Elucidation of radiation resistance mechanism of oral cancer targeting PARP and creation of new treatment strategy

• Project/Area Number: 20K18700
• 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: Sakata Junki 熊本大学, 病院, 医員 (70823326)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 口腔癌 / 治療抵抗性 / PARP / オラパリブ / 放射線抵抗性

Outline of Research at the Start

口腔癌の80%以上を占める 口腔扁平上皮癌 (OSCC) において放射線治療は主要な治療法の一つであるが、その有効性には個人差が大きく、治療効果の乏しい患者の病勢コントロールや患者予後の改善が課題となっている。ポリ（ADPリボース）ポリメラーゼ（PARP）はDNA一本鎖切断の修復に重要な役割を果たす酵素であり、PARP阻害剤であるオラパリブはBRCA1/2遺伝子に変異を有する卵巣癌や乳癌でその有効性が示されている。本研究では、OSCC患者に対するより有効性の高い治療法の開発を目指して、放射線抵抗性に関連するPARPの分子生物学的な働きの解明とPARP阻害剤併用の放射線治療の有効性の検討を行う。

Outline of Final Research Achievements

PARP is mainly involved in the repair of DNA single-strand breaks, and olaparib inhibits PARP to prevent the repair of DNA single-strand breaks, leading to cell death. In this study, we investigated the effect of olaparib on oral cancer. As a result, it was shown that the therapeutic effect of cisplatin and radiation may be improved by the combined use of olaparib in oral squamous cell carcinoma. In adenoid cystic carcinoma, it was shown that the combined use of olaparib may improve the therapeutic effect of radiation. As a mechanism for enhancing the therapeutic effect, it is possible that DNA single-strand repair is inhibited by olaparib in DNA damaged by anticancer agents or irradiation, resulting in more lethal DNA damages.

Academic Significance and Societal Importance of the Research Achievements

口腔癌において放射線治療との併用による有用性が示されている抗癌剤は限られているのが現状であるが、本研究の結果、オラパリブを放射線治療やシスプラチンのようなDNAに作用する一部の抗癌剤と併用することで治療効果が向上する可能性が示された。PRAPを標的とした治療を応用することにより、口腔癌患者の予後が改善する可能性が示された。

Research Products

• [Journal Article] Enhanced Expression of IGFBP-3 Reduces Radiosensitivity and Is Associated with Poor Prognosis in Oral Squamous Cell Carcinoma (2020)
  • Author(s): Sakata J, Hirosue A, Yoshida R, Matsuoka Y, Kawahara K, Arita H, Nakashima H, Yamamoto T, Nagata M, Kawaguchi S, Gohara S, Nagao Y, Yamana K, Toya R, Murakami R, Kuwahara Y, Fukumoto M, Nakayama H
  • Journal Title: Cancers (Basel) Volume: 12(2) Issue: 2 Pages: 494-494
  • DOI: 10.3390/cancers12020494
  • Peer Reviewed / Open Access
• [Journal Article] BRD4 promotes metastatic potential in oral squamous cell carcinoma through the epigenetic regulation of the MMP2 gene (2020)
  • Author(s): Yamamoto Tatsuro、Hirosue Akiyuki、Nakamoto Masafumi、Yoshida Ryoji、Sakata Junki、Matsuoka Yuichiro、Kawahara Kenta、Nagao Yuka、Nagata Masashi、Takahashi Nozomu、Hiraki Akimitsu、Shinohara Masanori、Nakao Mitsuyoshi、Saitoh Noriko、Nakayama Hideki
  • Journal Title: British Journal of Cancer Volume: 123 Issue: 4 Pages: 580-590
  • DOI: 10.1038/s41416-020-0907-6
  • Peer Reviewed / Open Access
• [Journal Article] Onodera's prognostic nutritional index correlates with tumor immune environment and survival in patients with oral squamous cell carcinoma undergoing chemoradiotherapy (2020)
  • Author(s): Yoshida Ryoji、Gohara Shunsuke、Sakata Junki、Matsuoka Yuichiro、Hirosue Akiyuki、Kawahara Kenta、Kawaguchi Sho、Nagao Yuka、Yamana Keisuke、Nagata Masashi、Fukuma Daiki、Toya Ryo、Murakami Ryuji、Hiraki Akimitsu、Shinohara Masanori、Nakayama Hideki
  • Journal Title: Translational Oncology Volume: 13 Issue: 12 Pages: 100850-100850
  • DOI: 10.1016/j.tranon.2020.100850
  • Peer Reviewed / Open Access
• [Presentation] 口腔癌に対するPARP阻害剤オラパリブと抗癌剤および放射線併用効果の検討 (2021)
  • Author(s): 坂田純基
  • Organizer: 第34回日本口腔診断学会・第31回日本口腔内科学会 合同学術大会