Investigation on prediction for medical treatment response to advanced hepatocellular carcinoma

• Project/Area Number: 18K07945
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kumamoto University
• Principal Investigator: Tanaka Motohiko 熊本大学, 大学院生命科学研究部(医), 特定研究員 (20346985)
• Co-Investigator(Kenkyū-buntansha): 渡邊 丈久 熊本大学, 大学院生命科学研究部(医), 助教 (20634843) ; 直江 秀昭 熊本大学, 病院, 講師 (30599246) ; 佐々木 裕 熊本大学, 病院, 非常勤診療医師 (70235282)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肝細胞癌 / ソラフェニブ / バイオマーカー / Clusterin / NR-index / 分子標的治療 / 治療抵抗性 / 分子標的治療薬 / CLU / バイオインフォマティクス / 化学療法 / 感受性 / 抵抗性 / 予後

Outline of Final Research Achievements

Sorafenib (SFN), one of the standard treatments for advanced hepatocellular carcinoma (HCC), does not have effective markers that can predict therapeutic efficacy and prognosis. We developed Clusterin (CLU) and NR-index, a prognostic equation related to CLU, as early predictors of therapeutic efficacy of SFN treatment by comprehensive proteomics using patient serum and analysis of clinical data. We also found that liver function assessment by a combination of modified ALBI (mALBI) grade and Child-Pugh score at the start of SFN treatment was useful in predicting whether patients would be eligible for treatment with another molecularly targeted agent at the time of SFN treatment progression.

Academic Significance and Societal Importance of the Research Achievements

長期に渡り進行肝細胞癌の薬物治療における第一選択薬であったSFNは依然として最もエビデンスが蓄積された治療薬であるが、治療効果予測式やSFNの次治療への移行時における治療適格の予測については明確な見解がなかった。本研究で得た知見はSFNの治療抵抗群を予測し次治療移行のタイミングを示唆するものであり、適切な治療薬の選択を補佐し予後およびQOLの改善に貢献することで、進行肝癌患者の実臨床に寄与し得るものと考える。

Research Products

• [Journal Article] Modified albumin?bilirubin grade to predict eligibility for second-line therapies at progression on sorafenib therapy in hepatocellular carcinoma patients (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] 薬剤性消化器疾患の治療 薬剤性消化器疾患の治療(3)肝臓 (2020)
  • Author(s): 長岡克弥、徳永尭之、田中基彦
  • Journal Title: 臨牀消化器内科 Volume: 35 Pages: 3-3
• [Journal Article] Loss of skeletal muscle mass affects the incidence of minimal hepatic encephalopathy: A case control study. (2020)
  • Author(s): Masakuni Tateyama,Motohiko Tanaka, et al.
  • Journal Title: BMC Gastroenterology Volume: 20 Pages: 371-371
  • Peer Reviewed / Open Access
• [Journal Article] A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011-2015 update. (2019)
  • Author(s): Tateishi R, Uchino K, Fujiwara N, Takehara T, Okanoue T, Seike M, Yoshiji H, Yatsuhashi H, Shimizu M, Torimura T, Moriyama M, Sakaida I, Okada H, Chiba T, Chuma M, Nakao K, Isomoto H, Sasaki Y, Kaneko S, Masaki T, Chayama K, Koike K.
  • Journal Title: J Gastroenterol. Volume: 54 Issue: 4 Pages: 367-376
  • DOI: 10.1007/s00535-018-1532-5
  • Peer Reviewed / Open Access
• [Journal Article] Predictors of hepatocellular carcinoma recurrence associated with the use of direct-acting antiviral agent therapy for hepatitis C virus after curative treatment: A prospective multicenter cohort study. (2019)
  • Author(s): Nakano M, Koga H, Ide T, Kuromatsu R, Hashimoto S, Yatsuhashi H, Seike M, Higuchi N, Nakamuta M, Shakado S, Sakisaka S, Miuma S, Nakao K, Yoshimaru Y, Sasaki Y, Oeda S, Eguchi Y, Honma Y, Harada M, Nagata K, Mawatari S, Ido A, Maeshiro T, Matsumoto S, Takami Y, Sohda T, Torimura T
  • Journal Title: Cancer Med. Volume: 印刷中 Issue: 5 Pages: 2646-2653
  • DOI: 10.1002/cam4.2061
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Direct-acting antiviral agents do not increase the incidence of hepatocellular carcinoma development: a prospective, multicenter study (2019)
  • Author(s): Ide T, Koga H, Nakano M, Hashimoto S, Yatsuhashi H, Higuchi N, Nakamuta M, Oeda S, Eguchi Y, Shakado S, Sakisaka S, Yoshimaru Y, Sasaki Y, Honma Y, Harada M, Seike M, Maeshiro T, Miuma S, Nakao K, Mawatari S, Ido A, Nagata K, Matsumoto S, Takami Y, Sohda T, Kakuma T, Torimura T
  • Journal Title: Hepatol Int. Volume: 印刷中 Issue: 3 Pages: 293-301
  • DOI: 10.1007/s12072-019-09939-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 1.Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial. (2018)
  • Author(s): Kudo M, Ueshima K, Yokosuka O, Ogasawara S, Obi S, Izumi N, Aikata H, Nagano H, Hatano E, Sasaki Y, Hino K, Kumada T, Yamamoto K, Imai Y, Iwadou S, Ogawa C, Okusaka T, Kanai F, Akazawa K, Yoshimura KI, Johnson P, Arai Y, SILIUS study group.
  • Journal Title: The lancet. Gastroenterology & hepatology Volume: 3 Pages: 424-432
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 2.Impact of surgical treatment after sorafenib therapy for advanced hepatocellular carcinoma. (2018)
  • Author(s): Takeyama H, Beppu T, Higashi T, Kaida T, Arima K, Taki K, Imai K, Nitta H, Hayashi H, Nakagawa S, Okabe H, Hashimoto D, Chikamoto A, Ishiko T, Tanaka M, Sasaki Y, Baba H.
  • Journal Title: Surgery today Volume: 48 Pages: 431-438
  • Peer Reviewed
• [Journal Article] 3.Modeling of the Weight Status and Risk of Nonalcoholic Fatty Liver Disease in Elderly Individuals: The Potential Impact of the Disulfide Bond-Forming Oxidoreductase A-Like Protein (DsbA-L) Polymorphism on the Weight Status. (2018)
  • Author(s): Oniki K, Watanabe T, Kudo M, Izuka T, Ono T, Matsuda K, Sakamoto Y, Nagaoka K, Imafuku T, Ishima Y, Watanabe H, Maruyama T, Otake K, Ogata Y, Saruwatari J.
  • Journal Title: CPT Pharmacometrics Syst Pharmacol Volume: 7 Pages: 384-393
  • Peer Reviewed
• [Journal Article] Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions. (2018)
  • Author(s): 4.Minayoshi Y, Maeda H, Yanagisawa H, Hamasaki K, Mizuta Y, Nishida K, Kinoshita R, Enoki Y, Imafuku T, Chuang VTG, Koga T, Fujiwara Y, Takeya M, Sonoda K, Wakayama T, Taguchi K, Ishima Y, Ishida T, Iwakiri Y, Tanaka M, Sasaki Y, Watanabe H, Otagiri M, Maruyama T.
  • Journal Title: Drug delivery Volume: 25 Pages: 1067-1077
  • NAID: 120006941111
  • Peer Reviewed
• [Presentation] Ｃ型慢性肝疾患,初発肝癌における高齢者に対する治療後の現状 (2020)
  • Author(s): 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 パネルディスカッション
• [Presentation] 肝炎ウイルス陽性患者の受診勧奨を目的とした肝臓非専門医療機関との診療連携システムの構築 (2020)
  • Author(s): 瀬戸山博子、田中基彦、佐々木裕
  • Organizer: 第106回日本消化器病学会総会 パネルディスカッション
• [Presentation] DAAs治療後の血清Exosome中miRNAの変化はSVR後の生体反応を反映する (2020)
  • Author(s): 渡邊丈久、田中基彦
  • Organizer: 第56回日本肝臓学会総会 ワークショップ
• [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血清バイオマーカーの解析 (2020)
  • Author(s): 楢原哲史、渡邊丈久、田中基彦
  • Organizer: 第56回日本肝臓学会総会 ワークショップ
• [Presentation] 翻訳後修飾の網羅的解析による肝癌の治療抵抗性の解明 (2020)
  • Author(s): 直江秀昭、渡邊丈久、田中基彦
  • Organizer: 第56回日本肝臓学会総会 シンポジウム
• [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, Motohiko Tanaka, et al.
  • Organizer: Liver Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] PROGNOSTIC FACTORS ASSOCIATED WITH SURVIVAL IN HEPATOCELLULAR CARCINOMA PATIENTS PROGRESSED ON LENVATINIB THERAPY, PREMISING SUBSEQUENT CHEMOTHERAPY (2020)
  • Author(s): Takayuki Tokunaga, Motohiko Tanaka, et al.
  • Organizer: Liver Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] Multi-omics analyses identify nucleophosmin as a key regulator of apoptosis resistance in human hepatocellular carcinoma. (2019)
  • Author(s): Hideaki Naoe, Takehisa Watanabe, Katsuya Nagaoka, Nahoko Fujimoto, Norie Araki, Jiro Fujimoto, Motohiko Tanaka, Yutaka Sasaki
  • Organizer: The Liver Meeting (AASLD) 2019
  • Int'l Joint Research
• [Presentation] Altered microrna expression profiles in serum exosome links to clinical phenotypes induced by direct-acting antiviral therapy. (2019)
  • Author(s): Takehisa Watanabe, Nahoko Fujimoto, Katsuya, Satoshi Narahara, Kentaro Tanaka, Takayuki Tokunaga, Takeshi Kawasaki, Yoko Yoshimaru, Masakuni Tateyama, Hideaki Naoe, Motohiko Tanaka, Yutaka Sasaki
  • Organizer: The Liver Meeting (AASLD) 2019
  • Int'l Joint Research
• [Presentation] Optimal strategy of switching from transarterial chemoembolization to molecular targeted therapy for patients with unresectable hepatocellular carcinoma. (2019)
  • Author(s): Takayuki Tokunaga, Motohiko Tanaka, Kentaro Tanaka, Satoshi Narahara, Yoko Yoshimaru, Tekeshi Kawasaki, Katsuya Nagaoka, Takehisa Watanabe, Masakuni Tateyama, Yutaka Sasaki
  • Organizer: The Liver Meeting (AASLD) 2019
  • Int'l Joint Research
• [Presentation] Upregulation of secretory clusterin in response to sorafenib links to acquired treatment resistance of hepatocellular carcinoma. (2019)
  • Author(s): Satoshi Narahara, Takehisa Watanabe, Katsuya Nagaoka, Nahoko Fujimoto, Kentaro Tanaka, Takeshi Kawasaki, Yoko Yoshimaru, Masakuni Tateyama, Hideaki Naoe, Motohiko Tanaka, Yutaka Sasaki
  • Organizer: The Liver Meeting (AASLD) 2019
  • Int'l Joint Research
• [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27回日本消化器関連学会週間
• [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: 第105回日本消化器病学会総会
• [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 (2019)
  • Author(s): 田中健太郎、德永尭之、楢原哲史、川崎剛、長岡克弥、吉丸洋子、
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] Ｃ型慢性肝疾患,初発肝癌における高齢者に対する治療後の現状 (2019)
  • Author(s): 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
• [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
• [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
• [Presentation] 切除不能肝細胞癌に対する肝動脈化学塞栓療法から分子標的治療への適切な切り替えタイミング (2019)
  • Author(s): 徳永尭之、田中基彦、佐々木裕
  • Organizer: 第55回日本肝癌研究会
• [Presentation] 肝内腫瘍量の多い切除不能進行肝細胞癌に対するlenvatinibの使用経験 (2019)
  • Author(s): 田中健太郎、楢原哲史、徳永尭之、川崎剛、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20回日本肝がん分子標的治療研究会
• [Presentation] 肝癌分子標的治療薬の治療効果予測と耐性獲得機序の解析 (2019)
  • Author(s): 長岡克弥、楢原哲史、渡邊丈久、田中基彦、佐々木裕
  • Organizer: 第26回肝細胞研究会
• [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 (2019)
  • 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19回日本肝がん分子標的治療研究会
• [Presentation] Prognostic Factors in Patients with Advanced HCC Receiving Sorafenib or Hepatic Arterial Infusion Chemotherapy. (2018)
  • Author(s): Motohiko Tanaka, Takayuki Tokunaga, Kentaro Tanaka, Satoshi Narahara, Takeshi Kawasaki, Yoko Yoshimaru, Takehisa Watanabe, Masakuni Tateyama, Hideaki Naoe, Yutaka Sasaki.
  • Organizer: The Asian Pacific Association for the Study of the Liver
  • Int'l Joint Research
• [Presentation] Analysis of the Changes of the Profiles of Exosomal miRNA in Serum of the Patients Induced By DAA Treatment. (2018)
  • Author(s): Takehisa Watanabe, Nahoko Fujimoto, Katsuya Nagaoka, Satoshi Narahara, Kentaro Tanaka, Takayuki Tokunaga, Takeshi Kawasaki, Youko Yoshimaru, Masakuni Tateyama, Hideaki Naoe, Motohiko Tanaka and Yutaka Sasaki.
  • Organizer: The Liver Meeting (AASLD) 2018
  • Int'l Joint Research
• [Presentation] Treatment Strategy Based on Sorafenib for Advanced Hepatocellular Carcinoma Premising Subsequent Treatment with Regorafenib. (2018)
  • Author(s): Tokunaga Takayuki, Tanaka Motohiko Tanaka Kentaro, Narahara Satoshi, Yoshimaru Yoko, Nagaoka Katsuya, Kawasaki Takeshi, Setoyama Hiroko, Watanabe Takehisa, Tateyama Masakuni, Sasaki Yutaka.
  • Organizer: The Liver Meeting (AASLD) 2018
  • Int'l Joint Research
• [Presentation] Early Prediction of Sorafenib Response in Patients with Hepatocellular Carcinoma: The Possible Role of Secretory Clusterin in Acquired Sorafenib Resistance. (2018)
  • Author(s): Narahara Satoshi, Watanabe Takehisa, Nagaoka Katsuya, Fujimoto Nahoko, Tanaka Kentaro, Tokunaga Takayuki, Kawasaki Takeshi, Yoshimaru Youko, Setoyama Hiroko, Tateyama Masakuni, Naoe Hideaki, Tanaka Motohiko, Sasaki Yutaka.
  • Organizer: The Liver Meeting (AASLD) 2018
  • Int'l Joint Research
• [Presentation] The Combination Therapy of Targeting Asph and DNA Topoisomerase Inhibitor Suppresses Cholangiocarcinoma Progression. (2018)
  • Author(s): Nagaoka Katsuya, Huang Chiung-kuei, Ji Chengcheng, Bai Xuewei, Cao Kevin, Zhang Hongyu, Sasaki Yutaka, Wands Jack R.
  • Organizer: The Liver Meeting (AASLD) 2018
  • Int'l Joint Research
• [Presentation] 進行肝細胞癌に対するソラフェニブ治療と肝動注化学療法の効果解析から検討する治療戦略. (2018)
  • Author(s): 徳永尭之、田中基彦、佐々木裕.
  • Organizer: 第104回日本消化器病学会総会
• [Presentation] 当科における肝細胞癌根治例における抗ウイルス療法後の再発に関する検討 (2018)
  • Author(s): 立山雅邦、田中基彦、田中健太郎、楢原哲史、徳永尭之、川崎剛、吉丸洋子、渡邊丈久、佐々木裕.
  • Organizer: 第104回日本消化器病学会総会,
• [Presentation] 当科におけるSVR後肝癌の実態 (2018)
  • Author(s): 吉丸洋子、田中基彦、佐々木裕
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] 進行肝細胞癌に対する肝動注化学療法の効果解析から検討する治療戦略 (2018)
  • Author(s): 田中健太郎、徳永尭之、楢原哲史、川崎剛、吉丸洋子、渡邊丈久、瀬戸山博子、立山雅邦、田中基彦、佐々木裕
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] 進行肝細胞癌に対するソラフェニブ治療の効果解析から検討する後治療を見据えた治療戦略 (2018)
  • Author(s): 徳永尭之、田中基彦、田中健太郎、楢原哲史、川崎剛、吉丸洋子、渡邊丈久、瀬戸山博子、立山雅邦、佐々木裕
  • Organizer: 第54回日本肝臓学会総会
• [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 (2018)
  • Author(s): 楢原哲史、渡邊丈久、田中健太郎、徳永尭之、川崎剛、吉丸洋子、立山雅邦、田中基彦、佐々木裕.
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] 切除不能の門脈浸潤を伴う肝細胞癌に対する肝動注化学療法とソラフェニブ治療の効果解析から検討する治療戦略 (2018)
  • Author(s): 徳永尭之、田中基彦、佐々木裕.
  • Organizer: 第25回日本門脈圧亢進症学会総会
• [Presentation] 11.TACE不応例に対する肝動注化学療法後に進行した肝細胞癌への後治療の検討 (2018)
  • Author(s): 田中健太郎、楢原哲史、徳永尭之、川崎剛、吉丸洋子、渡邊丈久、長岡克弥、立山雅邦、田中基彦、佐々木裕.
  • Organizer: 第112回日本消化器病学会九州支部例会