New drug discovery screening targeting autophagy

• Project/Area Number: 16K15621
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: NAKATA Kohei 九州大学, 大学病院, 助教 (30419569)
• Co-Investigator(Kenkyū-buntansha): 白羽根 健吾 九州大学, 医学研究院, 共同研究員 (10529803) ; 当間 宏樹 九州大学, 医学研究院, 共同研究員 (80437780) ; 冨永 洋平 九州大学, 医学研究院, 共同研究員 (90304823)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: オートファジー / 膵星細胞 / 創薬 / 膵癌 / 膵臓癌 / オートファジー抑制剤

Outline of Final Research Achievements

Pancreatic stellate cells (PSCs) change from a quiescent to activated state in the tumor microenvironment and secrete extracellular matrix (ECM) molecules and cytokines to increase the aggressiveness of tumors. However, it is not clear how PSCs are activated to produce these factors, or whether this process can be inhibited. We have recently reported regarding the relationships between autophagy and activation of the PSCs and found that autophagy inhibition in PSCs reduced the activation of PSC and proliferation of PSC, followed by the inhibition of the invasiveness of pancreatic cancer cells in vitro and vivo (Endo et al, gastroenterology, 2017). Based on these results we performed high-throughput screening in Drug Discovery for pancreatic cancer targeting pancreatic stellate cells. We found several candidates, which may inhibit the PSCs activation. We also validated and found the compound X truly inhibited PSCs activation and also found it inhibited the proliferation of PSCs.

Research Products

• [Journal Article] Autophagy inhibition enhances antiproliferative effect of salinomycin in pancreatic cancer cells (2017)
  • Author(s): Endo Sho、Nakata Kohei、Sagara Akiko、Koikawa Kazuhiro、Ando Yohei、Kibe Shin、Takesue Shin、Nakayama Hiromichi、Abe Toshiya、Okumura Takashi、Moriyama Taiki、Miyasaka Yoshihiro、Ohuchida Kenoki、Ohtsuka Takao、Mizumoto Kazuhiro、Nakamura Masafumi
  • Journal Title: Pancreatology Volume: 17 Issue: 6 Pages: 990-996
  • DOI: 10.1016/j.pan.2017.08.009
  • Peer Reviewed
• [Journal Article] Autophagy is required for activation of pancreatic sstellate cells, associated with pancreatic cancer progression and promotes growth of pancreatic tumors in mice. (2017)
  • Author(s): Endo S, Nakata K, Ohuchida K, Takesue S, Nakayama H, Abe T, Koikawa K, Okumura T, Sada M, Horioka K, Zheng B, Mizuuchi Y, Iwamoto C, Murata M, Moriyama T, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M.
  • Journal Title: Gastroenterology Volume: 印刷中 Issue: 6 Pages: 1492-1506
  • DOI: 10.1053/j.gastro.2017.01.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] オートファージは膵星細胞の活性化に関与しており、その抑制は膵癌の進展を制御する (2017)
  • Author(s): 仲田興平、遠藤翔、大内田研宙、水元一博、小田義直、橋爪誠、中村雅史
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Pancreatic organoids elucidate the new mechanisms of pancreatic cancer local invasion (2017)
  • Author(s): Koikawa K, Ohuchida K, Ando Y, Kibe S, Nakayama H, Takesue S, Yan Z, Abe T, Okumura T, Iwamoto C, Moriyama T, Nakata K, Miyasaka Y, Okabe Y, Ohtsuka T, Mizumoto K, Nakamura M
  • Organizer: The 48th Annual Meeting of The American Pancreatic Association
  • Int'l Joint Research
• [Presentation] Autophagy Drives Pancreatic Stellate Cells Activation and Promotes Pancreatic Cancer. (2016)
  • Author(s): Endo S,Nakata K,Ohuchida K,Ando Y,Kibe S,Takesue S,Nakayama H,Abe T,Koikawa K,Okumura T,Mizuuchi Y,Moriyama T,Miyasaka Y,Manabe T,Ohtsuka T,Nagai E,Mizumoto K,Oda Y,Nakamura M
  • Organizer: 47th Annual Meeting of the American Pancreatic Association
  • Place of Presentation: Boston(USA)
  • Year and Date: 2016-10-26
  • Int'l Joint Research