New treatment strategy for resistant brain tumors targeting brain tumor stem cell

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K19954
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: TAMURA Kaoru 東京医科歯科大学, 医学部附属病院, 助教 (70629146)
• Research Collaborator: SHAH Khalid ; WAKIMOTO Hiroaki ; FURUHASHI Yaeko
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: brain tumor / glioma stem cell / microRNA

Outline of Final Research Achievements

Recent evidence suggests that a glioma stem cell (GSC) subpopulation may determine the biological behavior of tumors, including resistance to therapy. microRNAs, which have a central role in the regulation of gene expression, might play a fundamental role in tumorigenesis, controlling cell proliferation and apoptosis. We showed that microRNA7 (miR7) is downregulated in GSC and expression of miR7 in glioma cells results in downregulation of EGFR and p-Akt. This leads to an upregulation of DR5, priming resistant GBM cells to TRAIL-induced apoptotic cell death. In vivo, an administration of AAV-miR7 significantly decreases tumor volumes, upregulates DR5, and enables TRAIL to eradicate GBM generated from patient-derived TRAIL-resistant GSC, significantly improving survival of mice. This study identifies the unique role of miR7 in linking cell proliferation to death pathways that can be targeted simultaneously to eliminate GBM, thus presenting a promising strategy for treating GBM.

Free Research Field

脳神経外科

Academic Significance and Societal Importance of the Research Achievements

脳腫瘍の治療抵抗性に関わることが示唆されている脳腫瘍幹細胞をターゲットとして研究を行い、脳腫瘍幹細胞で発現が抑制されているmicroRNAとその標的分子を同定した。これにより、悪性脳腫瘍の治療抵抗性の分子機序の一端を解明することができた。microRNAとTRAILを用いた治療が、膠芽腫を代表とする悪性脳腫瘍患者の治療効果の改善や新規創薬研究への応用に大きく貢献できる可能性が示唆された。