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Basic research and Clinical Application of Hepatocellular Carcinoma Therapy by Interaction of Epigenetic Drugs and Environmental Factors

Research Project

Project/Area Number 19K17403
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionKumamoto University

Principal Investigator

Nagaoka Katsuya  熊本大学, 病院, 助教 (00759524)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
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)
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
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。

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.

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。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (30 results)

All 2021 2020 2019

All Journal Article (10 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 10 results,  Open Access: 8 results) Presentation (19 results) (of which Int'l Joint Research: 6 results) Book (1 results)

  • [Journal Article] Murine neonatal ketogenesis preserves mitochondrial energetics by preventing protein hyperacetylation2021

    • Author(s)
      Arima Yuichiro、Nakagawa Yoshiko、Takeo Toru、Ishida Toshifumi、Yamada Toshihiro、et al.
    • Journal Title

      Nature Metabolism

      Volume: 3 Issue: 2 Pages: 196-210

    • DOI

      10.1038/s42255-021-00342-6

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Modified albumin?bilirubin grade to predict eligibility for second-line therapies at progression on sorafenib therapy in hepatocellular carcinoma patients2021

    • Author(s)
      Tokunaga Takayuki、Tanaka Motohiko、Tanaka Kentaro、Narahara Satoshi、Kawasaki Takeshi、Yoshimaru Yoko、Nagaoka Katsuya、Watanabe Takehisa、Tateyama Masakuni、Naoe Hideaki、Sasaki Yutaka、Tanaka Yasuhito
    • Journal Title

      International Journal of Clinical Oncology

      Volume: 26 Issue: 5 Pages: 922-932

    • DOI

      10.1007/s10147-020-01835-2

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ten‐Eleven Translocation 1 Promotes Malignant Progression of Cholangiocarcinoma With Wild‐Type Isocitrate Dehydrogenase 12021

    • Author(s)
      Bai Xuewei、Zhang Hongyu、Zhou Yamei、Nagaoka Katsuya、Meng Jialin、Ji Chengcheng、Liu Dan、Dong Xianghui、Cao Kevin、Mulla Joud、Cheng Zhixiang、Mueller William、Bay Amalia、Hildebrand Grace、Lu Shaolei、Wallace Joselynn、Wands Jack R.、Sun Bei、Huang Chiung‐Kuei
    • Journal Title

      Hepatology

      Volume: 73 Issue: 5 Pages: 1747-1763

    • DOI

      10.1002/hep.31486

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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.
    • Journal Title

      Hepatology Communications

      Volume: - Issue: 5 Pages: 1198-1212

    • DOI

      10.1002/hep4.1872

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Blood-Based Biomarkers in Hepatitis B Virus-Related Hepatocellular Carcinoma, Including the Viral Genome and Glycosylated Proteins2021

    • Author(s)
      Hayashi Sanae、Nagaoka Katsuya、Tanaka Yasuhito
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 20 Pages: 11051-11051

    • DOI

      10.3390/ijms222011051

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mac‐2 binding protein and its glycan isomer: Where does it come from? Where is it going?2021

    • Author(s)
      Nagaoka Katsuya、Tanaka Motohiko、Tanaka Yasuhito
    • Journal Title

      Hepatology Research

      Volume: 51 Issue: 10 Pages: 1026-1028

    • DOI

      10.1111/hepr.13697

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Loss of skeletal muscle mass affects the incidence of minimal hepatic encephalopathy: a case control study2020

    • Author(s)
      Tateyama Masakuni、Naoe Hideaki、Tanaka Motohiko、Tanaka Kentaro、Narahara Satoshi、Tokunaga Takayuki、Kawasaki Takeshi、Yoshimaru Yoko、Nagaoka Katsuya、Watanabe Takehisa、Setoyama Hiroko、Sasaki Yutaka、Tanaka Yasuhito
    • Journal Title

      BMC Gastroenterology

      Volume: 20 Issue: 1 Pages: 371-371

    • DOI

      10.1186/s12876-020-01501-x

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Targeting Aspartate Beta-Hydroxylase with the Small Molecule Inhibitor MO-I-1182 Suppresses Cholangiocarcinoma Metastasis2020

    • Author(s)
      Nagaoka Katsuya、Ogawa Kousuke、Ji Chengcheng、Cao Kevin Y.、Bai Xuewei、Mulla Joud、Cheng Zhixiang、Wands Jack R.、Huang Chiung-Kuei
    • Journal Title

      Digestive Diseases and Sciences

      Volume: 66 Issue: 4 Pages: 1080-1089

    • DOI

      10.1007/s10620-020-06330-2

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The metabolite, alpha-ketoglutarate inhibits non-alcoholic fatty liver disease progression by targeting lipid metabolism2020

    • Author(s)
      Nagaoka Katsuya、Mulla Joud、Cao Kevin、Cheng Zhixiang、Liu Dan、William Mueller、Bay Amalia、Hildebrand Grace、Lu Shaolei、Huang Chiung-Kuei
    • Journal Title

      Liver Research

      Volume: 4 Issue: 2 Pages: 94-100

    • DOI

      10.1016/j.livres.2020.04.001

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Lysine-specific demethylase-2 is distinctively involved in brown and beige adipogenic differentiation2019

    • Author(s)
      Takase Ryuta、Hino Shinjiro、Nagaoka Katsuya、Anan Kotaro、Kohrogi Kensaku、Araki Hirotaka、Hino Yuko、Sakamoto Akihisa、Nicholson Thomas B.、Chen Taiping、Nakao Mitsuyoshi
    • Journal Title

      The FASEB Journal

      Volume: 33 Issue: 4 Pages: 5300-5311

    • DOI

      10.1096/fj.201801422rr

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 肝内胆管癌におけるAspartateβ-hydroxylase阻害剤とDNA合成阻害剤による相乗的なDNA損傷と抗腫瘍効果の検討2021

    • Author(s)
      長岡克弥、HuangChiung-Kuei、田中靖人
    • Organizer
      第57回日本肝臓学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ヒストン修飾酵素LSD2による肝脂質代謝制御と栄養環境対応性の発現変化~NAFLDの病態解明を目指して~2021

    • Author(s)
      長岡克弥、渡邊丈久、楢原哲史、田中健太郎、徳永尭之、川崎剛、吉丸洋子、瀬戸山博子、立山雅邦、田中基彦、佐々木裕、田中靖人
    • Organizer
      第25回日本肝臓学会大会
    • Related Report
      2021 Annual Research Report
  • [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
      2020 Research-status Report
    • Int'l Joint Research
  • [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
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] 当院におけるHBV電子カルテスクリーニングシステム導入の有用性の評価2020

    • Author(s)
      渡邊丈久、楢原哲史、田中健太郎、徳永尭之、川崎剛、吉丸洋子、長岡克弥、瀬戸山博子、立山雅邦、田中基彦
    • Organizer
      第24回日本肝臓学会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 進行肝細胞癌に対する集学的なソラフェニブ治療戦略2020

    • Author(s)
      徳永尭之、田中基彦、田中健太郎、楢原哲史、吉丸洋子、川崎剛、長岡克弥、渡邊丈久、立山雅邦、佐々木裕
    • Organizer
      JDDW 2020(第28回 日本消化器関連学会週間)
    • Related Report
      2020 Research-status Report
  • [Presentation] C型肝硬変に対するインターフェロンフリー治療の食道胃静脈瘤に関する検討2020

    • Author(s)
      楢原哲史、立山雅邦、田中健太郎、徳永尭之、川崎剛、吉丸洋子、長岡克弥、渡邊丈久、田中基彦、佐々木裕
    • Organizer
      第106回日本消化器病学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 当科における切除不能肝細胞癌に対するレンバチニブ治療の初期経験2020

    • Author(s)
      田中健太郎、徳永尭之、楢原哲史、川崎剛、長岡克弥、瀬戸山博子、吉丸洋子、渡邊丈久、立山雅邦、田中基彦、佐々木裕
    • Organizer
      第106回日本消化器病学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 切除不能進行肝細胞癌に対するソラフェニブを基軸とした集学的治療戦略2020

    • Author(s)
      徳永尭之、田中健太郎、楢原哲史、長岡克弥、吉丸洋子、渡邊丈久、立山雅邦、田中基彦、佐々木裕
    • Organizer
      第106回日本消化器病学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] MULTI-OMICS ANALYSES IDENTIFY NUCLEOPHOSMIN AS A KEY REGULATOR OF APOPTOSIS RESISTANCE IN HUMAN HEPATOCELLULAR CARCINOMA2019

    • Author(s)
      Hideaki Naoe, Takehisa Watanabe, Katsuya Nagaoka, Nahoko Fujimoto, Norie Araki, Jiro Fujimoto, Motohiko Tanaka and Yutaka Sasaki
    • Organizer
      THE LIVER MEETING 2019 - AASLD
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] OPTIMAL STRATEGY OF SWITCHING FROM TRANSARTERIAL CHEMOEMBOLIZATION TO MOLECULAR TARGETED THERAPY FOR PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA2019

    • Author(s)
      Takayuki Tokunaga, Motohiko Tanaka, Kentaro Tanaka, Satoshi Narahara, Yoko Yoshimaru, Tekeshi Kawasaki, Katsuya Nagaoka, Takehisa Watanabe, Masakuni Tateyama and Yutaka Sasaki
    • Organizer
      THE LIVER MEETING 2019 - AASLD
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] UPREGULATION OF SECRETORY CLUSTERIN IN RESPONSE TO SORAFENIB LINKS TO ACQUIRED TREATMENT RESISTANCE OF HEPATOCELLULAR CARCINOMA2019

    • Author(s)
      Satoshi Narahara, Takehisa Watanabe, Katsuya Nagaoka, Nahoko Fujimoto, Kentaro Tanaka, Takeshi Kawasaki, Yoko Yoshimaru, Masakuni Tateyama, Hideaki Naoe, Motohiko Tanaka and Yutaka Sasaki
    • Organizer
      THE LIVER MEETING 2019 - AASLD
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Aspartate β-hydroxylaseを標的とした膵肝癌における抗体薬剤複合体の抗腫瘍効果2019

    • Author(s)
      長岡克弥、佐々木裕
    • Organizer
      第105回日本消化器病学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 切除不能進行肝細胞癌に対するソラフェニブを基軸とした集学的治療戦略2019

    • Author(s)
      徳永尭之、田中健太郎、楢原哲史、長岡克弥、吉丸洋子、渡邊丈久、立山雅邦、田中基彦、佐々木裕
    • Organizer
      第105回日本消化器病学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 肝細胞癌に対するソラフェニブの治療効果を早期に予測する新規血清バイオマーカーの解析2019

    • Author(s)
      楢原哲史、渡邊丈久、長岡克弥、田中健太郎、徳永尭之、川崎剛、吉丸洋子、瀬戸山博子、立山雅邦、直江秀昭、田中基彦、佐々木裕
    • Organizer
      第55回日本肝臓学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 肝細胞癌に対する肝動脈化学塞栓術から分子標的治療への適切な切り替えタイミングの検討2019

    • Author(s)
      徳永尭之、田中健太郎、楢原哲史、吉丸洋子、川崎剛、長岡克弥、渡邊丈久、立山雅邦、田中基彦、佐々木裕
    • Organizer
      第55回日本肝臓学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 胆管癌におけるAspartate-β-hydroxylaseに対する分子標的薬とDNA合成阻害剤の相乗的な抗腫瘍効果2019

    • Author(s)
      長岡克弥、Chiung-Kuei Huang、佐々木裕、Jack R Wands
    • Organizer
      第51回日本臨床分子形態学会総会・学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 進行肝細胞癌に対する集学的なソラフェニブ治療戦略2019

    • Author(s)
      徳永尭之、田中基彦、田中健太郎、楢原哲史、吉丸洋子、川崎剛、長岡克弥、渡邊丈久、立山雅邦、佐々木裕
    • Organizer
      JDDW 2019(第27回 日本消化器関連学会週間)
    • Related Report
      2019 Research-status Report
  • [Book] 薬剤性消化器疾患の治療 (3) 肝臓 『臨牀消化器内科 Vol.35 No.7(3-3)』2020

    • Author(s)
      長岡 克弥 , 德永 尭之 , 田中 基彦
    • Total Pages
      8
    • Publisher
      株式会社日本メディカルセンター
    • Related Report
      2020 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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