Development of new treatment targeting vascular endothelial cell related to cancer stem cell in gynocologic cancer.

• Project/Area Number: 16K20176
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: The University of Tokyo
• Principal Investigator: Mori-Uchino Mayuyo 東京大学, 医学部附属病院, 助教 (30570452)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 癌幹細胞 / 血管内皮細胞 / 血管新生阻害剤 / MDM2 / VEGF阻害剤 / 腫瘍内血管内皮細胞

Outline of Final Research Achievements

MDM2, a ubiquitin ligase, suppresses wild type TP53 via proteasome-mediated degradation. We evaluated the prognostic and therapeutic value of MDM2 in ovarian clear cell carcinoma. The anti-tumor effects of RG7112 in vivo were examined in a mouse xenograft model. MDM2 expression was significantly higher in clear cell carcinoma than in ovarian high-grade serous carcinoma and normal tissues. High MDM2 expression determined by microarray was significantly associated with poor progression-free survival and poor overall survival. Notably, RG7112 significantly suppressed cell viability in clear cell carcinoma cell lines with wild type TP53. RG7112 also strongly induced apoptosis, increased TP53 phosphorylation, and stimulated expression of the proapoptotic protein PUMA. Similarly, siRNA knockdown of MDM2 induced apoptosis. Finally, RG7112 significantly reduced the tumor volume of xenografted RMG-I clear cell carcinoma cells, and the density of microvessels.

Research Products

• [Journal Article] Therapeutic significance of targeting survivin in cervical cancer and possibility of combination therapy with TRAIL (2018)
  • Author(s): Nakamura H, Taguchi A, Kawana K, Baba S, Kawata A, Yoshida M, Fujimoto A, Ogishima J, Sato M, Inoue T, Nishida H, Furuya H, Yamashita A, Eguchi S, Tomio K, Mori-Uchino M, Adachi K, Arimoto T, Wada-Hiraike O, Oda K, Nagamatsu T, Osuga Y, Fujii T
  • Journal Title: Oncotarget Volume: 9 Issue: 17 Pages: 13451-13461
  • DOI: 10.18632/oncotarget.24413
  • Peer Reviewed / Open Access
• [Journal Article] Recent advances in targeting DNA repair pathways for the treatment of ovarian cancer and their clinical relevance (2017)
  • Author(s): Oda Katsutoshi、Tanikawa Michihiro、Sone Kenbun、Mori-Uchino Mayuyo、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: International Journal of Clinical Oncology Volume: 22 Issue: 4 Pages: 611-618
  • DOI: 10.1007/s10147-017-1137-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oncogenic histone methyltransferase EZH2: A novel prognostic marker with therapeutic potential in endometrial cancer. (2017)
  • Author(s): Oki S, Sone K, Oda K, Hamamoto R, Ikemura M, Maeda D, Takeuchi M, Tanikawa M, Mori-Uchino M, Nagasaka K, Miyasaka A, Kashiyama T, Ikeda Y, Arimoto T, Kuramoto H, Wada-Hiraike O, Kawana K, Fukayama M, Osuga Y, Fujii T.
  • Journal Title: Oncotarget Volume: in press Issue: 25 Pages: 40402-40411
  • DOI: 10.18632/oncotarget.16316
  • NAID: 120007089062
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] STAT3 activity regulates sensitivity to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cervical cancer cells. (2016)
  • Author(s): Nakamura H, Taguchi A, Kawana K, Kawata A, Yoshida M, Fujimoto A, Ogishima J, Sato M, Inoue T, Nishida H, Furuya H, Tomio K, Eguchi S, Mori-Uchino M, Yamashita A, Adachi K, Arimoto T, Wada-Hiraike O, Oda K, Nagamatsu T, Osuga Y, Fujii T.
  • Journal Title: Int J Oncol Volume: 49 Issue: 5 Pages: 2155-2162
  • DOI: 10.3892/ijo.2016.3681
  • Peer Reviewed / Open Access
• [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] Measurement of endometrial thickness by transvaginal ultrasonography to predict pathological response to medroxyprogesterone acetate in patients with grade 1 endometrioid adenocarcinoma. (2016)
  • Author(s): Sato M, Arimoto T, Kawana K, Miyamoto Y, Ikeda Y, Tomio K, Tanikawa M, Sone K, Mori-Uchino M, Tsuruga T, Nagasaka K, Adachi K, Matsumoto Y, Oda K, Osuga Y, Fujii T.
  • Journal Title: Mol Clin Oncol. Volume: 4 Pages: 492-496
  • Open Access / Acknowledgement Compliant