Target therapy of glutamine metabolism in glioma with IDH mutation

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10864
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Kobe University
• Principal Investigator: Tanaka Kazuhiro 神戸大学, 医学研究科, 助教 (70467661)
• Co-Investigator(Kenkyū-buntansha): 篠山 隆司 神戸大学, 医学部附属病院, 講師 (10379399) ; 水川 克 神戸大学, 医学部附属病院, 非常勤講師 (80403260)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: IDH変異 / グルタミン代謝 / グリオーマ

Outline of Final Research Achievements

Isocitrate dehydrogenase 1 (IDH1) gene mutations are frequently observed in low-grade glioma and strongly associated with the accumulation of 2-hydroxyglutarate (2HG). A metabolomic analysis demonstrated higher levels of 2HG in IDH1 mutant glioma cells and surgical tissues. Interestingly, glutamate levels were significantly decreased in IDH1 mutant gliomas. Through an analysis of metabolic enzyme genes in glutamine pathways, the expressions of branched-chain amino acid transaminase 1 (BCAT1) were reduced and glutamate dehydrogenase (GDH) levels were elevated in IDH1 mutant gliomas, suggesting that IDH1 mutant glioma cells are highly dependent on the glutaminolysis. There was, however, no significant difference in the growth and survival between IDH1 wild-type and mutant glioma cells treated with glutamine deprivation as well as glutaminase(GLS) and GDH inhibitor.

Free Research Field

脳神経外科

Academic Significance and Societal Importance of the Research Achievements

浸潤性の低悪性度グリオーマ、および低悪性度グリオーマから悪性化した続発性膠芽腫の50-80％にイソクエン酸デヒドロゲナーゼ（IDH）の変異が報告されている。しかし、IDH 変異によって特異的に産生される2-ヒドロキシグルタル酸（2HG）の分子機能や細胞内代謝変化については不明な点が多い。本研究ではグリオーマ培養細胞や手術で得られた組織標本を用いた代謝物解析によって報告してきたグルタミン代謝機構の変化がIDH変異型グリオーマの生存、増殖、他の代謝機構に及ぼす影響を分子生物学的手法などを用いて検証した。未だ効果的な治療法のないグリオーマに対して新しい治療法（個別化治療）の一助になると思われる。