Inhibition of gamma-secretase targeting nuclear NOTCH in colorectal cancer

• Project/Area Number: 17K10621
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: The University of Tokyo
• Principal Investigator: Nozawa Hiroaki 東京大学, 医学部附属病院, 准教授 (80529173)
• Co-Investigator(Kenkyū-buntansha): 川合 一茂 東京大学, 医学部附属病院, 講師 (80571942) ; 畑 啓介 東京大学, 医学部附属病院, 特任講師 (60526755) ; 渡邉 聡明 東京大学, 医学部附属病院, 教授 (80210920) ; 石原 聡一郎 東京大学, 医学部附属病院, 教授 (00376443)
• 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: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 大腸癌 / ガンマセクレターゼ / ガンマセクレターゼ阻害剤 / Notch / γセクレターゼ阻害 / Jagged-1

Outline of Final Research Achievements

In in vitro experiments, inhibitor of gamma secreatase (GSI), which cleaves Notch at the cell membrane, successfully inhibited the expressions of Hey1, Hey2, Hes1, and Ki-67 in colon cancer cell lines, as evaluated by quantitative RT-PCR methods. In these cells, the localization of Notch 3 was shifted from the nucleus to the cytoplasm.
Furthermore, we conducted a in vivo expreiment to test the effect of GSI. intraperitoneaal administration of GSI auppressed tumor growth in xanografts in the flank of Balb/c nude mice.

Academic Significance and Societal Importance of the Research Achievements

大腸癌患者における予後不良因子である核Notch発現について、その細胞膜におけるcleavageにかかわるガンマセクレターゼを阻害することが新規治療となるかを検証する目的で、in vitro, in vivoでその抗腫瘍効果を検証した。大腸癌細胞やマウスでの実験レベルにとどまるが、GSI投与が実際に細胞増殖を抑制し、細胞増殖に関わる分子の発現を低下させ、さらに生体における腫瘍の発育を抑制する傾向が示された。したがってNotchを高発現しているような大腸癌患者において、GSIは新規治療の１つとなりうる可能性が考えられた。

Research Products

• [Journal Article] Postoperative chemotherapy is associated with prognosis of stage IV colorectal cancer treated with preoperative chemotherapy/chemoradiotherapy and curative resection (2020)
  • Author(s): 6)Nozawa H, Sonoda H, Ishii H, Emoto S, Murono K, Kaneko M, Sasaki K, Nishikawa T, Shuno Y, Tanaka T, Kawai K, Hata K, Ishihara S.
  • Journal Title: Int J Colorectal Dis Volume: 35 Issue: 1 Pages: 177-180
  • DOI: 10.1007/s00384-019-03461-5
  • Peer Reviewed
• [Journal Article] Metastatic role of mammalian target of rapamycin signaling activation by chemoradiotherapy in advanced rectal cancer. (2020)
  • Author(s): 4)Shiratori H, Kawai K, Okada M, Nozawa H, Hata K, Tanaka T, Nishikawa T, Shuno Y, Sasaki K, Kaneko M, Murono K, Emoto S, Ishii H, Sonoda H, Ushiku T, Ishihara S.
  • Journal Title: Cancer Sci Volume: in press Issue: 4 Pages: 1291-1302
  • DOI: 10.1111/cas.14332
  • Peer Reviewed
• [Journal Article] Accelerated perineural invasion in colitis-associated cancer -;a retrospective cohort study- (2019)
  • Author(s): 15)Nozawa H, Hata K, Ushiku T, Kawai K, Tanaka T, Shuno Y, Nishikawa T, Sasaki K, Emoto S, Kaneko M, Murono K, Sonoda H, Ishihara S
  • Journal Title: Medicine Volume: 98 Issue: 42 Pages: e17570-e17570
  • DOI: 10.1097/md.0000000000017570
  • Peer Reviewed
• [Journal Article] Obstruction is associated with perineural invasion in T3/T4 colon cancer (2019)
  • Author(s): 24)Nozawa H, Morikawa T, Kawai K, Hata K, Tanaka T, Nishikawa T, Sasaki K, Shuno Y, Kaneko M, Hiyoshi M, Murono K, Emoto S, Sonoda H, Fukayama M, Ishihara S
  • Journal Title: Colorectal Dis Volume: 21 Issue: 8 Pages: 917-924
  • DOI: 10.1111/codi.14655
  • Peer Reviewed
• [Journal Article] Adjuvant chemotherapy improves prognosis of resectable stage IV colorectal cancer: A comparative study using inverse probability of treatment weighting. (2019)
  • Author(s): Nozawa H, Takiyama H, Hasegawa K, Kawai K, Hata K, Tanaka T, Nishikawa T, Sasaki K, Kaneko M, Murono K, Emoto S, Sonoda H, Nakajima J.
  • Journal Title: Ther Adv Med Oncol Volume: in press
  • Peer Reviewed
• [Journal Article] Obstruction is associated with perineural invasion in T3/T4 colon cancer (2019)
  • Author(s): Nozawa H, Morikawa T, Kawai K, Hata K, Tanaka T, Nishikawa T, Sasaki K, Shuno Y, Kaneko M, Hiyoshi M, Murono K, Emoto S, Sonoda H, Fukayama M, Ishihara S.
  • Journal Title: Colorectal Dis Volume: in press
  • Peer Reviewed
• [Presentation] Accelerated perineural invasion in colitis-associated cancer. (2019)
  • Author(s): Nozawa H, Ushiku T, Nishikawa T, Ishihara S.
  • Organizer: The 78th Annual Meeting of the Japanese Cancer Association
• [Presentation] Risk factors and therapeutic significance for inguinal lymph node metastasis in advanced lower rectal cancer. (2019)
  • Author(s): Nozawa H, Shiratori H, Kawai K, Hata K, Tanaka T, Nishikawa T, Shuno Y, Sasaki K, Kaneko M, Emoto S, Murono K, Sonoda H, Ishii H, Ishihara S.
  • Organizer: ASCO 2019 Breakthrough: A Global Summit for Oncology Innovators.
  • Int'l Joint Research
• [Presentation] ステント治療を行った大腸癌の病理に端を発した神経周囲侵襲のリスク因子に関する研究 (2019)
  • Author(s): 野澤宏彰、園田洋史、舘川裕一、畑啓介、川合一茂、田中敏明、秀野泰隆、西川武司、佐々木和人、金子学、江本成伸、室野浩司、石井博章、石原聡一郎
  • Organizer: 日本臨床外科学会総会