2022 Fiscal Year Final Research Report

Analysis of cancer microenvironment reconstruction by molecular-targeted drugs for the promotion of personalized medicine for renal cell carcinoma

Research Project

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Project/Area Number	19K07468
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 49020:Human pathology-related
Research Institution	National Hospital Organization Saitama National Hospital (2021-2022) Keio University (2019-2020)
Principal Investigator	Mikami Shuji 独立行政法人国立病院機構埼玉病院(臨床研究部), 診療部, 病理診断部長 (20338180)
Co-Investigator(Kenkyū-buntansha)	水野隆一慶應義塾大学, 医学部(信濃町), 准教授 (60383824) 田中伸之慶應義塾大学, 医学部(信濃町), 講師 (60445244)
Project Period (FY)	2019-04-01 – 2023-03-31
Keywords	腎細胞癌 / 分子標的薬 / 免疫チェックポイント阻害 / 薬剤耐性
Outline of Final Research Achievements	In this research project, we performed an immunohistochemical investigation of the mechanism of action of cabozantinib, a novel molecular-targeted drug that has recently been introduced into drug therapy for advanced renal cell carcinoma. Cabozantinib is thought to exert its therapeutic effect by inhibiting VEGFR, AXL, GAS6, and c-MET, and the expression of these molecules correlated with the malignancy of renal cell carcinoma. Furthermore, cases with high expression of these molecules had a poor prognosis. In addition, c-MET and AXL were highly expressed in tumor tissues after treatment with sunitinib, a VEGF inhibitor. Furthermore, we found that AXL and c-MET are involved in the formation of a tumor immunosuppressive microenvironment. In particular, there were many PD-L1-positive immunocompetent cells in cases with high c-MET expression.
Free Research Field	腎細胞癌の薬物治療に対する耐性機構の研究
Academic Significance and Societal Importance of the Research Achievements	進行性腎細胞癌の治療方針の決定の大部分は臨床的因子を加味したリスク分類に基づいて行われているのが現状であり、治療方針の決定に役立つバイオマーカーの確立が望まれている。本研究課題によりカボザンチニブの治療効果とAXL, GAS6, c-MET発現の相関が明らかとなった。現在のところ、カボザンチニブに治療効果を予測するバイオマーカーは確立されていないため、今後はこれらの因子とカボザンチニブの治療効果の関連を臨床的に検討することで、予後予測および治療効果予測因子の確立につながることが期待される。