The elucidation of the novel therapy specific for lung cancer targeting Arf6-induced EMT

• Project/Area Number: 17K10781
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: Kyoto University
• Principal Investigator: Menju Toshi 京都大学, 医学研究科, 講師 (30527081)
• Co-Investigator(Kenkyū-buntansha): 園部 誠 京都大学, 医学研究科, 准教授 (00432378)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 肺癌 / 浸潤転移 / 上皮間葉転換、ＥＭＴ / ＥＧＦＲ / ＧＥＰ１００ / Ａｒｆ６ / Ｇｒｂ２ / 肺腺癌 / ＥＭＴ / 浸潤転移能 / EGFR陽性肺腺癌 / Grb2 / GEP100 / Arf6 / AMAP1 / EPB41L5 / EMT / EGFR / 予後不良 / Arf6活性化 / 上皮間葉転換

Outline of Final Research Achievements

There are no therapies that directly target the invasive metastatic mechanism of lung cancer, which has an unmet medical need. While the GEP100-Arf6 pathway, a mechanism of cancer cell invasion and metastasis, has been reported so far, we have further analyzed the clinical significance and importance of these pathways associated with EMT. In this study, we further elucidated the mechanisms by which Grb2, a known EGFR-binding molecule, can enhance the GEP100-Arf6 pathway and worsen patients’ prognosis by binding to and forming a complex with GEP100 and EGFR. The elucidation of this mechanism will facilitate the development of new molecular targeting agents to inhibit invasion and metastasis.

Academic Significance and Societal Importance of the Research Achievements

現在、浸潤転移能を直接標的とした薬剤はみられず、臨床的観点から最も切望されている。我々と佐邊らのグループは、この臨床的問題点を認識し、GEP100-Arf6経路という癌細胞の浸潤メカニズムの解明を世界に先駆けて研究・報告しており、さらにEGFRとGrb2-GEP100複合体の結合様式の解明により、同結合部位を標的とする浸潤転移能抑制に有効な薬剤の開発につながる。
また、当然この経路を阻害して、浸潤転移の抑制が可能となれば、腫瘍の遠隔転移制御を通じて、術後再発予防や、発見時遠隔転移症例に対する治療適応の拡大など様々な点で、既存治療法に加えて新たな癌治療戦略を採ることが可能となることが期待される。

Research Products

• [Journal Article] Prognostic Significance of Phosphorylated Fyn in Patients with Lung Adenocarcinoma after Lung Resection (2019)
  • Author(s): Nishikawa S, Menju T, Takahashi K, Miyata R, Sonobe M, Yoshizawa A, Date H
  • Journal Title: Annals of Thoracic and Cardiovascular Surgery Volume: 25 Issue: 5 Pages: 246-252
  • DOI: 10.5761/atcs.oa.19-00078
  • NAID: 130007731493
  • ISSN: 1341-1098, 2186-1005
  • Peer Reviewed
• [Journal Article] The Ratios of monounsaturated to saturated phosphatidylcholines in lung adenocarcinoma microenvironment analyzed by Liquid Chromatography-Mass spectrometry and imaging Mass spectrometry. (2019)
  • Author(s): Muranishi, Y., T. Sato, S. Ito, J. Satoh, A. Yoshizawa, S. Tamari, Y. Ueda, Y. Yutaka, T. Menju, T. Nakamura and H. Date
  • Journal Title: Scientific Reports Volume: 1 Issue: 1 Pages: 8916-8916
  • DOI: 10.1038/s41598-019-45506-3
  • NAID: 120006777029
  • Peer Reviewed
• [Journal Article] P40 expression in small cell lung cancer: The presence of p40-positive cells does not always indicate squamous differentiation. (2019)
  • Author(s): Nakajima, N., A. Yoshizawa, K. Moriyoshi, M. Sonobe, T. Menju, S. Sumiyoshi, H. Date and H. Haga
  • Journal Title: Thoracic Cancer Volume: 11 Issue: 5 Pages: 3410-3432
  • DOI: 10.1111/1759-7714.13062
  • NAID: 120006624101
  • Peer Reviewed
• [Journal Article] Prognostic impact of microscopic vessel invasion and visceral pleural invasion and their correlations with epithelial-mesenchymal transition, cancer stemness, and treatment failure in lung adenocarcinoma. (2019)
  • Author(s): Neri, S., T. Menju, T. Sowa, Y. Yutaka, D. Nakajima, M. Hamaji, A. Ohsumi, T. F. Chen-Yoshikawa, T. Sato, M. Sonobe, A. Yoshizawa, H. Haga and H. Date
  • Journal Title: Lung Cancer Volume: 128 Pages: 13-19
  • DOI: 10.1016/j.lungcan.2018.12.001
  • Peer Reviewed
• [Journal Article] Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection (2019)
  • Author(s): Nishikawa Shigeto、Menju Toshi、Takahashi Koji、Miyata Ryo、Chen Yoshikawa Toyofumi Fengshi、Sonobe Makoto、Yoshizawa Akihiko、Sabe Hisataka、Sato Tosiya、Date Hiroshi
  • Journal Title: Cancer Management and Research Volume: Volume 11 Pages: 3419-3432
  • DOI: 10.2147/cmar.s200819
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathologic significance of epithelio-mesenchymal transition in human lung adenocarcinomas: an integrative analysis, inclusive of genetic alterations, on 256 surgically resected cases (2017)
  • Author(s): Toshi Menju, Terumasa Sowa, Makoto Sonobe, Ryo Miyata, Koji Takahashi, Shigeto Nishikawa, Takao Nakanishi, Shinya Neri1, Hiroyuki Cho1, Masatsugu Hamaji, Kyoko Hijiya, Hideki Motoyama, Akihiro Aoyama, Toyofumi F. Chen-Yoshikawa, Toshihiko Sato, Akihiko Yoshizawa, Hironori Haga, Hiroshi Date
  • Journal Title: Cancer Treatment and Research Communications Volume: 12 Pages: 62-68
  • Peer Reviewed / Open Access
• [Presentation] 上皮間葉転換を標的とした肺癌新規治療法の開発 (2019)
  • Author(s): 毛受暁史、西川滋人、曽和晃正２、千葉直久、宮本英明、玉里滋幸、野口未紗、石川浩之、宮田亮、伊達洋至
  • Organizer: 第60回日本肺癌学会学術集会
• [Presentation] 上皮間葉転換を標的とした肺癌新規治療法の開発 (2019)
  • Author(s): 毛受暁史、西川滋人、曽和晃正、玉里滋幸、野口未紗、石川浩之、宮田亮、田中里奈、山田義人、豊洋次郎、中島大輔、大角明宏、濱路政嗣、佐藤寿彦、陳豊史、伊達洋至
  • Organizer: 第72回日本胸部外科学会定期学術集会、
• [Presentation] Arf6-related Invasive Pathway Deteriorated Patients’ Prognosis in Mutant EGFR Lung Adenocarcinoma (2019)
  • Author(s): Toshi Menju, Misa Noguchi, Shigeyuki Tamari, Hiroyuki Ishikawa, Ryo Miyata, Koji Takahashi, Shigeto Nishikawa, Satona Tanaka, Yoshito Yamada, Yojiro Yutaka, Daisuke Nakajima, Fengshi-Toyofumi Chen-Yoshikawa, Toshihiko Sato, Hiroshi Date
  • Organizer: WCLC2019
  • Int'l Joint Research
• [Presentation] Arf6-related Invasive Pathway Deteriorated Patients’ Prognosis in Mutant EGFR Lung Adenocarcinoma (2018)
  • Author(s): Toshi Menjyu
  • Organizer: 6th American Association for Cancer Research-Japanese Cancer Association Special Joint Conference, Poster
  • Int'l Joint Research
• [Presentation] EGFR-Grb2結合は、GEP100-Arf6経路を介した肺癌浸潤転移能を亢進する (2017)
  • Author(s): 毛受暁史
  • Organizer: 第76回日本癌学会総会
• [Presentation] EGFR-Grb2-GEP100 complex promoted its invasive and metastatic potential via Arf6 pathway in lung adenocarcinoma (2017)
  • Author(s): Toshi Menjyu
  • Organizer: 18th World Conference on Lung Cancer
  • Int'l Joint Research
• [Remarks] 京都大学呼吸器外科
  • URL: https://www.thoracic-kyoto-u.gr.jp/