2023 Fiscal Year Final Research Report

Investigation of the mechanism for metronomic chemotherapy resistance in well-differentiated oral cancer driven by EphA4 activation

Research Project

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Project/Area Number	21K10084
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 57060:Surgical dentistry-related
Research Institution	Gunma University
Principal Investigator	Kina Shinichiro 群馬大学, 大学院医学系研究科, 講師 (40422422)
Co-Investigator(Kenkyū-buntansha)	金城貴夫琉球大学, 医学部, 教授 (30284962) 喜名美香群馬大学, 医学部附属病院, 医員 (80578914) 宮本昇札幌医科大学, 医学部, 助教 (80749565) 川端麗香群馬大学, 未来先端研究機構, 講師 (90721928)
Project Period (FY)	2021-04-01 – 2024-03-31
Keywords	口腔癌 / 術前化学療法 / メトロノーム化学療法
Outline of Final Research Achievements	Metronomic chemotherapy is defined as a high-frequency low-dose schedule of chemotherapy drug administration. The response rate of well-differentiated OSCC to metronomic chemotherapy was significantly lower. We investigated differences in molecular profiles between poorly or moderately differentiated head and neck squamous cell carcinoma (HNSCC) and well-differentiated HNSCC from patients with HNSCC TCGA data. An upstream regulator analysis correlated with EphA4 expression identified pathways associated with decreased mTORC1 signaling and T cell activation, including TCR, CD3, CD28, and CD40LG. Plasmacytoid dendritic cell and CD8+ T cell numbers were higher in the microenvironment of poorly or moderately differentiated HNSCC than in that of well-differentiated HNSCC. Moreover, KYL used with chemotherapeutic drugs synergistically increased cancer cell death.
Free Research Field	腫瘍薬理学
Academic Significance and Societal Importance of the Research Achievements	我々は、bleomycin 併用S-1 による術前メトロノーム化学療法のphase I/II 試験の結果を学術誌上にて報告した（Kina S, et al. Eur J Pharmacol. 2023）。上記化学療法による重篤な副作用は観察されなかった。約半数の患者で、組織学的に腫瘍が完全に消失しており、そのような患者集団では、外科切除を最初に行った患者群と比較して生存率が有意に高くなっていた。高分化型腫瘍は、抗がん剤耐性を示した。高分化型腫瘍周囲では、免疫細胞が枯渇しており、EphA4 が活性化していた。メトロノーム化学療法は、腫瘍免疫に関して働きかけていることが強く示唆された。