Development of new molecular target therapy for IGF1 signaling pathway in glioma stem cells

• Project/Area Number: 26830082
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Keio University
• Principal Investigator: Satoru Osuka 慶應義塾大学, 医学部, 特別研究員(PD) (70724574)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 脳腫瘍幹細胞 / グリオーマ / 放射線抵抗性 / IGF1 / 細胞接着 / FoxO3a

Outline of Final Research Achievements

Glioblastoma (GBM) is the most aggressive brain tumor in adult. Poor prognosis of patients with GBM is due to glioma stem cells (GSCs) that have characteristics of stem cells, with high chemo- and radio-resistance. In my prior study, we revealed a role for IGF1 signaling activation in the radioresistance of GSCs. In this study, we analyzed the detailed of IGF1 downstream signaling to implicate radioresistance in GSCs.
We found that: (i) adaptation of mouse GSCs to repeated irradiation increases cell-cell adhesion and radioresistance, (ii) recurrent human GBM display an increase in the expression of adhesion-related genes in microarray analysis, (iii) fractionated irradiation induces a gradual upregulation of N-cad in surviving GSCs.

Research Products

• [Int'l Joint Research] Emory University(米国)
• [Int'l Joint Research] The Hospital for Sick Children(Canada)
• [Journal Article] Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. (2016)
  • Author(s): Thompson EM, Hielscher T, Bouffet E, Remke M, Luu B, Kagawa N, Hashimoto N, Jabado N, Shih DJ, Kijima N, Northcott PA, Kool M, Jones DT, Chan JA, Hawkins CE, Tabori U, Drake J, Kulkarni A, Dirks P, Rutka JT, Korshunov A, Pfister SM, Packer RJ, Ramaswamy V, Taylor MD.
  • Journal Title: Lancet Oncol. Volume: 17(4) Issue: 4 Pages: 484-495
  • DOI: 10.1016/s1470-2045(15)00581-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolonged survival in pancreatic cancer patients with increased regucalcin gene expression: Overexpression of regucalcin suppresses the proliferation in human pancreatic cancer MIA PaCa-2 cells in vitro (2016)
  • Author(s): Yamaguchi M, Osuka S, Weitzmann MN, El-Rayes BF, Shoji M, Murata T
  • Journal Title: International Journal of Oncology Volume: 48 Issue: 5 Pages: 1955-1964
  • DOI: 10.3892/ijo.2016.3409
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Integrated analysis identifies different metabolic signatures for tumor-initiating cells in a murine glioblastoma model (2014)
  • Author(s): Saga I, Shibao S, Okubo J, Osuka S, Kobayashi Y, Yamada S, Fujita S, Urakami K, Kusuhara M, Yoshida K, Saya H, Sampetrean O
  • Journal Title: Neuro Oncol. Volume: 16 Issue: 8 Pages: 1048-1056
  • DOI: 10.1093/neuonc/nou096
  • Peer Reviewed / Open Access
• [Journal Article] IGF2 Preserves Osteosarcoma Cell Survival by Creating an Autophagic State of Dormancy That Protects Cells against Chemotherapeutic Stress (2014)
  • Author(s): Shimizu T, Sugihara E, Yamaguchi-Iwai S, Tamaki S, Koyama Y, Kamel W, Ueki A, Ishikawa T, Chiyoda T, Osuka S, Onishi N, Ikeda H, Kamei J, Matsuo K, Fukuchi Y, Nagai T, Toguchida J, Toyama Y, Muto A, Saya H
  • Journal Title: Cancer Res Volume: 74 Issue: 22 Pages: 6531-6541
  • DOI: 10.1158/0008-5472.can-14-0914
  • Peer Reviewed
• [Presentation] Does cell-cell adhesion play a role in adaptive radiation-resistance of glioma stem cells? (2015)
  • Author(s): Osuka S, Sampetrean O, Onishi N, Saya H, Van Meir EG
  • Organizer: Postdoc Research Symposium in Emory University
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2015-05-18
  • Int'l Joint Research
• [Presentation] 脳腫瘍幹細胞研究に基づく新規治療戦略の考案 (2014)
  • Author(s): 大須賀覚、サンペトラ オルテア、松村 明、佐谷秀行
  • Organizer: 第52回日本癌治療学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市西区）
  • Year and Date: 2014-08-28
  • Invited
• [Presentation] Achieving high spatial resolution in multi-color fluorescence imaging of brain tumor matrix components (2014)
  • Author(s): Osuka S, Sampetrean O, Onishi N, Matsumura A, Saya H
  • Organizer: The 29th Japan Neurosurgery English Forum
  • Place of Presentation: 学術総合センター（東京都千代田区）
  • Year and Date: 2014-07-25