Establishing New Therapeutic Strategy for Urothelial Carcinoma
| Project/Area Number |
21K16757
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 56030:Urology-related
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| Research Institution | Keio University |
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Principal Investigator |
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| Project Period (FY) |
2021-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2021: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
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| Keywords | 尿路上皮癌 / IDH2阻害薬 / 抗癌剤耐性 / シスチントランスポーター / CDDP / GSSG/GSH / 癌幹細胞仮説 / 筋層非浸潤性膀胱癌 / 代謝リプログラミング / CD44v / メタボローム解析 / RNA sequence |
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| Outline of Research at the Start |
当教室で樹立したヒト/マウス膀胱癌薬剤感受性株、耐性株両株においてメタボロミクスコアを用いて水溶性代謝産物の定量解析を行う。癌幹細胞モデルを利用した耐性細胞における嫌気解糖系酵素の発現をｍRNA、WBで確認し、特定した標的酵素に対し機能解析を行う。膀胱正所性モデルを使用し、Hif1-α阻害剤による抗腫瘍効果を確認する。組織マイクロアレイを用いて、嫌気解糖酵素群と臨床データ照合による予後解析を行う。
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| 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.
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| 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。
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Report
(3 results)
Research Products
(5 results)
