2023 Fiscal Year Final Research Report
Investigation for clinical application of PI3K inhibitor and Wee1 inhibitor in intrahepatic cholangiocarcinoma
| Project/Area Number |
21K16004
|
|---|
| Research Category |
Grant-in-Aid for Early-Career Scientists
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Basic Section 53010:Gastroenterology-related
|
|---|
| Research Institution | Yokohama City University |
|---|
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)
|
|---|
| Project Period (FY) |
2021-04-01 – 2024-03-31
|
| 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 |
|---|
| 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.
|
| Free Research Field |
消化器内科学
|
| 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．
|
