Establishment of the novel treatment strategy against urothelial carcinoma controlling for cancer stem-like property

• Project/Area Number: 17K11157
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: St. Marianna University School of Medicine (2019); Keio University (2017-2018)
• Principal Investigator: Kikuchi Eiji 聖マリアンナ医科大学, 医学部, 教授 (10286552)
• Co-Investigator(Kenkyū-buntansha): 小坂 威雄 慶應義塾大学, 医学部(信濃町), 講師 (30445407)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 尿路上皮癌 / 癌幹細胞 / 抗癌剤耐性 / シスプラチン / 膀胱癌 / 治療戦略

Outline of Final Research Achievements

The following five results were obtained. (1) High expression of CD44v9 in tumor specimen is a prognostic factor in patients with muscle invasive bladder cancer. (2) CD44v8-10 is highly associated with acquisition of resistance for anti-cancer agents in bladder cancer. (3) In current smoker bladder cancer patients high PD-1 expression in tumor nest is a prognostic factor (4) Metformin had cytotoxic effects against T24 cell line with high CD44v expression. (5) In mouse bladder cancer lung metastatic model, sulfasalazine plus cisplatin had strong anti-tumor effects.

Academic Significance and Societal Importance of the Research Achievements

尿路上皮癌におけるCD44v9、喫煙膀胱癌におけるPD-1は今後予後マーカーとしての確立が望まれる。このことにより予後不良症例の抽出、リスク分類が可能となり個別化治療への応用の意義が示唆される。CD44vは膀胱癌の抗癌剤耐性獲得に寄与し、CD44vをターゲットしたメトホルミンやサラゾスルファピリジンは次世代の新規治療戦略として期待されると考える。

Research Products

• [Journal Article] Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer (2018)
  • Author(s): Hagiwara Masayuki, Kikuchi Eiji, Tanaka Nobuyuki, Kosaka Takeo, Mikami Shuji, Saya Hideyuki, Oya Mototsugu
  • Journal Title: BMC Cancer Volume: 18 Issue: 1
  • DOI: 10.1186/s12885-018-3988-3
  • Peer Reviewed / Open Access
• [Presentation] 癌幹細胞を標的としたスルファサラジン膀胱内注入治療の効果 (2019)
  • Author(s): 荻原広一郎、菊地栄次、田中伸之、小坂威雄、佐谷秀行、大家基嗣
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 上部尿路上皮癌におけるPD-1発現と喫煙の既往歴の関連 (2018)
  • Author(s): 早川望、菊地栄次、三上修治、大家基嗣
  • Organizer: 第106回日本泌尿器科学会総会
• [Presentation] 尿路上皮癌細胞における糖尿病治療薬メトホルミンを用いた CD44v 制御 (2017)
  • Author(s): 萩原正幸、菊地栄次、小坂威雄、宮嶋哲、中川健、佐谷秀行
  • Organizer: 第105回日本泌尿器科学会総会