2021 Fiscal Year Final Research Report
Basic research and Clinical Application of Hepatocellular Carcinoma Therapy by Interaction of Epigenetic Drugs and Environmental Factors
| Project/Area Number |
19K17403
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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 | Kumamoto University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 肝癌 / エピゲノム薬 / 分子標的治療薬 / 治療抵抗性獲得機序 |
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| Outline of Final Research Achievements |
Analysis of molecular targeted therapy sorafenib (SFN)-resistant hepatocarcinoma cell lines revealed decreased intracellular energy levels, compensatory activation of the phosphatidylinositol 3-kinase/protein kinase B pathway, suppression of the de novo pathway and activation of the salvage pathway of purine metabolism. In addition, SFN-resistant hepatocellular carcinoma cell lines showed increased expression of transcription factors involved in lipid metabolism in response to re-administration of SFN. 43 epigenome modification inhibitors and 8 signal target inhibitors were used in drug screening, and 4 candidate drugs were identified that showed growth inhibitory effects against the resistant lines. These results may lead to the development of new therapeutic agents for liver cancer that is refractory to molecularly targeted therapies.
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| Free Research Field |
消化器内科学
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| Academic Significance and Societal Importance of the Research Achievements |
SFNは進行肝細胞癌に対する標準的治療のひとつで、アテゾリズマブ+ベバシズマブ併用療法の禁忌症例やC型肝炎ウイルス陽性症例においては有益であり、長期投与可能な症例も多い。一方でSFN治療耐性における細胞生物学的機序はよくわかっていない。本研究の結果は、SREBP-1cの機能阻害とSIRT2阻害はSFN耐性肝癌に効果的な可能性を示唆している。またメタボローム解析により見出されたプリン代謝salvage経路の活性化は将来的に新しい治療標的となり得る。
以上より、本成果は分子標的治療薬に抵抗性を示す肝癌に対する新しい治療薬の開発につながり得るため、潜在的な社会的意義がある成果であったと考える。
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