Development of surgical treatment strategies for intrahepatic cholangiocarcinoma targeting the Warburg effect using PDOX models

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16443
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kyoto University
• Principal Investigator: Yoh Tomoaki 京都大学, 医学研究科, 助教 (20842826)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 肝内胆管癌 / Warburg効果 / 糖代謝

Outline of Final Research Achievements

The aim of this study was to develop therapies targeting the Warburg effect and to investigate the mechanism using a patient-derived xenograft (PDX) model.
The PDX model could not be achieved within this study period due to the low viability of the graft specimens. On the other hand, we explored biomarkers focusing on the regulation of glucose metabolism including the Warburg effect, and found that glutathione perdoxidase 4 (GPX4), a regulator of ferroptosis, stratified the prognosis in patients with intrahepatic cholangiocarcinoma after surgery and was also identified the association with glucose metabolism. In vitro and vivo studies, we revealed that GPX4 inhibition suppressed tumor progression and expression of markers of glucose metabolism, and further demonstrated that regulation of glucose metabolism by GPX4 may be mediated via Akt-mTOR pathway.

Free Research Field

肝胆膵外科

Academic Significance and Societal Importance of the Research Achievements

肝内胆管癌は未だ予後不良な癌であり、予後改善には集学的外科治療の開発が求められる。本研究では新規細胞死であるフェロトーシス制御因子GPX4が肝内胆管癌において有意な予後因子であり、Warburg効果を含む癌糖代謝にGPX4が関与する可能性を明らかにした。このことはGPX4が単にバイオマーカーとして有用であるというだけではなく、GPX4による糖代謝制御を介した細胞死誘導など、今後の新たな癌治療法の開発につながる可能性を含んでいると考えられる。