New Treatment Strategy for Chemoresistant Urothelial Carcinoma Regarding of Metabolic Reprogramming

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K20811
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Keio University
• Principal Investigator: SHIGETA KEISUKE 慶應義塾大学, 医学部(信濃町), 訪問研究員 (10649875)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Keywords: 尿路上皮癌 / 抗癌剤耐性 / 代謝リプログラミング / IDH2

Outline of Final Research Achievements

We found a　unique metabolism in chemo　resistant urothelial carcinoma (UC). One key finding is the increased glycolytic flux observed in gemcitabine-resistant UC cells. This metabolic reprogramming promotes the activation of the pentose phosphate pathway (PPP), leading to enhanced pyrimidine biosynthesis. Consequently, there is an increase in the production of deoxycytidine triphosphate (dCTP), which competitively inhibits the therapeutic effects of gemcitabine.　The study also identified the induction of reductive carboxylation flux of glutamine to citrate, a process known as the "reductive tricarboxylic acid (TCA) cycle," in gemcitabine-resistant UC cells. This phenomenon is mediated by the expression of the enzyme IDH2, which leads to the accumulation of 2-hydroxyglutarate (2-HG). The accumulation of 2-HG stabilizes hypoxia-inducible factor 1-alpha (Hif1-α), establishing an aerobic metabolic reprogramming in gemcitabine-resistant UC.

Free Research Field

泌尿器科学

Academic Significance and Societal Importance of the Research Achievements

膀胱癌細胞は抗癌剤暴露の過程で細胞内代謝機構をリプログラミングすることで抗癌剤耐性機構を獲得することが分かった。IDH2阻害によるHif1-αの制御が難治癌を克服する新規治療標的になりうることが示唆された。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、今後IDH2を標的とした新規治療法の開発は治療選択の乏しい抗癌剤耐性UC患者への予後向上に向けて大きく寄与すると考えている。