Establishing New Therapeutic Strategy for Urothelial Carcinoma

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K16757
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Keio University
• Principal Investigator: Ogihara Koichiro 慶應義塾大学, 医学部(信濃町), 助教 (30626677)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: 尿路上皮癌 / IDH2阻害薬

Outline of Final Research Achievements

The objective of this study is to elucidate the intracellular metabolic network of cancer stem cells within treatment-resistant bladder cancer tissue, and to identify novel therapeutic targets that selectively exert effective effects, as well as to construct a treatment strategy for clinical application. Using two established bladder cancer cell lines in our department, metabolome analysis was performed using the metabolomics core facility at our institution, revealing the existence of a metabolic reprogramming mechanism centered around IDH2. In vivo experiments using an IDH2 inhibitor demonstrated a high antitumor effect of combination therapy with IDH2 inhibitors and existing anticancer drugs. Additionally, we confirmed strong expression of the IDH2 protein in UC samples where the preoperative chemotherapy was not effective.

Free Research Field

泌尿器科学

Academic Significance and Societal Importance of the Research Achievements

本研究より、難治性UCにおいてIDH2は逆行性TCA回路を駆動し、2-HGの蓄積とHif-1αの安定化を引き起こすことを確認した。またIDH2の機能制御によって、膀胱癌細胞の代謝リプログラミング機構を抑制させることで既存の抗癌剤の感受性回復を期待できる可能性が示唆された。IDH2阻害薬は悪性脳腫瘍や再発性急性骨髄性白血病に一部臨床応用が開始されていることから、難治性UCの治療選択肢の１つになり得ると予想される。