New drug discovery against ovarian cancer focusing on the multifaceted effects of statins and their effects on the Warburg effect

• Project/Area Number: 18K16780
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Keio University
• Principal Investigator: Kobayashi Yusuke 慶應義塾大学, 医学部(信濃町), 講師 (10439763)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ドラッグリポジショニング / 卵巣癌 / スタチン / がん代謝 / ワールブルク効果

Outline of Final Research Achievements

From the perspective of drug repositioning to develop an already approved drug as a novel treatment for another disease, we conducted a basic study to apply a statin for dyslipidemia into the treatment of ovarian cancer. In addition to the mevalonate pathway, various biological processes, components, and molecular functions have been identified as pathways of action by statin. The expression of PTBP1, a regulatory factor, was significantly up-regulated in the statin-treated group. We established a system of the Histoculture Drug Response Assay to confirm the response of statin to human ovarian cancer specimens by collecting tumors from patients with ovarian cancer diagnosed by rapid intraoperative diagnosis.

Academic Significance and Societal Importance of the Research Achievements

スタチンの抗腫瘍効果における多面的効果がメバロン酸経路以外の作用経路からも誘導されることを明らかにすることができた。加えて、スタチンががん細胞に特徴的なワールブルグ効果を酸化的リン酸化に誘導しうるのかという学術的問いに対して制御機構の一端を明らかとすることができた。また、Histoculture Drug Response Assay(HDRA)の系を樹立できたことで、ヒト卵巣癌検体にスタチンが奏効するかを明らかとすることができる。さらに、HDRAにおける増殖抑制率の結果から、奏効症例と非奏効症例に分類し、両群間の臨床病理学的背景を比較検討し有意に差のある因子を抽出することに繋げられる。

Research Products

• [Journal Article] Is antidyslipidemic statin use for cancer prevention a promising drug repositioning approach? (2019)
  • Author(s): Kobayashi Yusuke, Banno Kouji, Kunitomi Haruko, Nagai Shimpei, Takahashi Takayuki, Anko Mayuka, Iijima Moito, Takeda Takashi, Matoba Yusuke, Nakamura Kanako, Tsuji Kosuke, Tominaga Eiichiro, Aoki Daisuke.
  • Journal Title: European Journal of Cancer Prevention Volume: 28 Issue: 6 Pages: 562-567
  • DOI: 10.1097/cej.0000000000000497
  • Peer Reviewed / Open Access
• [Journal Article] Warburg effect in Gynecologic cancers (2019)
  • Author(s): Kobayashi Yusuke、Banno Kouji、Kunitomi Haruko、Takahashi Takayuki、Takeda Takashi、Nakamura Kanako、Tsuji Kosuke、Tominaga Eiichiro、Aoki Daisuke
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 45 Issue: 3 Pages: 542-548
  • DOI: 10.1111/jog.13867
  • Peer Reviewed
• [Journal Article] Current state and outlook for drug repositioning anticipated in the field of ovarian cancer (2019)
  • Author(s): Kobayashi Yusuke、Banno Kouji、Kunitomi Haruko、Tominaga Eiichiro、Aoki Daisuke
  • Journal Title: Journal of Gynecologic Oncology Volume: 30 Issue: 1
  • DOI: 10.3802/jgo.2019.30.e10
  • Peer Reviewed
• [Presentation] ドラッグリポジショニングによるメバロン酸経路を標的とした 卵巣癌予防薬・治療薬の創出 (2020)
  • Author(s): 小林佑介
  • Organizer: 第72回日本産科婦人科学会学術講演会シンポジウム
• [Presentation] ドラッグリポジショニングによるメバロン酸経路を標的とした卵巣癌予防薬・治療薬の創出 (2020)
  • Author(s): 小林佑介
  • Organizer: 第72回日本産科婦人科学会学術講演会 シンポジウム
  • Invited
• [Presentation] Drug repositioning strategy for ovarian cancer (2019)
  • Author(s): Yusuke Kobayashi
  • Organizer: Asian Society of Gynecologic Oncology (ASGO) 5th Workshop
  • Int'l Joint Research / Invited
• [Presentation] Drug repositioning for ovarian cancer targeting mevalonate pathway (2019)
  • Author(s): Yusuke Kobayashi, Haruko Kunitomi, Kouji Banno, Shimpei Nagai, Mayuka Anko, Takayuki Takahashi, Moito Iijima, Takashi Takeda, Keiko Watanabe, Yusuke Matoba, Kanako Nakamura, Kosuke Tsuji, Eiichiro Tominaga, Mamoru Tanaka, Daisuke Aoki
  • Organizer: Royal College of Obstetricians & Gynaecologists (RCOG) World Congress 2019
  • Int'l Joint Research
• [Presentation] Drug repositioning for ovarian cancer targeting mevalonate pathway. (2019)
  • Author(s): Yusuke Kobayashi, Haruko Kunitomi, Kouji Banno, Shimpei Nagai, Mayuka Anko, Takayuki Takahashi, Moito Iijima, Takashi Takeda, Keiko Watanabe, Yusuke Matoba, Kanako Nakamura, Kosuke Tsuji, Eiichiro Tominaga, Mamoru Tanaka, Daisuke Aoki.
  • Organizer: Royal College of Obstetricians & Gynaecologists (RCOG) World Congress 2019.
  • Int'l Joint Research
• [Presentation] Bisphosphonates, another candidate of drug repositioning for ovarian cancer. (2018)
  • Author(s): Yusuke Kobayashi, Kouji Banno, Haruko Kunitomi, Keiko Watanabe, Yusuke Matoba, Moito Iijima, Takashi Takeda, Masataka Adachi, Miho Iida, Kanako Nakamura, Kosuke Tsuji, Eiichiro Tominaga, Mamoru Tanaka, Daisuke Aoki.
  • Organizer: 第70回日本産科婦人科学会学術講演会 International Session Workshop.
• [Presentation] Drug repositioning strategy for ovarian cancer. (2018)
  • Author(s): Yusuke Kobayashi.
  • Organizer: Asian Society of Gynecologic Oncology (ASGO) 5th Workshop.
  • Int'l Joint Research / Invited