Analysis of histone modification in patient-derived pancreatic cancer cells.

• Project/Area Number: 18K07962
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Nakai Yousuke 東京大学, 医学部附属病院, 准教授 (80466755)
• Co-Investigator(Kenkyū-buntansha): 藤原 弘明 東京大学, 医学部附属病院, 特任臨床医 (00814500) ; 立石 敬介 東京大学, 医学部附属病院, 講師 (20396948)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 膵癌 / 膵臓癌

Outline of Final Research Achievements

Epigenetic regulation consists of DNA methylation or histone modification in affecting gene transcription. The system mutually relates to cellular differentiation, metabolic status or immune response, and so it governs the characteristics of pancreatic cancer cells. The purpose of this research is to unravel the profiles of histone modification to which pancreatic cancer cells addict for survival or growth. We further seek to find novel therapeutic candidates related to epigenetic regulation in pancreatic cancer cells.

Academic Significance and Societal Importance of the Research Achievements

エピゲノム修飾を標的とする薬剤は近年海外を中心に次々に開発され、一部の血液腫瘍ではすでにグローバルなDNAメチル化阻害薬（AZA）やHDAC阻害剤が臨床導入されている。ただし膵癌ではAZAやHDAC阻害薬の有効性は示されておらず、また様々なエピゲノム修飾酵素を阻害する特異的な分子標的薬の有効性についても未だ十分な検討はなされていない。その原因として、患者個々の膵癌細胞のエピゲノム解析が容易ではないことが一因である。今回我々は患者由来膵癌ゼノグラフトを用いた解析で、ヒト膵癌に有効なエピゲノム修飾阻害化合物を新たに同定した。本研究ではその有効性と分子学的機序について解析する。

Research Products

• [Journal Article] Deletion of Histone Methyltransferase G9a Suppresses Mutant Kras-driven Pancreatic Carcinogenesis Carcinogenesis (2020)
  • Author(s): Hiroyuki Kato, Keisuke Tateishi*, Hiroaki Fujiwara, Hideaki Ijichi, Keisuke Yamamoto, Takuma Nakatsuka, Miwako Kakiuchi, Makoto Sano, Yotaro Kudo, Yoku Hayakawa, Hayato Nakagawa, Yasuo Tanaka, Motoyuki Otsuka, Yoshihiro Hirata, Makoto Tachibana, Yoichi Shinkai, Kazuhiko Koike
  • Journal Title: Cancer Genomics Proteomics Volume: 17 Issue: 6 Pages: 695705-695705
  • DOI: 10.21873/cgp.20224
  • Peer Reviewed / Open Access
• [Journal Article] Soluble VCAM-1 promotes gemcitabine resistance via macrophage infiltration and predicts therapeutic response in pancreatic cancer (2020)
  • Author(s): Takahashi Ryota、Ijichi Hideaki、Sano Makoto、Miyabayashi Koji、Mohri Dai、Kim Jinsuk、Kimura Gen、Nakatsuka Takuma、Fujiwara Hiroaki、Yamamoto Keisuke、Kudo Yotaro、Tanaka Yasuo、Tateishi Keisuke、Nakai Yousuke、Morishita Yasuyuki、Soma Katsura、Takeda Norihiko、Moses Harold L.、Isayama Hiroyuki、Koike Kazuhiko
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41598-020-78320-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A phase II trial of gemcitabine, S-1 and LV combination (GSL) therapy in patients with advanced pancreatic cancer. (2019)
  • Author(s): Saito K, Isayama H, Nakai Y, Takahara N, Ishigaki K, Hamada T, Mizuno S, Sasaki T, Kogure H, Matsubara S, Yamamoto N, Ijichi H, Tateishi K, Tada M, Koike K.
  • Journal Title: Invest New Drugs. Volume: 37 Pages: 338-344
  • Peer Reviewed
• [Journal Article] Blocking CXCLs?CXCR2 axis in tumor?stromal interactions contributes to survival in a mouse model of pancreatic ductal adenocarcinoma through reduced cell invasion/migration and a shift of immune-inflammatory microenvironment (2019)
  • Author(s): Sano Makoto、Ijichi Hideaki、Takahashi Ryota、Miyabayashi Koji、Fujiwara Hiroaki、Yamada Tomoharu、Kato Hiroyuki、Nakatsuka Takuma、Tanaka Yasuo、Tateishi Keisuke、Morishita Yasuyuki、Moses Harold L.、Isayama Hiroyuki、Koike Kazuhiko
  • Journal Title: Oncogenesis Volume: 8 Issue: 2 Pages: 8-8
  • DOI: 10.1038/s41389-018-0117-8
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic yield of the plasma free amino acid index for pancreatic cancer in patients with diabetes mellitus (2019)
  • Author(s): Mizuno Suguru、Isayama Hiroyuki、Nakai Yousuke、Ishigaki Kazunaga、Saito Kei、Sato Tatsuya、Takeda Tsuyoshi、Hakuta Ryunosuke、Saito Tomotaka、Takahara Naminatsu、Kogure Hirofumi、Ijichi Hideaki、Tateishi Keisuke、Tada Minoru、Shikata Nahoko、Tagami Tomoyuki、Koike Kazuhiko
  • Journal Title: Pancreatology Volume: 19 Issue: 5 Pages: 695-698
  • DOI: 10.1016/j.pan.2019.07.002
  • Peer Reviewed / Open Access
• [Journal Article] Isocitrate dehydrogenase 1 mutation sensitizes intrahepatic cholangiocarcinoma to the BET inhibitor JQ1 (2018)
  • Author(s): Fujiwara Hiroaki、Tateishi Keisuke、Kato Hiroyuki、Nakatsuka Takuma、Yamamoto Keisuke、Tanaka Yasuo、Ijichi Hideaki、Takahara Naminatsu、Mizuno Suguru、Kogure Hirofumi、Matsubara Saburo、Nakai Yousuke、Koike Kazuhiko
  • Journal Title: Cancer Science Volume: 109 Issue: 11 Pages: 3602-3610
  • DOI: 10.1111/cas.13784
  • Peer Reviewed
• [Journal Article] A phase II trial of gemcitabine, S-1 and LV combination (GSL) neoadjuvant chemotherapy for patients with borderline resectable and locally advanced pancreatic cancer (2018)
  • Author(s): Saito Kei、Isayama Hiroyuki、Sakamoto Yoshihiro、Nakai Yousuke、Ishigaki Kazunaga、Tanaka Mariko、Watadani Takeyuki、Arita Junichi、Takahara Naminatsu、Mizuno Suguru、Kogure Hirofumi、Ijichi Hideaki、Tateishi Keisuke、Tada Minoru、Hasegawa Kiyoshi、Fukayama Masashi、Kokudo Norihiro、Koike Kazuhiko
  • Journal Title: Medical Oncology Volume: 35 Issue: 7 Pages: 100-100
  • DOI: 10.1007/s12032-018-1158-8
  • Peer Reviewed
• [Presentation] VCAM-1阻害は膵癌の進展と癌関連血栓症/血栓塞栓症を抑制し予後に寄与する (2020)
  • Author(s): 佐野誠，高橋良太，伊地知秀明，石垣和祥，山田友春，宮林弘至，水野卓，中塚拓馬，田中康雄，眞杉洋平，森下保幸，田中麻理子，立石敬介，Harold L Moses，小池和彦
  • Organizer: 第79回日本癌学会学術総会