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

• 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
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: mTORC2 / mTORC1 / mTORC1阻害薬 / 耐性化 / Trabectedin / 耐性化機構 / 卵巣癌 / 明細胞腺癌 / 卵巣明細胞腺癌 / everolimus

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] 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 Issue: 7 Pages: 1367-77
  • DOI: 10.1158/1535-7163.mct-12-1185
  • Peer Reviewed
• [Journal Article] A phase I study of concurrent weekly carboplatin and paclitaxel combined with intensity-modulated pelvic radiotherapy as an adjuvant treatment for early-stage cervical cancer patients with positive pelvic lymph nodes (2013)
  • Author(s): Mabuchi, S. Takahashi, R. Isohashi, F. Yokoi, T. Ito, K. Tsutui, T. Ogata, T. Yoshioka, Y. Ogawa, K. Kimura, T.
  • Journal Title: Int J Gynecol Cancer Volume: 23 Issue: 7 Pages: 1279-1286
  • DOI: 10.1097/igc.0b013e31829c3e32
  • Peer Reviewed
• [Journal Article] Utility of serum squamous cell carcinoma antigen levels at the time of recurrent cervical cancer diagnosis in determining the optimal treatment choice (2013)
  • Author(s): Shimura, K. Mabuchi, S. Yokoi, T. Sasano, T. Sawada, K. Hamasaki, T. Kimura, T.
  • Journal Title: J Gynecol Oncol Volume: 24 Issue: 4 Pages: 321-9
  • DOI: 10.3802/jgo.2013.24.4.321
  • Peer Reviewed
• [Journal Article] Estradiol and raloxifene induce the proliferation of osteoblasts through G-protein-coupled receptor GPR30 (2013)
  • Author(s): Noda-Seino, H. Sawada, K. Hayakawa, J. Ohyagi-Hara, C. Mabuchi, S. Takahashi, K. Nishio, Y. Sakata, M. Kurachi, H. Kimura, T.
  • Journal Title: J Endocrinol Invest Volume: 36 Pages: 21-27
  • Peer Reviewed
• [Journal Article] Dose-volume histogram predictors of chronic gastrointestinal complications after radical hysterectomy and postoperative concurrent nedaplatin-based chemoradiation therapy for early-stage cervical cancer (2013)
  • Author(s): Isohashi, F. Yoshioka, Y. Mabuchi, S. Konishi, K. Koizumi, M. Takahashi, Y. Ogata, T. Maruoka, S. Kimura, T. Ogawa, K.
  • Journal Title: Int J Radiat Oncol Biol Phys Volume: 85 Pages: 728-734
  • Peer Reviewed
• [Journal Article] Impact of the Addition of Concurrent Chemotherapy to Pelvic Radiotherapy in Surgically Treated Stage IB1-IIB Cervical Cancer Patients With Intermediate-Risk or High-Risk Factors: A 13-Year Experience (2013)
  • Author(s): Okazawa, M. Mabuchi, S. Isohashi, F. Suzuki, O. Yoshioka, Y. Sasano, T. Ohta, Y. Kamiura, S. Ogawa, K. Kimura, T.
  • Journal Title: Int J Gynecol Cancer Volume: 23 Pages: 567-575
  • Peer Reviewed
• [Journal Article] Significance of lymphovascular space invasion in epithelial ovarian cancer (2012)
  • Author(s): Matsuo, K. Sheridan, T. B. Yoshino, K. Miyake, T. Hew, K. E. Im, D. D. Rosenshein, N. B. Mabuchi, S. Enomoto, T. Kimura, T. Sood, A. K. Roman, L. D.
  • Journal Title: Cancer Med Volume: 1 Pages: 156-164
  • Peer Reviewed
• [Journal Article] Impact of histological subtype on survival of patients with surgically-treated stage IA2-IIB cervical cancer: adenocarcinoma versus squamous cell carcinoma (2012)
  • Author(s): Mabuchi, S. Okazawa, M. Matsuo, K. Kawano, M. Suzuki, O. Miyatake, T. Enomoto, T. Kamiura, S. Ogawa, K. Kimura, T.
  • Journal Title: Gynecol Oncol Volume: 127 Pages: 114-120
  • Peer Reviewed
• [Journal Article] 卵巣明細胞腺癌に対する分子標的治療の分子背景 (2012)
  • Author(s): 馬淵誠士・久松武志・松本有里・木村正
  • Journal Title: 産科と婦人科 Volume: 79 Pages: 1285-1292
  • Peer Reviewed
• [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
• [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, et al
  • Journal Title: Clin Cancer Res Volume: 17 Pages: 4462-4473
  • Peer Reviewed
• [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: 2960-2968
  • Peer Reviewed
• [Journal Article] Nedaplatin: a radiosensitizing agent for patients with cervical cancer (2011)
  • Author(s): Mabuchi S, Kimura T.
  • Journal Title: Chemother Res Pract Volume: 2011 Pages: 963159-963159
  • Peer Reviewed
• [Presentation] The significance of vascular endothelial growth factor C in the lymphangiogenesis and lymph node metastasis of ovarian cancer (2013)
  • Author(s): Hisamatsu, T. Mabuchi, S. Sasano, T. Takahashi, R. Kawano, M. Matsumoto, Y. Hashimoto, K. Isobe, A. Sawada, K. Sakata, M. Kimura, T.
  • Organizer: The 104th Annual Meeting American Association for Cancer Research
  • Place of Presentation: Washington DC, U.S.A
• [Presentation] mTOR complexesをターゲットとした卵巣癌の分子標的治療 浸潤・脈管新生・増殖の抑制を目指して (2013)
  • Author(s): 馬淵 誠士
  • Organizer: 第65回日本産科婦人科学会
  • Place of Presentation: 札幌
• [Presentation] 卵巣癌のMolecular Medicine PI3K/AKT/mTOR経路を標的とした卵巣癌治療 (2013)
  • Author(s): 馬淵 誠士
  • Organizer: 第54回日本婦人科腫瘍学会
  • Place of Presentation: 東京
• [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
• [Presentation] What is clear and unclear about clear cell carcinoma of the ovary; Molecular issues) (2012)
  • Author(s): Mabuchi S
  • Organizer: IGCS 14th Biennial Meeting
  • Place of Presentation: Vancouver, Canada
  • Invited
• [Presentation] 上皮性卵巣癌におけるmTOR complex 2 (mTORC2) の発現とその臨床的意義の検討 (2012)
  • Author(s): 久松武志、馬淵誠士、河野まひる、橋本香映、磯部晶、澤田健二郎、木村正
  • Organizer: 第52回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 東京
• [Presentation] 上皮性卵巣癌におけるmTOR complex 2 (mTORC2) の発現とその臨床的意義の検討 (2012)
  • Author(s): 久松武志、馬淵誠士、河野まひる、橋本香映、磯部晶、澤田健二郎、木村正
  • Organizer: 第64回日本産科婦人科学会学術講演会
  • Place of Presentation: 兵庫
• [Presentation] mTORC2 is a promising therapeutic target in epithelial ovarian cancer (2012)
  • Author(s): Takeshi, H. Seiji, M. Kae, H. Aki, I. Kenjiro, S. Tadashi, K.
  • Organizer: 102th Annual Meeting of the American Association for Cancer Reserch
  • Place of Presentation: Chicago, U.S.A.
• [Presentation] 子宮頸癌 IA2-IIB 期の骨盤リンパ節複数個転移症例に対する術後補助療法の検討（ CCRT と拡大放射線治療の比較 ） (2011)
  • Author(s): 馬淵誠士
  • Organizer: 第50回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 北海道
• [Presentation] 卵巣明細胞腺癌に対する新規抗癌剤Trabectedinの抗腫瘍効果および耐性化のメカニズムの検討 (2011)
  • Author(s): 馬淵誠士
  • Organizer: 第63回日本産科婦人科学会学術講演会
  • Place of Presentation: 大阪