| Project/Area Number |
21K16004
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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 53010:Gastroenterology-related
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| Research Institution | Yokohama City University |
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Principal Investigator |
Kaneko Takashi 横浜市立大学, 附属市民総合医療センター, 助教 (70588152)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2023: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | 胆道癌 / PI3K阻害薬 / Wee1阻害薬 / マウスモデル / PIK3CA / PTEN / TP53 / 分子標的薬 / 肝内胆管癌 / オルガノイド / 阻害薬 / PI3K経路 / Precision medicine |
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| Outline of Research at the Start |
肝内胆管癌は未だ十分な化学療法レジメンも開発されておらず，予後不良な難治癌であるの一つであるが，その遺伝子変異パターンは複雑で，今後のPrecision medicineの実践が求められる癌種である．本研究課題では，新規のPI3K経路亢進・Tp53欠損型肝内胆管癌マウスモデル，患者由来肝内胆管癌3次元オルガノイド細胞を用いた，PI3K阻害薬及びWee1阻害薬の臨床応用に向けた基盤研究を目的とする．
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| Outline of Final Research Achievements |
Two novel mouse models of intrahepatic cholangiocarcinoma, PIK3CA mutant and PTEN-deficient, were generated. Both strains showed neoplastic lesions in the liver due to co-existing TP53 deficiency, which were confirmed to be intrahepatic cholangiocarcinoma by immunohistochemical analysis.
The PIK3CA mutated Huh28 cell line showed growth inhibition with a lower concentration of alpelisib than the KRAS mutated HuCCT1 cell line, suggesting that alpelisib is effective against PIK3CA mutated biliary tract carcinoma. The combination of Alpelisib and Adavosertib showed synergistic growth inhibition in both cell lines.
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| Academic Significance and Societal Importance of the Research Achievements |
未だ胆道癌の薬物治療開発は困難を極めており，がんゲノムプロファイルに基づくPrecision medicineの恩恵も限定的である．本研究では，PI3K経路亢進・Tp53欠損型の胆道癌に着目し，PIK3CA変異型，PTEN欠損型の2系統のPI3K亢進型の肝内胆管癌マウスモデルを創出した．また，培養細胞株を用いた検討により，Alpelisib，Adavosertibの2剤が相乗的な増殖抑制効果を示した．本研究を将来的なPI3K阻害薬とWee1阻害薬の臨床応用へと展開し，Precision medicineの実装化が期待される．
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