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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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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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 / 治療耐性獲得機構 / SIRT阻害薬 / 脂質代謝 / 転写因子 / HDAC阻害薬 / 合成致死性 / 治療抵抗性 / 肝発癌 / 細胞環境 |
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| Outline of Research at the Start |
近年、腫瘍のエピゲノム修飾の異常を制御することで抗腫瘍効果を発揮する薬剤（以下エピゲノム薬）が次世代の抗がん剤として注目されている。本研究では、肝癌における細胞環境とエピゲノム薬との相互作用に焦点をあて、エピゲノム薬の効果を増強または阻害する細胞環境の分子基盤を解明し、新たな治療法の開発を目的とする。
具体的には、１）エピゲノム修飾酵素阻害薬、２）肝発癌に関連する環境誘導因子を準備し、１）２）の組み合わせを網羅的に探索し、肝癌細胞における相互作用を詳細に解析する。臨床に還元可能なレベルでの研究体系を構築し、最終的には肝癌の治療成績の向上を目指す。
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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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| 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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Report
(4 results)
Research Products
(30 results)
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[Journal Article] Clusterin and Related Scoring Index as Potential Early Predictors of Response to Sorafenib in Hepatocellular Carcinoma2021
Author(s)
Narahara S, Watanabe T, Nagaoka K, Fujimoto N, Furuta Y, Tanaka K, Tokunaga T, Kawasaki T, Yoshimaru Y, Setoyama H, Oniki K, Saruwatari J, Tateyama M, Naoe H, Tanaka M, Tanaka Y, Sasaki Y.
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Journal Title
Hepatology Communications
Volume: -
Issue: 5
Pages: 1198-1212
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Elevated 2-oxoglutarate antagonizes chemotherapeutic effects in cholangiocarcinoma by targeting DNA damage response signaling pathways.2021
Author(s)
Katsuya Nagaoka, Chengcheng Ji, Xuewei Bai, Kevin Cao, Joud Mulla, Amalia Bay, William Mueller, Grace Hildebrand, Yasuhito Tanaka, Jack R Wands, Chiung-Kuei Huang
Organizer
The 72nd Annual Meeting of the American Association for the Study of Liver Diseases
Related Report
Int'l Joint Research
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[Presentation] A NOVEL SERUM BIOMARKER, CLUSTERIN, AND RELATED PREDICTIVE INDEX SCORING COULD BE AN EARLY PREDICTOR OF RESPONSE TO SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA.2020
Author(s)
Satoshi Narahara, Takehisa Watanabe, Katsuya Nagaoka, Nahoko Fujimoto, Kentaro Tanaka, Takayuki Tokunaga, Takeshi Kawasaki, Yoko Yoshimaru, Masakuni Tateyama, Hideaki Naoe, Motohiko Tanaka, Yutaka Sasaki, Yasuhito Tanaka
Organizer
Liver Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD)
Related Report
Int'l Joint Research
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[Presentation] PROGNOSTIC FACTORS ASSOCIATED WITH SURVIVAL IN HEPATOCELLULAR CARCINOMA PATIENTS PROGRESSED ON LENVATINIB THERAPY, PREMISING SUBSEQUENT CHEMOTHERAPY2020
Author(s)
Takayuki Tokunaga, Motohiko Tanaka, Kentaro Tanaka, Satoshi Narahara, Takeshi Kawasaki, Yoko Yoshimaru, Katsuya Nagaoka, Takehisa Watanabe, Masakuni Tateyama, Yasuhito Tanaka
Organizer
Liver Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD)
Related Report
Int'l Joint Research
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