyme activity. (2017)
  • Author(s): Shiiba, M., Yamagami, H., Yamamoto, A., Minakawa, Y., Okamoto, A., Kasamatsu, A., Sakamoto, Y., Uzawa, K., Takiguchi, Y. and Tanzawa, H.
  • Journal Title: Oncol Rep Volume: 37 Issue: 4 Pages: 2025-2032
  • DOI: 10.3892/or.2017.5480
  • Peer Reviewed / Open Access
• [Journal Article] Potential Activity of Amrubicin as a Salvage Therapy for Merkel Cell Carcinoma (2017)
  • Author(s): Sakaida, E., Ebata, T., Iwasawa, S., Kurimoto, R., Yonemori, S., Ota, S., Nakatani, Y., Sekine, I. and Takiguchi, Y.
  • Journal Title: Internal Medicine Volume: 56 Issue: 5 Pages: 567-570
  • DOI: 10.2169/internalmedicine.56.7675
  • NAID: 130005399427
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Pirfenidone may revert the epithelial-to-mesenchymal transition in human lung adenocarcinoma (2017)
  • Author(s): Kurimoto, R. Ebata, T. Iwasawa, S. Ishiwata, T. Tada, Y. Tatsumi, K. Takiguchi, Y.
  • Journal Title: Oncol Lett Volume: 14 Issue: 1 Pages: 944-950
  • DOI: 10.3892/ol.2017.6188
  • Peer Reviewed / Open Access
• [Presentation] Randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine /cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small-cell lung cancer (Ns-NSCLC): The JIPANG study (2019)
  • Author(s): Kenmotsu, Hirotsugu Yamamoto, Nobuyuki Yamanaka, Takeharu Yoshiya, Katsuo Takahashi, Toshiaki Ueno, Tsuyoshi Goto, Koichi Daga, Haruko Ikeda, Norihiko Sugio, Kenji Seto, Takashi Toyooka, Shinichi Date, Hiroshi Mitsudomi, Tetsuya Okamoto, Isamu Yokoi, Kohei Saka, Hideo Okamoto, Hiroaki Takiguchi, Yuichi Tsuboi, Masahiro
  • Organizer: 2019 ASCO Annual Meeting
  • Int'l Joint Research
• [Presentation] Final PFS analysis and safety data from the phase III J-ALEX study of alectinib (ALC) vs. crizotinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung cancer (ALK+ NSCLC) (2019)
  • Author(s): Seto,（途中9名省略）Takiguchi, Yuichi （途中14名省略）Tamura, Tomohide
  • Organizer: 2019 ASCO Annual Meeting
  • Int'l Joint Research
• [Presentation] EGFR変異陽性NSCLCに対するオシメルチニブ+ラムシルマブとオシメルチニブのランダム化第II相試験: TORG1833 (2019)
  • Author(s): 本田 健 中原 善朗 磯村 玲子 古屋 直樹 猶木 克彦 葉 清隆 熊谷 融 滝口 裕一 湊 浩一 下川 恒生 山中 竹春 岡本 浩明 加藤 晃史
  • Organizer: 第17回日本臨床腫瘍学会学術集会
• [Presentation] 悪性胸膜中皮腫に対しNK4遺伝子発現型アデノウイルスベクターを用いた胸腔内遺伝子治療の第I相試験 (2019)
  • Author(s): 多田裕司 鈴木敏夫 下村巌 石綿司 穴澤梨江 滝口裕一 廣島健三 関根郁夫 巽浩一郎
  • Organizer: 第59回日本呼吸器学会
• [Presentation] がん治療医からみた口腔ケアの課題 (2019)
  • Author(s): 滝口裕一
  • Organizer: 第16回日本口腔ケア学会総会・学術大会
  • Invited
• [Presentation] Pemetrexed resistance irrelevant to nucleotide synthesis is linked with up-regulated AMP-activated protein kinase (English Oral) (2018)
  • Author(s): Zhong, Boya Sekine, Ikuo Takiguchi, Yuichi Thao Nguyen, Thi Thanh Morinaga, Takao Tada, Yuji Yamaguchi, Naoto Tagawa, Masatoshi
  • Organizer: 第77回日本癌学会学術総会
• [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 (ポスター） (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 関根郁夫 巽浩一郎 田川雅敏
  • Organizer: 第59回日本肺癌学会学術集会
• [Presentation] 悪性中皮腫におけるペメトレキセート耐性はAMPKの活性化が関与する (2017)
  • 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76回日本癌学会学術総会
• [Presentation] 新しいがん免疫療法～免疫チェックポイント阻害治療～（県民公開講座） (2017)
  • Author(s): 滝口裕一
  • Organizer: 平成29年度千葉県医師会医学会 第18回学術大会
  • Invited
• [Presentation] 肺がん（教育セッション） (2017)
  • Author(s): 滝口裕一
  • Organizer: 第55回日本癌治療学会学術集会
  • Invited
• [Presentation] Updated efficacy and safety of the jalex study comparing alectinib (ALC) with crizotinib (CRZ) in ALK-inhibitor naive ALK fusion positive non small cell lung cancer (ALK+ NSCLC). (2017)
  • Author(s): Y. Takiguchi, T. Hida, et al.
  • Organizer: 2017 ASCO
  • Int'l Joint Research
• [Presentation] Biology/Pathology and Epidemiology/Primary Prevention/Tobacco Control and Cessation. Highlights of the Previous Day (2017)
  • Author(s): Yuichi Takiguchi
  • Organizer: IASLC 18th World Conference on Lung Cancer
  • Int'l Joint Research / Invited