Development of new predictive markers for the onset of side effects of molecularly targeted drugs and their prevention using a medaka (Japanese killifish) model

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K20861
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Niigata University
• Principal Investigator: Norihiro Sakai 新潟大学, 医歯学総合病院, 特任助教 (00911984)
• Project Period (FY): 2021-08-30 – 2024-03-31
• Keywords: レンバチニブ / メダカ

Outline of Final Research Achievements

Lenvatinib, a drug used in the treatment of hepatocellular carcinoma, was administered to a medaka (Japanese killifish) model, and a concentration-dependent lenvatinib toxicity was observed. Specifically, concentration-dependent edema and weight gain were observed, as well as decreased vascular area and blood flow velocity in the tail fin. We also found that the vascular area and blood flow velocity of the tail fin were maintained when histidine was administered simultaneously. Proteomic analysis of exosomes of human serum before and after lenvatinib treatment revealed that 55 proteins (CXCL7 0.13-fold, COL1A1 0.20-fold, etc.) were reduced by less than 1/4 before and after treatment, and 15 proteins (LMTK2 (apoptosis-related) 13.6-fold, TGM3 (epidermal keratinization, hair formation) 10.0-fold were observed.

Free Research Field

肝臓

Academic Significance and Societal Importance of the Research Achievements

レンバチニブは肝細胞癌の全身化学療法として、その有効性から肝癌ガイドラインでも推奨されている標準治療のひとつである。いっぽうで、その副作用（手足症候群など）により継続が困難となる場合も多い。（日本人で手足症候群の発症率が高いという報告もされている。）そこで、レンバチニブを投与する際の副作用予測マーカーや、副作用予防薬を探索することで治療を受ける患者様の予後の延長やQOLの改善につなげていきたいと考え、本研究を開始した。