Elucidation of the mechanism of therapeutic resistance in liver cancer using circulating tumor DNA

• Project/Area Number: 17K15948
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Hiroshima University
• Principal Investigator: ONO ATSUSHI 広島大学, 医系科学研究科(医), 助教 (80774645)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肝癌 / レンバチニブ / サイトカイン / 肝細胞癌 / バイオマーカー / 肝がん / 血中循環腫瘍DNA / circulating tumor DNA

Outline of Final Research Achievements

Circulating tumor DNA and serum cytokines in the advanced liver cancer patients before and during the treatment with lenvatinib have been analyzed. Decreasing relative dose intensity due to side effects is one of the biggest challenges of lenvatinib treatment．In the current study, we identified the pattern of the serum levels of 9 cytokines before the start of treatment which is associated with low relative dose intensity leading to the short progression-free survival and overall survival. Changes of ctDNA profile and mutant allele frequency during the treatment is still under analysis.

Academic Significance and Societal Importance of the Research Achievements

相対用量強度（あらかじめ決められた抗癌剤の標準投与量と比べて実際の投与量の抗癌剤治療強度を評価する指標）を高く保つことは癌に対する薬物治療の効果を高めるのに重要である．相対用量強度の低下の多くは副作用により治療の中断を余儀なくされることが原因である．本研究で同定された血中サイトカインのパターンにより治療開始前に相対用量強度が低下しやすい症例を予想することができれば，早期に予定休薬日を設ける等の内服スケジュールの調整を行うことにより，長期の休薬期間を回避し，相対用量強度を高く保つことができる可能性がある．

Research Products

• [Journal Article] Circulating cytokines and angiogenic factors based signature associated with the relative dose intensity during treatment in patients with advanced hepatocellular carcinoma receiving lenvatinib (2020)
  • Author(s): Ono A, Aikata H, Yamauchi M, Kodama K, Ohishi W, Takeshi K, Ohya K, Teraoka Y, Osawa M, Fujino H, Nakahara T, Murakami E, Miki D, Kawaoka T, Abe-Chayama H, Zhang P, Liu S, Makokha , Tsuge M, Imamura M, Hayes CN, Chayama K
  • Journal Title: Therapeutic Advances in Medical Oncology Volume: in press
  • Peer Reviewed / Open Access
• [Presentation] 進行肝癌におけるレンバチニブ治療のバイオマーカーの探索, (2019)
  • Author(s): 大野 敦司
  • Organizer: 第56回日本臨床分子医学会学術集会
• [Presentation] EXPLORATORY ANALYSIS OF BIOMARKERS ASSOCIATED WITH CLINICAL OUTCOMES OF LENVATINIB IN HEPATOCELLULAR CARCINOMA (2019)
  • Author(s): Atsushi Ono, Hiroshi Aikata, Masami Yamauchi, Kenichiro Kodama, Daiki Miki, Waka Ohishi, Yuji Teraoka, Hatsue Fujino, Takashi Nakahara, Eisuke Murakami, Tomokazu Kawaoka, Hiromi Abe-Chayama, Masataka Tsuge, Michio Imamura, Clair Nelson Hayes, Kazuaki Chayama
  • Organizer: The Liver Meeting 2019, American Association for the Study of Liver Diseases
  • Int'l Joint Research
• [Presentation] 進行肝癌におけるレンバチニブ治療のバイオマーカーの探索 (2019)
  • Author(s): 大野 敦司
  • Organizer: 第56回 日本臨床分子医学会学術集会
• [Funded Workshop] The Liver Meeting 2019, American Association for the Study of Liver Diseases (2019)