The effect of the Notch inhibitor and a preclinical study for glioma stem cells

• Project/Area Number: 25861263
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: Kanazawa University
• Principal Investigator: TANAKA Shingo 金沢大学, 医学系, 協力研究員 (40507084)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 膠芽腫 / MRK-003 / Notch阻害剤 / グリオーマ幹細胞 / 膠芽腫幹細胞 / Notchシグナル

Outline of Final Research Achievements

Glioblastoma is the most malignant primary brain tumor in humans. The patients with glioblastoma have a uniformly poor prognosis. The significance of targeting glioblastoma-initiating cells (GICs) may be important for successful treatment of glioblastoma. In this study, we analyzed the effect of the Notch inhibitor MRK-003 on nine patient-derived GICs. MRK-003 suppressed GIC's proliferation and stemness maintenance, and promoted their apoptosis. Based on their sensitivities to MRK-003, the nine GICs were divided into “relatively sensitive” and “relatively resistant” GICs. The IC50(half maximal inhibitory concentration) of MRK003 in a set of GICs exhibited a negative correlation with CD44 and positive correlation with CD133. Our study suggested that MRK-003 may exhibit significant therapeutic potential for GICs with CD44-high and CD133-low expression.

Research Products

• [Journal Article] Strong therapeutic potential of γ-secretase inhibitor MRK003 for CD44-high and CD133-low glioblastoma initiating cells. (2015)
  • Author(s): Tanaka S, Nakada M, Yamada D, Nakano I, Todo T, Ino Y, Hoshii T, Tadokoro Y, Ohta K, Ali MA, Hayashi Y, Hamada J, Hirao A.
  • Journal Title: J Neurooncol. Volume: 121 Issue: 2 Pages: 239-50
  • DOI: 10.1007/s11060-014-1630-z
  • Peer Reviewed / Open Access
• [Journal Article] Cerebral Infarction Related to Carmustine Wafers in Glioblastoma: A Case Report (2015)
  • Author(s): Nakada M, Tanaka S, Oishi M, Miyashita K, Misaki K, Mohri M, Hayashi Ya, Uchiyama N, Watanabe T, Hayashi Yu
  • Journal Title: NMC Case Report Journal Volume: 2 Issue: 1 Pages: 36-39
  • DOI: 10.2176/nmccrj.2014-0080
  • NAID: 130004698823
  • ISSN: 2188-4226
  • Peer Reviewed
• [Journal Article] Epithelioid glioblastoma arising from pleomorphic xanthoastrocytoma with the BRAF V600E mutation. (2014)
  • Author(s): Tanaka S, Nakada M, Nobusawa S, Suzuki SO, Sabit H, Miyashita K, Hayashi Y.
  • Journal Title: Brain Tumor Pathology Volume: 31 Issue: 3 Pages: 172-6
  • DOI: 10.1007/s10014-014-0192-2
  • Peer Reviewed
• [Journal Article] Loss of Tsc1 accelerates malignant gliomagenesis when combined with oncogenic signals. (2014)
  • Author(s): Yamada D, Hoshii T, Tanaka S, Hegazy AM, Kobayashi M, Tadokoro Y, Ohta K, Ueno M, Ali MAE, Hirao A.
  • Journal Title: J Biochem. Volume: 155 Issue: 4 Pages: 227-33
  • DOI: 10.1093/jb/mvt112
  • Peer Reviewed
• [Presentation] 膠芽腫幹細胞株に対するγ‐セクレターゼ阻害剤MRK003の効果 (2013)
  • Author(s): 田中慎吾、中田光俊、中野伊知郎、藤堂具紀、稲生靖、林裕、濵田潤一郎、平尾敦
  • Organizer: 第72回日本脳神経外科学会総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Notch阻害による膠芽腫幹細胞の制御 (2013)
  • Author(s): 田中慎吾、中田光俊、山田大祐、中野伊知郎、藤堂具紀、稲生靖、林裕、濵田潤一郎、平尾敦
  • Organizer: 第14回日本分子脳神経外科学会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Strong therapeutic potential of γ-secretase inhibitor MRK003 for GBM stem-like cells with high CD44 and low CD133 expression (2013)
  • Author(s): Shingo Tanaka, Mitsutoshi Nakada, Daisuke Yamada, Ichiro Nakano, Tomoki Todo, Yutaka Hayashi, Jun-ichiro Hamada, Atsushi Hirao
  • Organizer: 4th Quadrennial Meeting of the World Federation of Neuro-Oncology
  • Place of Presentation: San Francisco, USA
• [Presentation] Mesenchymal type GBMに対するNotch阻害剤の有効性 (2013)
  • Author(s): 田中慎吾、中田光俊、山田大祐、中野伊知郎、藤堂具紀、稲生靖、林裕、濵田潤一郎、平尾敦
  • Organizer: 第31回日本脳腫瘍学会
  • Place of Presentation: 宮崎シーガイア