Development of a new therapeutic method for pancreatic cancer using a cell-penetrating peptide targeting C16orf74

• Project/Area Number: 18K08667
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Hokkaido University
• Principal Investigator: Nakamura Toru 北海道大学, 医学研究院, 助教 (70645796)
• Co-Investigator(Kenkyū-buntansha): 浅野 賢道 北海道大学, 大学病院, 特任助教 (10756688) ; 平野 聡 北海道大学, 医学研究院, 教授 (50322813) ; 土川 貴裕 北海道大学, 大学病院, 講師 (50507572)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 膵癌分子標的治療 / 細胞膜透過性ペプチド / C16orf74 / 膵癌 / 分子標的治療

Outline of Final Research Achievements

DAC). The analysis of C16orf74 interaction, we demonstrate a strategy to inhibit the growth and invasion of PDAC. C16orf74 exists in the homodimer form and binds integrin aVb3 and is involved in invasion by activating Rho family and MMP2. Considering that dimeric form was found to be involved in the function of C16orf74, we designed an 11R-DB (dimer block) cell-permeable dominant negative peptide that inhibits the dimer form of C16orf74. 11R-DB suppressed invasion and proliferation of PDAC by inhibiting phosphorylation of Akt and mTOR and also by inactivation of MMP2. 11R-DB showed antitumor effects in an orthotopic xenograft model and peritoneal metastasis model. Thus, dimerized C16orf74 is involved in pancreatic cancer invasion and proliferation. In addition, the C16orf74 dimer block cell-permeable peptide has a potent therapeutic effect on PDAC in vitro and in vivo.

Academic Significance and Societal Importance of the Research Achievements

学術的には、C16orf74蛋白の二量体形成がインテグリンシグナルとMMP2に関与することを示し、膵癌の浸潤・転移機構解明の一助となった。またC16orf74蛋白の二量体を特異的に阻害するペプチド配列を特定し、治療法開発の基盤となる成果を得た。今回の結果に基づき、阻害ペプチドを応用した治療薬開発のみならず、低分子化合物をスクリーニングするなど、新たな研究の起点となり、非常に予後不良な膵癌の克服に向け、社会的意義は大きい。

Research Products

• [Journal Article] Role of dimerized C16orf74 in aggressive pancreatic cancer: A novel therapeutic target. (2020)
  • Author(s): Kushibiki T, Nakamura T, Tsuda M, Tsuchikawa T, Hontani K, Inoko K, Takahashi M, Asano T, Okamura K, Murakami S, Kurashima Y, Ebihara Y, Noji T, Nakanishi Y, Tanaka K, Maishi N, Sasaki K, Park W-R, Shichinohe T, Hida K, Tanaka S, Hirano S.
  • Journal Title: Mol Cancer Ther Volume: 19 Issue: 1 Pages: 187-198
  • DOI: 10.1158/1535-7163.mct-19-0491
  • Peer Reviewed / Open Access / Int'l Joint Research