Development of novel strategies for the chemoresistant pancreatic tumors using the patient-derived library

• Project/Area Number: 17K09454
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: TAKAHARA NAMINATSU 東京大学, 医学部附属病院, 助教 (10750622)
• Co-Investigator(Kenkyū-buntansha): 立石 敬介 東京大学, 医学部附属病院, 講師 (20396948)
• 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: 膵癌

Outline of Final Research Achievements

In this project, we established the library of patient-derived tumor xenografts (PDX) and Patient-derived organoids (PDO). Using the system, we performed the drug screening in epigenetic field for the pancreatic cancer cells. Especially, we tried to analyze the mechanism of drug resistance in pancreatic cancer cells. We found the effectiveness of BET inhibitor against the growth of pancreatic cancer PDOs and published the report. We are conducting in vivo validation of in vitro data. Additionally, we analyze the function of target genes in pancreatic cancer.

Academic Significance and Societal Importance of the Research Achievements

申請者らはこれまでに標準治療に抵抗性となった膵癌に対する腹腔内化学療法や新規化学療法regimen の開発に携わるとともに、遺伝子多型SNPや腫瘍マーカーを用いた治療効果予測の有用性を報告してきた。本研究では、患者由来ヒト膵癌異種移植腫瘍を用いることで、化学療法への耐性を改善する低分子化合物の探索とその機序の解明を試みた。ヒト膵癌細胞とマウスでの分子機序における相違点の有無についても解析を行い、新たな膵癌増殖抑制効果を持つエピゲノム分子としての意義を確立した。

Research Products

• [Journal Article] Long-term Risk of Malignancy in Branch-Duct Intraductal Papillary Mucinous Neoplasms. (2020)
  • Author(s): Oyama H, Tada M, Takagi K, Tateishi K, Hamada T, Nakai Y, Hakuta R, Ijichi H, Ishigaki K, Kanai S, Kogure H, Mizuno S, Saito K, Saito T, Sato T, Suzuki T, Takahara N, Morishita Y, Arita J, Hasegawa K, Tanaka M, Fukayama M, Koike K.
  • Journal Title: Gastroenterology. Volume: 158 Issue: 1 Pages: 226-237
  • DOI: 10.1053/j.gastro.2019.08.032
  • Peer Reviewed
• [Journal Article] The impact of age and comorbidity in advanced or recurrent biliary tract cancer receiving palliative chemotherapy. (2020)
  • Author(s): Takahara N, Nakai Y, Saito K, Sasaki T, Suzuki Y, Inokuma A, Oyama H, Kanai S, Suzuki T, Sato T, Hakuta R, Ishigaki K, Saito T, Hamada T, Mizuno S, Kogure H, Tada M, Isayama H, Koike K.
  • Journal Title: J Gastroenterol Hepatol. Volume: 10 Issue: 10 Pages: 15066-15066
  • DOI: 10.1111/jgh.15066
  • Peer Reviewed
• [Journal Article] Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation (2019)
  • Author(s): Fujiwara H、Tateishi K、Misumi K、Hayashi A、Igarashi K、Kato H、Nakatsuka T、Suzuki N、Yamamoto K、Kudo Y、Hayakawa Y、Nakagawa 、Tanaka Y、Ijichi H、Kogure H、Nakai Y、Isayama H、Hasegawa K、Fukayama M、Soga T、Koike K
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 18859-18859
  • DOI: 10.1038/s41598-019-55211-w
  • Peer Reviewed / Open Access
• [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] A feasibility study of gemcitabine, S-1 and leucovorin combination therapy (GSL) for advanced biliary tract cancer (2019)
  • Author(s): Takahara Naminatsu、Isayama Hiroyuki、Nakai Yousuke、Sasaki Takashi、Saito Kei、Sato Tatsuya、Hakuta Ryunosuke、Ishigaki Kazunaga、Saito Tomotaka、Hamada Tsuyoshi、Mizuno Suguru、Kogure Hirofumi、Tada Minoru、Koike Kazuhiko
  • Journal Title: Journal of Chemotherapy Volume: 31 Issue: 5 Pages: 284-289
  • DOI: 10.1080/1120009x.2019.1626088
  • Peer Reviewed
• [Journal Article] Second-line chemotherapy in patients with advanced or recurrent biliary tract cancer: a single center, retrospective analysis of 294 cases (2018)
  • Author(s): Takahara Naminatsu、Nakai Yousuke、Isayama Hiroyuki、Sasaki Takashi、Saito Kei、Oyama Hiroki、Kanai Sachiko、Suzuki Tatsunori、Sato Tatsuya、Hakuta Ryunosuke、Ishigaki Kazunaga、Takeda Tsuyoshi、Saito Tomotaka、Mizuno Suguru、Kogure Hirofumi、Tada Minoru、Koike Kazuhiko
  • Journal Title: Investigational New Drugs Volume: 36 Issue: 6 Pages: 1093-1102
  • DOI: 10.1007/s10637-018-0670-1
  • 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
• [Journal Article] Gemcitabine and S-1 versus gemcitabine and cisplatin treatment in patients with advanced biliary tract cancer: a multicenter retrospective study. (2017)
  • Author(s): Takahara N, Isayama H, Nakai Y, Sasaki T, Ishigaki K, Saito K, Akiyama D, Uchino R, Mizuno S, Yagioka H, Kogure H, Togawa O, Matsubara S, Ito Y, Toda N, Tada M, Koike K.
  • Journal Title: Invest New Drugs Volume: 35(3) Issue: 3 Pages: 269-276
  • DOI: 10.1007/s10637-017-0430-7
  • Peer Reviewed
• [Journal Article] A Novel Partially Covered Self-Expandable Metallic Stent with Proximal Flare in Patients with Malignant Gastric Outlet Obstruction. (2017)
  • Author(s): Takahara N, Isayama H, Nakai Y, Yoshida S, Saito T, Mizuno S, Yagioka H, Kogure H, Togawa O, Matsubara S, Ito Y, Yamamoto N, Tada M, Koike K.
  • Journal Title: Gut Liver. Volume: 11(4) Issue: 4 Pages: 481-488
  • DOI: 10.5009/gnl16259
  • Peer Reviewed
• [Journal Article] CA19-9 kinetics during systemic chemotherapy in patients with advanced or recurrent biliary tract cancer. (2017)
  • Author(s): Takahara N, Nakai Y, Isayama H, Sasaki T, Saito K, Noguchi K, Suzuki T, Nakamura T, Sato T, Ishigaki K, Hakuta R, Takeda T, Uchino R, Mizuno S, Kogure H, Tada M, Koike K.
  • Journal Title: Cancer Chemother Pharmacol. Volume: 80(6) Issue: 6 Pages: 1105-1112
  • DOI: 10.1007/s00280-017-3456-9
  • Peer Reviewed