Control of pancreatic cancer through the regulation of novel molecular target in the tumor microenvironment using a genetically-engineered mouse model

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08278
• 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: Ijichi Hideaki 東京大学, 医学部附属病院, 講師 (70463841)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 膵癌 / がん微小環境 / 接着因子 / alpha4-integrin

Outline of Final Research Achievements

We have reported that treatment with neutralizing antibody of adhesion molecule VCAM-1 strikingly prolonged the overall survival of clinically-relevant genetically-engineered mouse model of pancreatic cancer. The underlying mechanisms included the inhibition of cancer-associated thromboembolism. Since VCAM-1 binds to alpha4-integrin (a4ITG), this study investigated the therapeutic effect of neutralizing antibody of a4ITG on pancreatic cancer. Neutralizing antibody of a4ITG is already in clincal practice for other diseases. a4ITG neutralization delayed the subcutaneous tumor growth of human pancratic cancer cell lines, however, treatment the mouse model with a4ITG neutralizing antibody did not show significant effect on the tumor growth, thrombosis and the overall survival. At present, VCAM-1 inhibition is superior to a4ITG inhibition to down-regulate pancreatic cancer and we have no foundation for drug repositioning of a4ITG neutralizing antibody to pancreatic cancer.

Free Research Field

消化器内科学　膵癌

Academic Significance and Societal Importance of the Research Achievements

最難治癌である膵癌の制御のために、alpha4-integrin阻害による抗腫瘍効果、血栓抑制効果、予後改善効果を明らかにし、臨床に存在するalpha4-integrin中和抗体薬を膵癌に適用する根拠を得ようとしたが、ここまでの結果では、alpha4-integrinよりもVCAM-1を阻害することの優位性が示されることになった。しかしヒト膵癌細胞を使った一部の結果ではalpha4-integrinの阻害による膵癌抑制効果も示されている。進行膵癌の極めて厳しい予後改善のために、2種の接着因子阻害による膵癌制御法の知見が蓄積された。