Elucidate the mechanism of radioresistance via Nrf2 anti-oxidative pathway in oral squamous cell carcinoma and development of novel therapeutic strategy

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K19237
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Kumamoto University
• Principal Investigator: Matsuoka Yuichiro 熊本大学, 病院, 医員 (10802100)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 口腔癌 / 口腔扁平上皮癌 / 放射線耐性 / Nrf2 / IL-6 / トシリズマブ

Outline of Final Research Achievements

We investigated the mechanism of radioresistance via Nrf2 anti-oxidative pathway in oral squamous cell carcinoma (OSCC) and developed novel therapies, and obtained the following results. 1) The radiotherapy (X-rays 4 Gy/day, total 60 Gy) that combined tocilizumab significantly suppressed the tumor growth in vivo mice model. 2) The tocilizumab sensitized radiosensitivity by suppressing STAT3 pathway and Nrf2 anti-oxidative pathway stimulated by IL-6 in vivo mice model. 3) We analyzed the expression of phosphorylated Nrf2 in the immunohistochemical staining using biopsy specimens of 110 OSCC patients. A high phosphorylated Nrf2 tumour expression was significantly correlated with a poor response to preoperative chemoradiotherapy. A Kaplan–Meier analysis revealed that higher numbers of phosphorylated Nrf2 were significantly correlated with a poor prognosis.

Free Research Field

口腔扁平上皮癌

Academic Significance and Societal Importance of the Research Achievements

本研究では、従来のより臨床的なプロトコルの放射線療法とIL-6シグナリングを標的とした治療法の併用の可能性を模索することは、口腔扁平上皮癌の放射線耐性を克服という観点から重要かつ独創的なアプローチである。また、トシリズマブは、関節リウマチなどに対して既に承認されおり、高い効果を示している。従って、このトシリズマブを用いた非臨床試験の良好な結果は、トシリズマブはドラッグ・リ・ポジショニングの観点からも臨床試験のデザインにおいて非常に期待できる。
さらに、本研究ではがん微小環境においてOSCC細胞のNrf2抗酸化経路を介した放射線耐性機構の更なる解明を目指した。