The impact of activated PI3K signal on pancreatic cancer

2012 Fiscal Year Final Research Report

• Project/Area Number: 22590756
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: SASAHIRA Naoki 東京大学, 医学部附属病院, 助教 (30401102)
• Co-Investigator(Kenkyū-buntansha): TADA Minoru 東京大学, 医学部附属病院, 講師 (80302719) ; IJICHI Hideaki 東京大学, 医学部附属病院, 助教 (70463841) ; ASAOKA Yoshinari 東京大学, 医学部附属病院, 助教 (90431858)
• Co-Investigator(Renkei-kenkyūsha): IKENOUE Tsuneo 東京大学, 医科学研究所, 准教授 (80396712)
• Project Period (FY): 2010 – 2012
• Keywords: 膵癌 / マウスモデル / 薬剤耐性 / 遺伝子異常

Research Abstract

We generated pancreatic cancer mouse model by inducing pancreas-specific expression of activated Kras and deletion of Pten. All the mice died from pancreas tumor in six weeks. We analyzed the effect of mTOR inhibitor, rapamycin, on pancreatic cancer cell lines with PTEN deletion or AKT2 amplification. Rapamycin had no anti-tumor effect using as a single agent or combination with gemcitabine. We discovered that low glucose medium predisposed these cells to apoptosis and rapamycin prevented this phenomenon. The result suggested that, under some conditions, mTOR inhibition could not exert anti-tumor effect even on PTEN-PI3K-AKT activated cancer.交付決定額（

Research Products

• [Journal Article] Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression. (2012)
  • Author(s): Mohri D, Asaoka Y, Ijichi H, Miyabayashi K, Kudo Y, Seto M, Ohta M, Tada M, Tanaka Y, Ikenoue T, Tateishi K, IsayamaH, Kanai F, Fukushima N, Tada M, Kawabe T, Omata M, Koike K.J
  • Journal Title: Gastroenterol Volume: 47(2) Pages: 203-13
  • DOI: doi:10.1007/s00535-011-0482-y.
• [Journal Article] Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1. (2012)
  • Author(s): Nakai Y, Isayama H, Ijichi H, Sasaki T, Kogure H, Yagioka H, Miyabayashi K, Mizuno S, Yamamoto K, Mouri D, Kawakubo K, Yamamoto N, Hirano K, Sasahira N, Tateishi K, Tada M, Koike K.
  • Journal Title: Cancer Sci Volume: 103(8) Pages: 1489-92
  • DOI: doi:10.1111/j.1349-7006.2012.02311.x.
  • Peer Reviewed
• [Journal Article] Comorbidity, not age, is prognostic inpatients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy. (2011)
  • Author(s): Nakai Y, Isayama H, Sasaki T, Sasahira N, Tsujino T, Kogure H, Yagioka H, Yashima Y, Togawa O, Arizumi T, Matsubara S, Hirano K, Tada M, Omata M, Koike K.
  • Journal Title: Crit Rev Oncol Hematol Volume: 78(3) Pages: 252-9
  • DOI: doi:10.1016/j.critrevonc.2010.05.007.
  • Peer Reviewed
• [Journal Article] Incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasms of the pancreas. (2011)
  • Author(s): Kawakubo K, Tada M, Isayama H, Sasahira N, Nakai Y, Yamamoto K, Kogure H, Sasaki T, Hirano K, Ijichi H, Tateishi K, Yoshida H, Koike K.
  • Journal Title: Gut Volume: 60(9) Pages: 1249-53
  • DOI: doi:10.1136/gut.2010.227306.
  • Peer Reviewed
• [Journal Article] Specific increase in serum autotaxin activity in patients with pancreatic cancer (2011)
  • Author(s): Nakai Y, Ikeda H, Nakamura K, Kume Y, Fujishiro M, Sasahira N, Hirano K, Isayama H, Tada M, Kawabe T, Komatsu Y, Omata M, Aoki J, Koike K, Yatomi Y.
  • Journal Title: Clin Biochem Volume: 44(8-9) Pages: 576-81
  • DOI: doi:10.1016/j.clinbiochem.2011.03.128.
  • Peer Reviewed
• [Journal Article] Gemcitabine and oxaliplatin combination chemotherapy for patients with refractory pancreatic cancer. (2011)
  • Author(s): Isayama H, Nakai Y, Yamamoto K, Sasaki T, Mizuno S, Yagioka H, Yashima Y, Kawakubo K, Kogure H, Arizumi T,Togawa O, Ito Y, Matsubara S, Yamamoto N, Sasahira N, Hirano K, Tsujino T, Tada M, Omata M, Koike K.
  • Journal Title: Oncology Volume: 80(1-2) Pages: 97-101
  • DOI: doi:10.1159/000328767.
  • Peer Reviewed
• [Journal Article] Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma. (2011)
  • Author(s): Ijichi H, Chytil A, Gorska AE, Aakre ME, Bierie B, Tada M, Mohri D, Miyabayashi K, Asaoka Y, Maeda S, Ikenoue T, Tateishi K, Wright CV, Koike K, Omata M, Moses HL.J Clin
  • Journal Title: Invest Volume: 121(10) Pages: 4106-17
  • DOI: doi:10.1172/JCI42754. Epub 2011 Sep 19.
  • Peer Reviewed
• [Journal Article] Impact of S-1 in patients withgemcitabine-refractory pancreatic cancerin Japan (2010)
  • Author(s): Nakai Y, Isayama H, Sasaki T,Sasahira N, Kogure H, Hirano K, Tsujino T,Ijichi H, Tateishi K, Tada M, Omata M,Koike K.
  • Journal Title: Jpn J Clin Oncol Volume: 40(8) Pages: 774-80
  • DOI: doi:10.1093/jjco/hyq059.
  • Peer Reviewed
• [Journal Article] Impact of S-1 on the survival of patientswith advanced pancreatic cancer (2010)
  • Author(s): Nakai Y,Isayama H, Sasaki T, Sasahira N, Ito Y,Kogure H, Togawa O, Matsubara S,Arizumi T, Yagioka H, Yashima Y,Kawakubo K, Mizuno S, Yamamoto K,Hirano K, Tsujino T, Ijichi H, Tateishi K,Toda N, Tada M, Omata M, Koike K.
  • Journal Title: Pancreas Volume: 39(7) Pages: 989-93
  • DOI: doi:10.1097/MPA.0b013e3181d91936.
  • Peer Reviewed
• [Journal Article] A genetic polymorphism of CYP2C19 is associated with susceptibility to biliarytract cancer (2010)
  • Author(s): Isomura Y, Yamaji Y, OhtaM, Seto M, Asaoka Y, Tanaka Y, Sasaki T,Nakai Y, Sasahira N, Isayama H, Tada M,Yoshida H, Kawabe T, Omata M, Koike K.
  • Journal Title: J Gastroenterol Volume: 45(10) Pages: 1045-52
  • DOI: doi:10.1007/s00535-010-0246-0.
  • Peer Reviewed
• [Presentation] Eose extracorporeal shockwave lithotripsy combined with endotherapy really improve the natural course of chronic pancreatitis (2011)
  • Author(s): Sasahira N.
  • Organizer: Digestive Disease Week (DDW)
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 20110507-0510
• [Presentation] Fully covered self-expandable metal stent (FCSEMS) for refractory pancreatic duct stricture associated with chronic pancreatitis. (2010)
  • Author(s): Sasahira N.
  • Organizer: Asian Pacific Digestive Week 2010
  • Place of Presentation: Kuala Lumpur, Malaysia
  • Year and Date: 20100919-0922