Novel anti-cancer therapeutic strategy with mTORC1/2 inhibitor against bladder cancer

• Project/Area Number: 26462428
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Keio University
• Principal Investigator: KIKUCHI EIJI 慶應義塾大学, 医学部(信濃町), 講師 (10286552)
• Co-Investigator(Kenkyū-buntansha): 宮嶋 哲 慶應義塾大学, 医学部(信濃町), 准教授 (90245572) ; 小坂 威雄 慶應義塾大学, 医学部(信濃町), 講師 (30445407)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 分子標的 / 膀胱癌 / 腎盂尿管癌 / 抗癌剤 / 尿路上皮癌 / 転写因子 / シグナル伝達 / 喫煙

Outline of Final Research Achievements

The following five results were obtained.
1) We found that AXL, which is in the TAM family of receptor tyrosine kinases and its ligand, Gas6 expression were the independent prognostic factors for upper tract urothelial carcinoma. 2) After exposed to nicotine, T24 bladder tumor cell growth was induced through activation of PI3K-Akt-mTOR. NVP-BEZ235 reduced the cell growth by inhibiting the activated PI3K-Akt-mTOR. 3) NVP-BEZ235 inhibited subcutaneous tumor growth and pS6 overexpression induced by nicotine. 4) The combination of cisplatin and NVP-BEZ235 had strong cytotoxic effect. 5) In an orthotopic bladder tumor model, intravesical administration of NVP-BEZ235 had a significant antitumor effect through inhibiting PI3K-Akt-mTOR pathway.

Research Products

• [Journal Article] Relationship between increased expression of the Axl/Gas6 signal cascade and prognosis of patients with upper tract urothelial carcinoma. (2016)
  • Author(s): Hattori S, Kikuchi E, Kosaka T, Miyazaki Y, Tanaka N, Miyajima A, Mikami S, Oya M
  • Journal Title: Ann Surg Oncol Volume: 23 Issue: 2 Pages: 663-670
  • DOI: 10.1245/s10434-015-4848-x
  • Peer Reviewed
• [Presentation] Nicotine induces aggressiveness and acquiring chemoresistance in bladder cancer cells (2016)
  • Author(s): Yuge K, Kikuchi E, Ogihara K, Fukumoto K, Hagiwara M, Yasumizu Y, Tanaka N, Matsumoto K, Kosaka T, Miyajima A, Iinuma S, Oya M
  • Organizer: 第104回日本泌尿器科学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-04-23
• [Presentation] 尿路上皮癌細胞におけるニコチンのPI3K/Akt/mTOR経路を介した抗癌剤耐性獲得に関わる基礎的研究 (2016)
  • Author(s): 弓削和之、菊地栄次、荻原広一郎、福本桂資郎、萩原正幸、安水洋太、田中伸之、松本一宏、小坂威雄、宮嶋哲、大家基嗣
  • Organizer: 第25回泌尿器科分子・細胞研究会
  • Place of Presentation: ハイアット リージェンシー 大阪（大阪府大阪市）
  • Year and Date: 2016-02-26
• [Presentation] AXL-Gas6カスケード亢進と上部尿路上皮癌術後の予後との関連 (2015)
  • Author(s): 服部盛也、菊地栄次、小坂威雄、宮嶋哲、三上修治、大家基嗣
  • Organizer: 第103回日本泌尿器科学会総会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
  • Year and Date: 2015-04-18
• [Presentation] 尿路上皮癌におけるニコチン曝露がPI3K/Akt pathwayに及ぼす影響の基礎的検討 (2015)
  • Author(s): 弓削和之、菊地栄次、安水洋太、萩原正幸、小坂威雄、宮嶋哲、飯沼誠一、大家基嗣
  • Organizer: 第103回日本泌尿器科学会総会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
  • Year and Date: 2015-04-18
• [Presentation] 上部尿路上皮癌における新規術予後予測因子の検索 (2014)
  • Author(s): 服部盛也、菊地栄次、小坂威雄、、宮嶋哲、三上修治、大家基嗣
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27