| Project/Area Number |
20K09083
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 55020:Digestive surgery-related
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| Research Institution | Fukushima Medical University |
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Principal Investigator |
SAZE Zenichiro 福島県立医科大学, 医学部, 准教授 (10468126)
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| Co-Investigator(Kenkyū-buntansha) |
齋藤 元伸 福島県立医科大学, 医学部, 講師 (90611749)
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| Keywords | 胃癌 / 特異的阻害剤 / 癌抑制遺伝子 / ARID1A / 合成致死 / 標的療法 |
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| Outline of Research at the Start |
ARID1A変異に対する阻害剤の有用性の検討に加え、免疫チェックポイント阻害剤の有用性とその治療候補患者数などの把握、さらに、胃癌切除検体におけるバイオマーカーとしての役割の検討をおこなう
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| Outline of Final Research Achievements |
In this study, we conducted fundamental research to develop a targeted therapy for ARID1A mutations, a member of the SWI/SNF chromatin remodeling complex, using cell experiments with an EZH2 inhibitor targeting ARID1A and EZH2, which is synthetically lethal. ARID1A-deficient cells showed reduced cell proliferation rates and colony formation in response to EZH2 inhibitors compared to ARID1A wild-type cells. Furthermore, since the PI3K/AKT pathway was found to be activated in gastric cancer cells with ARID1A deficiency, we investigated the potential of ARID1A deficiency as a therapeutic target. As a result, AKT inhibitors suppressed cell proliferation in ARID1A-deficient HER2-negative gastric cancer cells, but not in ARID1A-deficient HER2-positive cells, suggesting that AKT inhibitors may be useful as therapeutic targets.
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| Academic Significance and Societal Importance of the Research Achievements |
ARID1A遺伝子はがん抑制遺伝子であるために、その失活型の変異を直接の治療標的とすることができない。しかしながら、本研究では合成致死に基づく特異的阻害剤が有用であることを示せた。また、本研究ではARID1A欠損にともなってPI3K/AKT経路が活性化されることを確認し、AKT阻害剤の有用性の検討結果を追加することができた。AKT阻害剤はARID1A欠損HER2陰性胃癌細胞においてのみ細胞増殖抑制を示すという選択的な結果であったが、胃癌に対する個別化医療の展開に役立つ結果と思われる。
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