Development of novel therapy for pancreatic cancer targeting Notch/Hes1 signaling

• Project/Area Number: 16K09395
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kobe University (2018); Kyoto University (2016-2017)
• Principal Investigator: Kodama Yuzo 神戸大学, 医学研究科, 教授 (80378687)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 膵癌 / Hes1 / Notchシグナル / 膵臓 / 前癌病変 / 癌 / 遺伝子 / シグナル伝達

Outline of Final Research Achievements

Pancreatic cancer develops from precancerous lesions called ADM and PanIN by accumulation of genetic abnormalities including KRAS gene mutation. In this study, we focused on Notch/Hes1 signaling and aimed to elucidate the pathogenesis of pancreatic cancer and to develop new treatment options. Analysis using human pancreatic cancer specimens and cell lines showed that activation of mutant KRAS gene induced Hes1. Mouse model demonstrated that the formation of pancreatic cancer was almost completely suppressed by knocking out the Hes1 gene. Furthermore, the novel Hes1 inhibitor significantly suppressed the growth of human pancreatic cancer cell lines. These findings suggest that Hes1 plays an essential role in the formation of pancreatic cancer and could be a new therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

膵癌はその５年生存率が10%に満たない難治癌であり、その病態の解明と新規治療開発が急務となっている。膵癌症例の95%はKRAS遺伝子の変異を有し、病態の中心を担っていることが示唆されてきた。本研究では、膵癌に発現が認められるHes1に着目し、その機能解析を行った。その結果、変異KRAS遺伝子の活性化による膵癌の形成には、変異KRASの活性化により誘導されるHes1が必須であることが明らかとなった。また、膵癌細胞にHes1阻害を投与したところ、その増殖が抑制されたことから、Hes1が膵癌の新しい治療標的となる可能性が示唆された。

Research Products

• [Journal Article] Hes1 plays an essential role in Kras-driven pancreatic tumorigenesis (2019)
  • Author(s): Nishikawa Y、Kodama Y、Shiokawa M、Matsumori T、Marui S、Kuriyama K、Kuwada T、Sogabe Y、Kakiuchi N、Tomono T、Mima A、Morita T、Ueda T、Tsuda M、Yamauchi Y、Sakuma Y、Ota Y、Maruno T、Uza N、Uesugi M、Kageyama R、Chiba T、Seno H
  • Journal Title: Oncogene Volume: in press Issue: 22 Pages: 4283-4296
  • DOI: 10.1038/s41388-019-0718-5
  • Peer Reviewed / Open Access
• [Journal Article] Small-molecule screening yields a compound that inhibits the cancer-associated transcription factor Hes1 via the PHB2 chaperone. (2018)
  • Author(s): Perron A, Nishikawa Y, Iwata J, Shimojo H, Takaya J, Kobayashi K, Imayoshi I, Mbenza NM, Takenoya M, Kageyama R, Kodama Y, Uesugi M.
  • Journal Title: J Biol Chem. Volume: 印刷中 Issue: 21 Pages: 8285-8294
  • DOI: 10.1074/jbc.ra118.002316
  • Peer Reviewed
• [Presentation] Hes1 は膵癌マウスモデルにおいて膵発癌を抑制する (2017)
  • Author(s): 西川義浩、児玉裕三、桒田威、丸井彩子、曽我部裕子、森田敏広、垣内伸之、美馬淳志、松森友昭、友野輝子、上田樹、津田喬之、山内雄揮、佐久間洋二朗、栗山勝利、丸野貴久、塩川雅広、宇座徳光、妹尾浩
  • Organizer: 第48回 日本膵臓学会大会
• [Presentation] 膵癌形成における Hes1 の機能解析 (2017)
  • Author(s): 西川義浩、児玉裕三、山内雄揮、津田喬之、妹尾浩
  • Organizer: 第76回 日本癌学会学術総会
• [Presentation] Hes1 plays an essential role in pancreatic carcinogenesis (2016)
  • Author(s): Yoshihiro Nishikawa, Yuzo Kodama, Tsutomu Chiba, Hiroshi Seno
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2016-10-06
• [Presentation] Biphasic Role of Hes1 in Pancreatic Development (2016)
  • Author(s): Katsutoshi Kuriyama, Yuzo Kodama, Masahiro Shiokawa, Nobuyuki Kakiuchi, Tomoaki Matsumori, Atsushi Mima, Teruko Tomono, Yoshihiro Nishikawa, Motoyuki Tsuda, Tatsuki Ueda, Yuki Yamauchi, Yojiro Sakuma, Yuji Ota, Takahisa Maruno, Norimitsu Uza, Hiroshi Seno, Tsutomu Chiba
  • Organizer: American Gastroenterological Association, DDW 2016
  • Place of Presentation: San Diego
  • Year and Date: 2016-05-23
  • Int'l Joint Research