Development of strategies to treat malignant mesothelioma by novel PIK3CA inhibitors
| Project/Area Number |
17K10813
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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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| Research Field |
Respiratory surgery
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| Research Institution | Kawasaki Medical School |
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Principal Investigator |
Naomoto Yoshio 川崎医科大学, 医学部, 特任教授 (00237190)
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| Co-Investigator(Kenkyū-buntansha) |
深澤 拓也 川崎医科大学, 医学部, 准教授 (20379845)
山辻 知樹 川崎医科大学, 医学部, 教授 (40379730)
高岡 宗徳 川崎医科大学, 医学部, 講師 (50548568)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 胸膜中皮腫 / PIK3CA / AKT / Midkaine / 分子標的治療法 / 悪性胸膜中皮腫 |
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| Outline of Final Research Achievements |
We have developed an inhibitor, iMDK, that is specific for the cancer related growth factor Midkine and reported that this small compound can inhibit the PI3Kinase / AKT pathway and induce an antitumor effect in lung cancer. In the present study, we have synthesized derivatives of iMDK and investigated the antitumor properties of these small molecule compounds in malignant mesothelioma.
In MSTO-211H malignant pleural mesothelioma cells, two of the newly synthesized compounds showed antitumor activity at lower concentrations than iMDK. Furthermore, immunoblot assays revealed that these two compounds suppressed the phosphorylation of AKT at a lower concentration than iMDK 48 hours after treatment. Moreover, a Bcl-2 inhibitor, ABL263, enhanced the antitumor effect induced by iMDK in MSTO-211H cells, suggesting that inhibition of PIK3CA and Bcl-2 might be a promising therapy to treat mesothelioma.
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| Academic Significance and Societal Importance of the Research Achievements |
胸膜中皮腫における有効な分子標的療法は未だ樹立されていない。その中で近年、悪性胸膜中皮腫におけるPI3Kinase活性が予後不良因子であり、当該活性を抑制することで中皮腫の増殖を抑制できることが報告された（Varghese et al. Cancer 117. 361-71. 2011）。本研究において、iMDK派生化合物X,Yは中皮腫細胞株MSTO211Hに対し低濃度で抗腫瘍性を示し、臨床化合物として有望と考えられた。本研究による新規治療開発は、平均生存期間が1年未満という悪性胸膜中皮腫の予後の改善、胸水貯留による呼吸困難や胸痛等の症状の緩和を目指すものであり、その学術的意義は大きい。
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Report
(4 results)
Research Products
(2 results)
