Dual inhibition of MAPK and mTOR signaling on Pancreatic Cancer

• Project/Area Number: 23790773
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo (2011, 2013); Saitama Medical University (2012)
• Principal Investigator: MOHRI DAI 東京大学, 医学部附属病院, その他 (20582513)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 膵発癌マウスモデル / 分子標的薬

Research Abstract

A crosstalk between mitogen-activated protein kinase (MAPK) and mammalian target of Rapamycin (mTOR) signaling pathways has been reported in several cancers. We have already established pancreas-specific TGF-b receptor II (Tgfbr2) knockout mice in the context of Kras activation and the cell lines derived from these mice. The clinical and histopathologic manifestations of the mice recapitulated human pancreatic ductal adenocarcinoma (PDAC). We report here that the combination therapy using CI-1040, an inhibitor of MEK (mitogen-activated protein kinase kinase) and RAD001, an inhibitor of mTOR, inhibited cell growth of pancreatic cancer in vivo and prolonged survival in a murine model of PDAC. We found that the combination therapy significantly induced cell cycle arrest dramatically compared to the single agent. These findings suggest that the double blockade of MAPK and mTOR signaling pathways might inhibit the signal crosstalk and benefit patients with advanced pancreatic cancer.

Research Products

• [Journal Article] Erlotinib prolongs survival in pancreatic cancer by blocking gemcitabine-induced MAPK signals (2013)
  • Author(s): Miyabayashi K, Ijichi H, Mohri D, Tada M, Yamamoto K, Asaoka Y, Ikenoue T, Tateishi K, Nakai Y, Isayama H, Morishita Y, Omata M, Moses HL, Koike K
  • Journal Title: Cancer Res Volume: 73(7) Pages: 2221-34
  • Peer Reviewed
• [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, Isayama H, Kanai F, Fukushima N, Tada M, Kawabe T, Omata M, Koike K
  • Journal Title: J Gastroenterol Volume: 47(2) Pages: 203-13
  • Peer Reviewed
• [Presentation] 胆嚢癌に対するmTORとMAPKを標的とした治療法の検討 (2011)
  • Author(s): 毛利大、伊地知秀明、小池和彦
  • Organizer: 第53回日本消化器病学会大会・パネルディスカッション
  • Place of Presentation: 福岡