Establishment of novel molecular targeted therapy focused on apoptosis induction in ovarian clear cell adenocarcinoma

• Project/Area Number: 15H06173
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Obstetrics and gynecology
• Research Institution: The University of Tokyo
• Principal Investigator: Kashiyama Tomoko 東京大学, 医学部附属病院, 助教 (70755719)
• Project Period (FY): 2015-08-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: PI3K/mTOR阻害薬 / 卵巣明細胞癌 / アポトーシス / 婦人科悪性腫瘍 / 卵巣癌 / PI3K/mTOR阻害剤 / 分子標的薬 / 癌 / 分子標的治療 / 卵巣明細胞腺癌 / 婦人科腫瘍

Outline of Final Research Achievements

We confirmed that a PI3K / mTOR inhibitor suppressed the growth signal and showed the antitumor effect in a concentration-dependent manner in ovarian clear cell adenocarcinoma cell line. In addition, the the PI3K/mTOR inhibitor leaded apoptosis in ovarian clear cell adenocarcinoma cell lines with wild type TP53 more effectively than that with TP53 mutation. The absence of TP53 mutation may be a promising biomarker for using PI3K / mTOR inhibitors for patients with ovarian clear cell adenocarcinoma. We are investigating whether combination with PI3K/mTOR inhibitor and other molecular target drugs or anticancer drugs can induce more efficient apoptosis, and MDM 2 inhibitors and MEK inhibitors are considered to be promising candidates.

Research Products

• [Journal Article] Synergistic antitumor effects of combination of PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging. (2016)
  • Author(s): Inaba K, Oda K, Aoki K, Sone K, Ikeda Y, Miyasaka A, Kashiyama T, Fukuda T, Makii C, Arimoto T, Wada-Hiraike O, Kawana K, Yano T, Osuga Y, Fujii T
  • Journal Title: Oncotarget Volume: 7 Issue: 20 Pages: 29577-29591
  • DOI: 10.18632/oncotarget.8807
  • NAID: 120005820854
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of TP53 and PI3K signaling pathways as molecular targets in gynecologic malignancies. (2016)
  • Author(s): Oda K, Ikeda Y, Kashiyama T et al.
  • Journal Title: The journal of obstetrics and gynecological research Volume: 42 Issue: 7 Pages: 757-62
  • DOI: 10.1111/jog.13018
  • Peer Reviewed
• [Journal Article] MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53. (2016)
  • Author(s): Makii C, Oda K, Ikeda Y, Sone K, Hasegawa K, Uehara Y, Nishijima A, Asada K, Koso T, Fukuda T, Inaba K, Oki S, Machino H, Kojima M, Kashiyama T, Mori-Uchino M, Arimoto T, Wada-Hiraike O, Yano KK, Fujiwara K, Aburatani H, Osuga Y, Fujii T.
  • Journal Title: Oncotarget Volume: 7 Issue: 46 Pages: 75328-75338
  • DOI: 10.18632/oncotarget.12175
  • Peer Reviewed / Open Access
• [Journal Article] 卵巣癌新規治療薬候補PI3K/mTOR 阻害薬DS–7423によるTP53依存性アポトーシス誘導能の活性化 (2015)
  • Author(s): 織田克利、樫山智子
  • Journal Title: 産科と婦人科 Volume: vol.10 Pages: 1113-1118