Development of novel therapy with inhibition of Notch signaling for glioma stem cells

• Project/Area Number: 15K19980
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: Toho University
• Principal Investigator: SAITO Norihiko 東邦大学, 医学部, 講師 (60459766)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 神経膠腫 / グリオーマ幹細胞 / 神経膠芽腫 / Notch / 新規治療 / 分子標的治療 / γ-セクレターゼ阻害剤 / γセクレターゼ阻害薬 / 新規分子標的治療

Outline of Final Research Achievements

The Notch signaling is an evolutionarily conserved pathway that plays an important role in multiple cellular processes. We investigated the effects of Notch inhibition in glioma stem cell (GSC) populations using γ secretase inhibitors. Drug cytotoxicity testing showed differential growth responses to the inhibitors. Responder GSCs had an enriched proneural gene signature in comparison to nonresponders. Analysis of TCGA dataset identified a group (43.9%) of tumors with proneural signature showing high Notch pathway activation. Inhibition of Notch pathway by γ secretase inhibitor treatment attenuated proliferation and self-renewal of responder GSCs and induces both neuronal and astrocytic differentiation. Our results suggest that proneural GBM characterized by high Notch pathway activation may exhibit greater sensitivity to γ secretase inhibitor treatment, holding a promise to improve the efficiency of current glioma therapy.

Research Products

• [Presentation] 神経膠芽腫におけるLMO2のSTAT3を介した細胞増殖機構の検討 (2016)
  • Author(s): 齋藤紀彦, 青木和哉, 平井希, 藤田聡, 伊古田雅史, 岩間淳哉, 中山晴雄, 林盛人, 伊藤圭介, 櫻井貴敏, 岩渕聡
  • Organizer: 第34回日本脳腫瘍学会学術集会
  • Place of Presentation: 富士屋ホテル（山梨県甲府市）
  • Year and Date: 2016-12-05
• [Presentation] Bevacizumab-induced normalization of tumor vasculature in glioblastoma (2016)
  • Author(s): Saito N, Aoki K, Hirai N, Fujita S, Iwama J, Nakayama H, Hayashi M, Ito K, Sakurai T, Iwabuchi S
  • Organizer: 21st Annual Meeting and Education Day of The Society for Neuro-Oncology(SNO2016)
  • Place of Presentation: Scottsdale, Arizona, USA
  • Year and Date: 2016-11-19
  • Int'l Joint Research
• [Presentation] 神経膠芽腫におけるLMO2発現とその機能解析 (2016)
  • Author(s): 齋藤紀彦, 青木和哉, 平井希, 藤田聡, 伊古田雅史, 岩間淳哉, 中山晴雄, 林盛人, 伊藤圭介, 櫻井貴敏, 岩渕聡
  • Organizer: 日本脳神経外科学会第75回学術総会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-09-29
• [Presentation] Levetiracetam downregulates O6-Methylguanine DNA methyltransferase expression and sensitizes temozolomide-resistant glioma cells (2016)
  • Author(s): Saito N, Aoki K, Hirai N, Fujita S, Iwama J, Nakayama H, Hayashi M, Ito K, Sakurai T, Iwabuchi S
  • Organizer: 3th Asian Society for Neuro-Oncology Meeting (ASNO)
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2016-09-12
  • Int'l Joint Research
• [Presentation] 神経膠芽腫に対するベバシズマブ療法による腫瘍血管正常化作用の検討 (2016)
  • Author(s): 齋藤紀彦, 青木和哉, 平井希, 岩間淳哉, 藤田聡, 中山晴雄, 林盛人, 大原関利章, 高橋啓, 岩渕聡
  • Organizer: 第34回日本脳腫瘍病理学会学術集会
  • Place of Presentation: 東京カンファレンスセンター有明（東京都江東区）
  • Year and Date: 2016-05-28
• [Presentation] グリオーマ幹細胞におけるOlig2の機能解析と分子標的治療への応用 (2015)
  • Author(s): 齋藤紀彦、青木和哉、平井希、平元侑、藤田聡、中山晴雄、林盛人、木村仁、伊藤圭介、櫻井貴敏、岩渕聡
  • Organizer: 第33回日本脳腫瘍学会学術集会
  • Place of Presentation: グランドプリンスホテル京都（京都府京都市）
  • Year and Date: 2015-12-07
• [Presentation] A proneural signature profile predicts resistance to bevacizumab therapy in glioblastoma (2015)
  • Author(s): Norihiko Saito, Kazuya Aoki, Nozomi Hirai, Satoshi Fujita, Yu Hiramoto, Haruo Nakayama, Keisuke Ito, Takatoshi Sakurai, Satoshi Iwabuchi
  • Organizer: 2015 Society for Neuro-Oncology Annual Scientific Meeting and Education Day
  • Place of Presentation: San Antonio, USA
  • Year and Date: 2015-11-21
  • Int'l Joint Research
• [Presentation] 神経膠芽腫におけるNotchシグナル発現解析 (2015)
  • Author(s): 齋藤紀彦、青木和哉、平井希、藤田聡、平元侑、中山晴雄、林盛人、伊藤圭介、木村仁、櫻井貴敏、大原関利章、高橋啓、岩渕聡
  • Organizer: 日本脳神経外科学会 第74回学術総会
  • Place of Presentation: ロイトン札幌（北海道札幌市）
  • Year and Date: 2015-10-14
• [Presentation] 神経膠芽腫におけるNotch 発現がbevacizumab療法に対する治療反応性に及ぼす影響 (2015)
  • Author(s): 齋藤紀彦、石井匡
  • Organizer: 第146回東邦医学会
  • Place of Presentation: 東邦大学（東京都大田区）
  • Year and Date: 2015-06-19
• [Remarks] 東邦大学医療センター大橋病院脳神経外科
  • URL: http://www.ohashi-neurosurgery.com/
• [Remarks] 東邦大学医療センター大橋病院脳神経外科
  • URL: http://www.lab.toho-u.ac.jp/med/ohashi/neurosurgery/