Drug discovery screening targeting gastrointestinal cancer stem cells

• Project/Area Number: 17K09395
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: TAKANO AI 慶應義塾大学, 医学部(信濃町), 研究員 (50647584)
• Co-Investigator(Kenkyū-buntansha): 股野 麻未 慶應義塾大学, 医学部(信濃町), 研究員 (20439889) ; 佐藤 俊朗 慶應義塾大学, 医学部(信濃町), 教授 (70365245)
• 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: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: オルガノイド / 幹細胞 / HTS / 創薬スクリーニング / がん幹細胞 / 消化器がん / 化合物ライブラリー / organoid / High Throughput / High Contents Analyzer / cancer / 大腸癌 / 膵癌 / 医療・福祉 / 薬剤反応性 / 創薬

Outline of Final Research Achievements

We conducted HTS screening using visualized human gastrointestinal cancer stem cells. In the 1st screening, 3 sets of compound libraries were used and about 30,000 compounds were verified. In the 2nd screening, validation of Dose-responds was performed. From these results, two Hit compounds that have LGR5-specific killing ability were selected. The molecular targeted therapeutic drug A, which is one of the selected compounds, was validated. As a result, it was revealed that it has an effect on cells other than LGR5-positive cells. From the results of this time, we could not obtain a drug that works specifically for human gastrointestinal cancer stem cells, but in the future it will be necessary to set control standards and study more accurate analysis systems and alternatives.

Academic Significance and Societal Importance of the Research Achievements

本研究は，独自に開発したオルガノイド培養技術により，消化器がん組織を直接培養しその生物学的特性と遺伝子変異プロファイルを基に最も効果的な治療薬の組み合わせを個別に選択するという，極めてシンプルな研究であるが，実際の臨床に直結した研究である．多くの研究者が類似した研究開発に取り組んでいるものの，未だ誰も成功していない．つまり，本研究は独創的というよりは源流的な研究基盤開発といえる．我々の研究の成功により，国内外の研究者や製薬会社にとって，実用面での多大なインパクトがあり，必然的に本邦の臨床・産業・研究に与える影響は極めて大きい.

Research Products

• [Journal Article] Somatic inflammatory gene mutations in human ulcerative colitis epithelium. (2020)
  • Author(s): Nanki K, Fujii M, Shimokawa M, Matano M, Nishikori S, Date S, Takano A, Toshimitsu K, Ohta Y, Takahashi S, Sugimoto S, Ishimaru K, Kawasaki K, Nagai Y, Ishii R, Yoshida K, Sasaki N, Hibi T, Ishihara S, Kanai T, Sato T.
  • Journal Title: Nature Volume: 7789 Issue: 7789 Pages: 254-259
  • DOI: 10.1038/s41586-019-1844-5
  • Peer Reviewed / Open Access
• [Journal Article] Human Intestinal Organoids Maintain Self-Renewal Capacity and Cellular Diversity in Niche-Inspired Culture Condition (2018)
  • Author(s): Fujii Masayuki、Matano Mami、Toshimitsu Kohta、Takano Ai、Mikami Yohei、Nishikori Shingo、Sugimoto Shinya、Sato Toshiro
  • Journal Title: Cell Stem Cell Volume: 23 Issue: 6 Pages: 787-793
  • DOI: 10.1016/j.stem.2018.11.016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis (2018)
  • Author(s): Nanki Kosaku、Toshimitsu Kohta、Takano Ai、Fujii Masayuki、Takahashi Sirirat、Sukawa Yasutaka、Ishida Hiroki、Sugimoto Shinya、Kawakubo Hirofumi、Kim Jihoon、Kitagawa Yuko、Sekine Shigeki、Koo Bon-Kyoung、Kanai Takanori、Sato Toshiro
  • Journal Title: Cell Volume: 174 Issue: 4 Pages: 856-869
  • DOI: 10.1016/j.cell.2018.07.027
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Visualization and Targeting of LGR5+ Human Colon Cancer Stem Cells (2017)
  • Author(s): Shimokawa M, Ohta Y, Nishikori S, Matano M, Takano A, Fujii M, Date S, Sugimoto S, Kanai T, Sato T
  • Journal Title: Nature Volume: 印刷中 Issue: 7653 Pages: 13-14
  • DOI: 10.1038/nature22081
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant