Development of combined cellular and molecular target-directed therapies for glioblastoma

• Project/Area Number: 26893096
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Neurosurgery
• Research Institution: Kanazawa University
• Principal Investigator: Pyko Ilya 金沢大学, がん進展制御研究所, 研究員 (00731853)
• Project Period (FY): 2014-08-29 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: glioblastoma / temozolomide / mesenchymal stem cells / GSK 3β

Outline of Final Research Achievements

We investigated whether mesenchymal stem cells (MSCs) transplantation benefits to treatment of glioblastoma (GBM) by enhancing anti-tumor effect in combination with GSK3β inhibitors and temozolomide (TMZ). Our experiments showed that transplantation of MSCs and GSK3β inhibition synergizes for treatment of experimental GBM and that MSCs co-cultured with GBM cells participate in regulation of GBM stemness similar to that observed under GSK3β inhibition. We also examined the interaction between patient-derived GBM stem-like cells and adipose tissue-derived MSCs in the presence and absence of GSK3β inhibition and TMZ and its influence on GBM stemness. We found that the interaction of MSCs with GBM stem-like cells is enhanced by a combined treatment by GSK3β inhibitor. These observations encouraged us to continue investigation of the biological mechanisms by which MSCs regulate GBM stemness under the control by GSK3β addressing the role of cell-to-cell interactions and local signals.

Research Products

• [Journal Article] Glycogen synthase kinase 3β sustains invasion of glioblastoma via the focal adhesion kinase, Rac1 and c-Jun N-terminal kinase-mediated pathway. (2015)
  • Author(s): Chikano Y, Domoto T, Furuta T, Sabit H, Kitano-Tamura A, Ilya V. Pyko, Takino T, Sai Y, Hayashi Y, Sato H, Miyamoto K, Nakada M, MinamotoT.
  • Journal Title: Molecular Cancer Therapeutics Volume: 14 Issue: 2 Pages: 564-574
  • DOI: 10.1158/1535-7163.mct-14-0479
  • Peer Reviewed / Open Access
• [Presentation] 大腸がん糖代謝特性におけるGSK3βの役割 (2015)
  • Author(s): 堂本 貴寛, 紙 健次郎, 廣瀬 まゆみ, Ilya V. Pyko, 土原 一哉, 曽我 朋義, 江角 浩安, 源 利成
  • Organizer: 第3回がんと代謝研究会
  • Place of Presentation: 金沢市・県立音楽堂
  • Year and Date: 2015-07-16
• [Presentation] Glycogen synthase kinase 3β inhibition sensitizes human glioblastoma cells to temozolomide by affecting O6-methylguanine DNA methyltransferase promoter methylation via c-Myc signaling (2015)
  • Author(s): Ilya V. Pyko, Mitsutoshi Nakada, Hemragul Sabit, Lei Teng, Natsuki Furuyama, Yutaka Hayashi, Kazuyuki Kawakami, Toshinari Minamoto, Аliaksandr S. Fedulau and Jun-ichiro Hamada
  • Organizer: Japan Cancer Association (JCA) Symposium
  • Place of Presentation: Kanazawa, Ishikawa, Japan
  • Year and Date: 2015-01-21 – 2015-01-22