Potential role of mTORC2 as a therapeutic target in epithelial ovarian cancer

2013 Fiscal Year Final Research Report

• Project/Area Number: 23592446
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Osaka University
• Principal Investigator: MABUCHI Seiji 大阪大学, 医学(系)研究科(研究院), 助教 (00452441)
• Co-Investigator(Kenkyū-buntansha): SAWADA Kenjiro 大阪大学, 医学系研究科, 講師 (00452392) ; SOBE I Aki 大阪大学, 医学系研究科, 助教 (60397619) ; HASHIMOTO Kae 大阪大学, 医学系研究科, 助教 (90612078)
• Project Period (FY): 2011 – 2013
• Keywords: mTORC2 / mTORC1 / mTORC1阻害薬 / 耐性化 / Trabectedin

Research Abstract

In the current study, we found that mTORC2 is frequently activated in ovarian cancer, especially in clear cell carcinoma of the ovary (CCC). mTORC2 stimulated cell proliferation and mediate the acquired resistance to mTORC1 inhibitor (Mol Cancer Ther. 2013;12:1367-77.). We also identified trabectedin shows significant antitumor activity toward chemosensitive and chemoresistant CCC cells. The inhibition of mTORC1 significantly enhanced the therapeutic efficacy of trabectedin and prevented CCC cells from acquiring resistance to trabectedin. Finally, we found that treatment with trabectedin plus irinotecan in combination with mTOR inhibitors displays the strong anti-tumor effect against ovarian CCC (Clin Cancer Res 2011;17:4462-73., Int J Gynecol Cancer 2014, in press). Our studies provide the rationale for future clinical trials of mTOR targeting therapies in combination with trabectedin in patients with ovarian CCC.

Research Products

• [Journal Article] Potential Role of mTORC2 as a Therapeutic Target in Clear Cell Carcinoma of the Ovary (2013)
  • Author(s): Hisamatsu T, Mabuchi S, Matsumoto Y, Kawano M, Sasano T, Takahashi R, Sawada K, Ito K, Kurachi H, Schilder RJ, Testa JR, Kimura T
  • Journal Title: Mol Cancer Ther Volume: 12 Pages: 1367-77
• [Journal Article] Targeting mTOR signaling pathway in ovarian cancer (2011)
  • Author(s): Mabuchi S, Hisamatsu T, Kimura T
  • Journal Title: Curr Med Chem Volume: 18 Pages: 2960-8
• [Journal Article] The activity of trabectedin as a single agent or in combination with everolimus for clear cell carcinoma of the ovary (2011)
  • Author(s): Mabuchi S, Hisamatsu T, Kawase C, Hayashi M, Sawada K, Mimura K, Takahashi K, Takahashi T, Kurachi H, Kimura T
  • Journal Title: Clin Cancer Res Volume: 17 Pages: 4462-73
• [Presentation] What's clear and not clear about clear cell cancer (2012)
  • Author(s): Seiji Mabuchi
  • Organizer: 14^<th> Biennial meeting of International Gynecologic Cancer Society
  • Place of Presentation: Vancouver Canada
  • Year and Date: 20121013-16