Building personalised pharmacotherapy for liver cancer based on driver gene abnormalities.

• Project/Area Number: 21K07894
• 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: Osaka University
• Principal Investigator: Tatsumi Tomohide 大阪大学, 大学院医学系研究科, 准教授 (20397699)
• Co-Investigator(Kenkyū-buntansha): 小玉 尚宏 大阪大学, 大学院医学系研究科, 助教 (10623275)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 肝癌 / 複合免疫療法 / IL-6 / cfDNA / ctDNA / アテゾリズマブ / ベバシズマブ / 肝細胞癌 / リキッドバイオプシー

Outline of Research at the Start

１）肝がん腫瘍間不均一性モデルマウスを用いた分子標的薬治療効果に影響を与える肝がんドライバー遺伝子の探索
申請者は、様々ながん遺伝子が不均一に活性化し腫瘍間不均一性を生じる内在性肝発癌マウスを樹立している。このモデルを用いて、進行肝がんに用いられる薬剤の治療効果予測バイオマーカー候補を同定する。

２）進行肝がん臨床試料を用いた、肝がんドライバー遺伝子異常の治療効果予測バイオマーカーとしての有用性の検討
進行肝がん患者においてリキッドバイオプシー検体を用いてゲノム異常の有無や遺伝子発現変化を検討し、各種薬剤の奏効率や無再発生存期間との相関について検討する。

Outline of Final Research Achievements

A variety of drug therapies exist for patients with hepatocellular carcinoma, all of which have limited efficacy, and it is unclear which drugs are suitable for which patients. We therefore searched for non-invasive biomarkers to predict treatment efficacy and prognosis in combination therapy with anti-PD-L1 and anti-VEGF antibodies, which is currently the standard of care. We found that blood cell free DNA levels, the presence of specific circulating tumour DNA and IL-6 levels are useful for predicting the therapeutic efficacy of combined immunotherapy.

Academic Significance and Societal Importance of the Research Achievements

これらの研究成果は、進行肝癌治療における個別化医療の実現に向けた重要な進展と考えられる。血液中のcfDNA/ctDNAやIL-6濃度を測定し、これらをバイオマーカーとして使用することで、複合免疫療法を受ける肝癌患者の治療効果や生存期間をより正確に予測できる可能性が示された。これにより、患者が最適な治療法を選択し、治療効果が最大化されることが期待される。また、個別化医療の進展は医療費の削減につながる可能性がある。学術的にも、複合免疫療法の治療効果の解明につながる研究成果であると考えられる。

Research Products

• [Journal Article] Clinical factors associated with the therapeutic efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma: A multicenter prospective observational study (2024)
  • Author(s): Kai M, Hikita H, Kazuki M, Tahata Y, Shinkai K, Doi A, Ohkawa K, Miyazaki M, Ishida H, Matsumoto K, Nozaki Y, Yakushijin T, Sakamori R, Kaneko A, Iio S, Nawa T, Kakita N, Morishita N, Hiramatsu N, Usui T, Imanaka K, Doi Y, Sakakibara M, Yoshida Y, Oze T, Kodama T, Tatsumi T, Takehara T.
  • Journal Title: PLOS ONE Volume: 19 Issue: 1 Pages: e0294590-e0294590
  • DOI: 10.1371/journal.pone.0294590
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The impact of the COVID‐19 pandemic on hepatocellular carcinoma diagnosis and treatment in Japan: A multicenter collaborative observational study (2023)
  • Author(s): Murai Kazuhiro、Hikita Hayato、Kodama Takahiro、Kaibori Masaki、Nishimura Yuki、Tatsumi Tomohide、Yamada Tomomi、Kanto Tatsuya、Mochida Satoshi、Takehara Tetsuo
  • Journal Title: Hepatology Research Volume: in press Issue: 5 Pages: 439-450
  • DOI: 10.1111/hepr.13990
  • Peer Reviewed
• [Journal Article] Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma (2022)
  • Author(s): Murai Hiroki、Kodama Takahiro、Maesaka Kazuki、Tanaka Satoshi、Mita Eiji、Ohkawa Kazuyoshi、Hikita Hayato、Sakamori Ryotaro、Tatsumi Tomohide、Eguchi Hidetoshi、Morii Eiichi、Takehara Tetsuo
  • Journal Title: Hepatology Volume: 77 Issue: 1 Pages: 77-91
  • DOI: 10.1002/hep.32573
  • Peer Reviewed / Open Access
• [Journal Article] Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy (2022)
  • Author(s): Matsumae Takayuki、Kodama Takahiro、Myojin Yuta、Maesaka Kazuki、Nakabori Tasuku、Ohkawa Kazuyoshi、Miyazaki Masanori、Tanaka Satoshi、Mita Eiji、Tawara Seiichi、Yakushijin Takayuki、Nozaki Yasutoshi、Hagiwara Hideki、Tahata Yuki、Yamada Ryoko、Hikita Hayato、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Cancers Volume: 14 Issue: 14 Pages: 3367-3367
  • DOI: 10.3390/cancers14143367
  • Peer Reviewed
• [Journal Article] Liver-related events after direct-acting antiviral therapy in patients with hepatitis C virus-associated cirrhosis (2022)
  • Author(s): Tahata Y, Hikita H, Mochida S, Enomoto N, Kawada N, Kurosaki M, Ido A, Miki D, Yoshiji H, Takikawa Y, Sakamori R, Hiasa Y, Nakao K, Kato N, Ueno Y, Yatsuhashi H, Itoh Y, Tateishi R, Suda G, Takami T, Nakamoto Y, Asahina Y, et al.
  • Journal Title: Journal of Gastroenterology Volume: 57 Issue: 2 Pages: 120-132
  • DOI: 10.1007/s00535-021-01845-5
  • Peer Reviewed
• [Journal Article] The absence of warfarin treatment and situs inversus are associated with the occurrence of hepatocellular carcinoma after Fontan surgery (2022)
  • Author(s): Sakamori Ryotaro、Yamada Ryoko、Tahata Yuki、Kodama Takahiro、Hikita Hayato、Tatsumi Tomohide、Yamada Tomomi、Takehara Tetsuo
  • Journal Title: Journal of Gastroenterology Volume: 57 Issue: 2 Pages: 111-119
  • DOI: 10.1007/s00535-021-01842-8
  • Peer Reviewed
• [Journal Article] Interleukin-6 Is a Circulating Prognostic Biomarker for Hepatocellular Carcinoma Patients Treated with Combined Immunotherapy (2022)
  • Author(s): Myojin Yuta、Kodama Takahiro、Sakamori Ryotaro、Maesaka Kazuki、Matsumae Takayuki、Tahata Yuki、Yamada Ryoko、Hikita Hayato、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Cancers Volume: 14 Issue: 4 Pages: 883-883
  • DOI: 10.3390/cancers14040883
  • Peer Reviewed
• [Journal Article] Prediction Model for Intrahepatic Distant Recurrence After Radiofrequency Ablation for Primary Hepatocellular Carcinoma 2cm or Smaller (2022)
  • Author(s): Takigawa Atsuo、Sakamori Ryotaro、Tahata Yuki、Yoshioka Teppei、Yamada Ryoko、Kodama Takahiro、Hikita Hayato、Yakushijin Takayuki、Ohkawa Kazuyoshi、Hiramatsu Naoki、Mita Eiji、Hagiwara Hideki、Ito Toshifmi、Imai Yasuharu、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Digestive Diseases and Sciences Volume: in press Issue: 12 Pages: 5704-5711
  • DOI: 10.1007/s10620-022-07455-2
  • Peer Reviewed
• [Journal Article] Efficacy of Ramucirumab <i>Versus</i> Sorafenib as Subsequent Treatment for Hepatocellular Carcinoma (2021)
  • Author(s): MAESAKA KAZUKI、SAKAMORI RYOTARO、YAMADA RYOKO、TAHATA YUKI、OHKAWA KAZUYOSHI、OSHITA MASAHIDE、TAMURA SHINJI、HAGIWARA HIDEKI、MITA EIJI、YAKUSHIJIN TAKAYUKI、INADA MASAMI、KODAMA TAKAHIRO、HIKITA HAYATO、TATSUMI TOMOHIDE、TAKEHARA TETSUO
  • Journal Title: Anticancer Research Volume: 41 Issue: 4 Pages: 2187-2192
  • DOI: 10.21873/anticanres.14993
  • Peer Reviewed
• [Journal Article] Prediction model for hepatocellular carcinoma occurrence in patients with hepatitis C in the era of direct‐acting anti‐virals (2021)
  • Author(s): Tahata Yuki、Sakamori Ryotaro、Yamada Ryoko、Kodama Takahiro、Hikita Hayato、Tatsumi Tomohide、Takehara Tetsuo、the Osaka Liver Forum
  • Journal Title: Alimentary Pharmacology &amp; Therapeutics Volume: 54 Issue: 10 Pages: 1340-1349
  • DOI: 10.1111/apt.16632
  • Peer Reviewed
• [Journal Article] Serum growth differentiation factor 15 predicts hepatocellular carcinoma occurrence after hepatitis C virus elimination (2021)
  • Author(s): Myojin Yuta、Hikita Hayato、Tahata Yuki、Doi Akira、、Kodama Takahiro、Hagiwara Hideki、Imai Yasuharu、Hiramatsu Naoki、Tamura Shinji、Yamamoto Keiji、Ohkawa Kazuyoshi、Hijioka Taizo、Fukui Hiroyuki、Doi Yoshinori、Yamada Yukinori、Yakushijin Takayuki、Mita Eiji、Sakamori Ryotaro、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Alimentary Pharmacology &amp; Therapeutics Volume: 55 Issue: 4 Pages: 422-433
  • DOI: 10.1111/apt.16691
  • Peer Reviewed
• [Journal Article] Hyperprogressive disease in patients with unresectable hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy (2021)
  • Author(s): Maesaka Kazuki、Sakamori Ryotaro、Yamada Ryoko、Tahata Yuki、Imai Yasuharu、Ohkawa Kazuyoshi、Miyazaki Masanori、Mita Eiji、Ito Toshifumi、Hagiwara Hideki、Yakushijin Takayuki、Kodama Takahiro、Hikita Hayato、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Hepatology Research Volume: 52 Issue: 3 Pages: 298-307
  • DOI: 10.1111/hepr.13741
  • Peer Reviewed
• [Presentation] 肝細胞癌に対する複合免疫療法効果予測バイオマーカー探索 (2023)
  • Author(s): 小玉尚宏、西尾 啓、竹原 徹郎
  • Organizer: 第109回日本消化器病学会総会
• [Presentation] 癌免疫微小環境解析による進行肝細胞癌の複合免疫療法効果予測 (2023)
  • Author(s): 山本修平、小玉尚宏、竹原徹郎
  • Organizer: 第59回日本肝臓学会総会
• [Presentation] Immunokinetic Analysis Predicts Efficacy of Combination Immunotherapy for Advanced Hepatocellular Carcinoma (2023)
  • Author(s): Takahiro Kodama, Shuhei Yamamoto, Akira Nishio, Kazuki Maesaka, Akira Doi, Yuki Tahata, Hayato Hikita, Tomohide Tatsumi, Tetsuro Takehara
  • Organizer: APASL Oncology
  • Int'l Joint Research / Invited
• [Presentation] 肝細胞癌に対するアテゾリズマブ＋ベバシズマブ併用療法における、リキッドバイオプシーを用いた治療効果予測 (2022)
  • Author(s): 小玉 尚宏、巽 智秀、竹原 徹郎
  • Organizer: 第58回日本肝臓学会総会
• [Presentation] 肝細胞癌に対するアテゾリズマブ＋ベバシズマブ併用療法の治療効果予測バイオマーカー としてのIL-6の有用性 (2022)
  • Author(s): 松前高幸、小玉尚宏、阪森亮太郎、前阪和城、野﨑泰俊、俵誠一、田中聡司、宮﨑昌典、澤井良之、藥師神崇行、大川和良、三田英治、萩原秀紀、今井康陽、田畑優貴、山田涼子、疋田隼人、巽智秀、竹原徹郎
  • Organizer: 第26回日本肝がん分子標的治療研究会
• [Presentation] Serum ST6GAL1 is a novel biomarker for predicting efficacy of tyrosine kinase inhibitors in hepatocellular carcinoma by detecting FGF19 expressing tumor (2021)
  • Author(s): Yuta Myojin, Takahiro Kodama, Hayato Hikita, Ryotaro Sakamori, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: AACR ANNUAL MEETING 2021
  • Int'l Joint Research
• [Presentation] 肝細胞癌薬物療法効果予測バイオマーカーとしての血清ST6GAL1の有用性 (2021)
  • Author(s): 小玉 尚宏、巽 智秀、竹原 徹郎
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] 進行肝細胞癌に対するラムシルマブとソラフェニブの比較検討：多施設共同研究 (2021)
  • Author(s): 前阪 和城、阪森 亮太郎、山田 涼子、田畑 優貴、小玉 尚宏、疋田 隼人、大川 和良、尾下 正秀、田村 信司、萩原 秀紀、三田 英治、藥師神 崇行、稲田 正己、巽 智秀、竹原 徹郎
  • Organizer: 第57回日本肝癌研究会
• [Presentation] 切除不能肝細胞癌に対するアテゾリズマブ/ベバシズマブ併用療法の初期治療成績 (2021)
  • Author(s): 前阪 和城、阪森 亮太郎、山田 涼子、田畑 優貴、小玉 尚宏、疋田 隼人、今井 康陽、尾下 正秀、大川 和良、三田 英治、伊藤 敏文、萩原 秀紀、藥師神 崇行、巽 智秀、竹原 徹郎
  • Organizer: 第24回日本肝癌分子標的治療研究会
• [Presentation] Biomarker-driven precision medicine for hepatocellular carcinoma (2021)
  • Author(s): Takahiro Kodama, Yuta Myojin, Hayato Hikita, Ryotaro Sakamori, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: 第80回日本癌学会学術総会
  • Invited