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Target therapy of glutamine metabolism in glioma with IDH mutation

Research Project

Project/Area Number 17K10864
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurosurgery
Research InstitutionKobe 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
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsIDH変異 / グルタミン代謝 / グリオーマ / 一炭素代謝 / 2-hydroxyglutarate / IDH変異 / glioma / gluamine / metabolism / target therapy
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.

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。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (15 results)

All 2019 2018 2017

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 3 results) Presentation (10 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results)

  • [Journal Article] Tumor-associated macrophage related interleukin-6 in cerebrospinal fluid as a prognostic marker for glioblastoma.2019

    • Author(s)
      Hori T, Sasayama T, Tanaka K, Koma YI, Nishihara M, Tanaka H, Nakamizo S, Nagashima H, Maeyama M, Fujita Y, Yokozaki H, Hirose T, Kohmura E.
    • Journal Title

      J Clin Neurosci

      Volume: 68 Pages: 281-289

    • DOI

      10.1016/j.jocn.2019.07.020

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] DWI for Monitoring the Acute Response of Malignant Gliomas to Photodynamic Therapy.2019

    • Author(s)
      Fujita Y, Sasayama T, Tanaka K, Kyotani K, Nagashima H, Kohta M, Kimura H, Fujita A, Kohmura E.
    • Journal Title

      AJNR Am J Neuroradiol

      Volume: 40 Pages: 2045-2051

    • DOI

      10.3174/ajnr.a6300

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MicroRNA regulating stanniocalcin-1 is a metastasis and dissemination promoting factor in glioblastoma2019

    • Author(s)
      Sakata Junichi、Sasayama Takashi、Tanaka Kazuhiro、Nagashima Hiroaki、Nakada Mitsutoshi、Tanaka Hirotomo、Hashimoto Naoya、Kagawa Naoki、Kinoshita Manabu、Nakamizo Satoshi、Maeyama Masahiro、Nishihara Masamitsu、Hosoda Kohkichi、Kohmura Eiji
    • Journal Title

      Journal of Neuro-Oncology

      Volume: 142 Issue: 2 Pages: 241-251

    • DOI

      10.1007/s11060-019-03113-2

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Embryonal brain tumor with unknown primary lesion and massive cerebrospinal fluid dissemination: A case report.2018

    • Author(s)
      Tanaka H, Yamamoto D, Ikeda M, Morikawa M, Ueda K, Tanaka K, Sasayama T, Kohmura E.
    • Journal Title

      J Clin Neurosci.

      Volume: 54 Pages: 125-128

    • DOI

      10.1016/j.jocn.2018.04.046

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Myo-inositol concentration in MR spectroscopy for differentiating high grade glioma from primary central nervous system lymphoma.2018

    • Author(s)
      Nagashima H, Sasayama T, Tanaka K, Kyotani K, Sato N, Maeyama M, Kohta M, Sakata J, Yamamoto Y, Hosoda K, Itoh T, Sasaki R, Kohmura E.
    • Journal Title

      J Neurooncol.

      Volume: 136 Issue: 2 Pages: 317-326

    • DOI

      10.1007/s11060-017-2655-x

    • NAID

      120006769211

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Photodynamic therapy (PDT) for malignant brain tumors2019

    • Author(s)
      Tanaka K, Sasayama T, Fujita Y, Nakai T and Kohmura E
    • Organizer
      24th Annual Scientific Meeting and Education Day of the society for Neuro-Oncology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 悪性脳腫瘍に対する光線力学療法 (PDT)の治療経験2019

    • Author(s)
      田中 一寛、篠山 隆司、中井 友昭、甲村 英二
    • Organizer
      第24回日本脳腫瘍の外科学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Gliosarcoma with primitive neuronal component の1 例2019

    • Author(s)
      田中一寛、篠山隆司、塩見亮司、神保直江、伊藤智雄、廣瀬隆則、甲村英二
    • Organizer
      第37回日本脳腫瘍病理学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Magnetic resonance spectroscopy of glutamate and 2-hydroxyglutarate in patients with the IDH1 mutant glioma: A prospective validation study2018

    • Author(s)
      Tanaka K, Sasayama T, Nagashima H, Maeyama M, and Kohmura E
    • Organizer
      第22回国際脳腫瘍治療研究会議 (ICBTRT)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] カルムスチン脳内留置用剤(ギリアデル)の治療効果と問題点2018

    • Author(s)
      田中一寛、篠山隆司、前山昌博、藤田祐一、伊藤智雄、甲村英二
    • Organizer
      日本脳神経外科学会第77回学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Glutamine deprivation alters one-carbon metabolism to maintain glioma cell survival2018

    • Author(s)
      Tanaka K, Sasayama T, Uno T, Maeyama M, Fujita Y, Nagashima H, Irino Y, and Kohmura E
    • Organizer
      23rd Annual Scientific Meeting and Education Day of the society for Neuro-Oncology (SNO)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] グルタミン飢餓状態のグリオーマ細胞における一炭素代謝の調整と新規治療標的の探索2018

    • Author(s)
      田中一寛、篠山隆司、宇野滝子、前山昌博、藤田祐一、入野康宏、甲村英二
    • Organizer
      第36回日本脳腫瘍学会
    • Related Report
      2018 Research-status Report
  • [Presentation] 術前MR SpectroscopyによるグリオーマIDH1遺伝子変異予測の検討2018

    • Author(s)
      田中一寛、篠山隆司、長嶋宏明、前山昌博、甲村英二
    • Organizer
      第47回日本神経放射線学会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] MR Spectroscopyを用いた2HG測定によるIDH遺伝子変異陽性脳幹グリオーマ診断の有用性2017

    • Author(s)
      田中一寛、長嶋宏明、篠山隆司、前山昌博、佐藤直子、京谷勉輔、伊藤智雄、甲村英二
    • Organizer
      日本脳神経外科学会第76回学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 脳幹グリオーマに対するMR Spectroscopyを用いたIDH遺伝子変異診断の有用性2017

    • Author(s)
      田中一寛、長嶋宏明、篠山隆司、前山昌博、佐藤直子、小山淳二、河村淳史、京谷勉輔、伊藤智雄、甲村英二
    • Organizer
      第35回日本脳腫瘍学会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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