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Therapeutic strategy for IDH mutant gliomas with DNA hypermutation phenotype

Research Project

Project/Area Number 19K09488
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56010:Neurosurgery-related
Research InstitutionYokohama City University

Principal Investigator

TATEISHI Kensuke  横浜市立大学, 附属病院, 助教 (00512055)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords脳腫瘍 / 神経膠腫 / IDH変異 / DNA修復異常 / NAD+ / テモゾロミド / アルキル化剤 / グリオーマ / IDH1変異 / DNA高変異 / NAD代謝 / 悪性転化 / 新規治療法 / DNA hypermutation / Target therapy
Outline of Research at the Start

本研究では申請者らが樹立した内因性IDH変異神経膠腫細胞株を用いてIDH 変異神経膠腫の悪性化を引き起こす機序の解明ととともに, 悪性化回避を目指した治療法の開発を行う. またDNA高変異による悪性化をきたした際には免疫チェックポイント阻害剤を用いた治療法が臨床的に期待されているが, 神経膠腫において根拠となる基礎研究結果は乏しいのが現状である. そこで世界に先駆けて樹立したDNA高変異状態を呈した内因性IDH 変異神経膠腫細胞株を用いることでDNA高変異状態下における免疫機構を解明するとともに, 免疫チェックポイント阻害剤を用いた治療法を基礎研究レベルで提唱し臨床応用につなげることを目指す.

Outline of Final Research Achievements

We performed in vitro and in vivo experiments to elucidate the mechanism of DNA hypermutation and malignant transformation of gliomas after alkylating agent treatment. We also explored therapeutic targets for gliomas with DNA hypermutation. In this study, we could establish endogenous and exogenous IDH gliomas with DNA hypermutation. Using these models, we investigated the effects of DNA hypermutation on tumor progression. We also explored for therapeutic target molecules. We published peer reviewed international journals to demonstrate these data.

Academic Significance and Societal Importance of the Research Achievements

IDH変異神経膠腫は30-40代の働き盛りの世代に好発して発症する疾患である。治療はアルキル化剤テモゾロミドを用いることが多いが、治療に伴うDNA修復異常が問題となっている。本研究ではDNA修復異常がもたらす影響を調べたところ治療によって生じるDNA高変異は腫瘍の増悪に及ぼす影響は強くないことをモデルを通じて明らかにした。このことは治療によるDNAレベルの異常は必ずしも患者さんの治療計画に影響を及ぼさないことが明らかになった。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (28 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (2 results) Journal Article (14 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 14 results,  Open Access: 8 results) Presentation (12 results) (of which Invited: 4 results)

  • [Int'l Joint Research] Massachusetts General Hospital/Brigham Women's Hospital(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] Harvard University/New York University(米国)

    • Related Report
      2019 Research-status Report
  • [Journal Article] HSP90 inhibition overcomes resistance to molecular targeted therapy in BRAFV600E mutant high-grade glioma2022

    • Author(s)
      Sasame J, Ikegaya N, Kawazu M, Natsumeda M, Hayashi T, Isoda M, Satomi K, Tomiyama A, Oshima A, Honma H, Miyake Y, Takabayashi K, Nakamura T, Ueno T, Matsushita Y, Iwashita H, Kanemaru Y, Murata H, Ryo A, Terashima K, Yamanaka S, Fujii Y, Mano H, Komori T, Ichimura K, Cahill DP, Wakimoto H, Yamamoto T, Tateishi K.
    • Journal Title

      Clin Cancer Res

      Volume: 印刷中 Issue: 11 Pages: 2425-2439

    • DOI

      10.1158/1078-0432.ccr-21-3622

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] 特集 グリオーマ-現在の常識と近未来のスタンダード Ⅰ知っておくべきグリオーマの生物学的基礎知識 グリオーマの細胞生物学2021

    • Author(s)
      立石 健祐
    • Journal Title

      Neurological Surgery 脳神経外科

      Volume: 49 Issue: 3 Pages: 476-484

    • DOI

      10.11477/mf.1436204419

    • ISSN
      0301-2603, 1882-1251
    • Year and Date
      2021-05-10
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A rapid genotyping panel for detection of primary central nervous system lymphoma2021

    • Author(s)
      Gupta Mihir、Tateishi K et al.
    • Journal Title

      Blood

      Volume: 138 Issue: 5 Pages: 382-386

    • DOI

      10.1182/blood.2020010137

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Primary central nervous system lymphoma: clinicopathological and genomic insights for therapeutic development2021

    • Author(s)
      Tateishi Kensuke、Miyake Yohei、Nakamura Taishi、Yamamoto Tetsuya
    • Journal Title

      Brain Tumor Pathology

      Volume: 38 Issue: 3 Pages: 173-182

    • DOI

      10.1007/s10014-021-00408-z

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Fine-tuning approach for segmentation of gliomas in brain magnetic resonance images with a machine learning method to normalize image differences among facilities2021

    • Author(s)
      Takahashi Satoshi、Takahashi Masamichi、Kinoshita Manabu、et al
    • Journal Title

      Cancers

      Volume: 13 Issue: 6 Pages: 1

    • DOI

      10.3390/cancers13061415

    • URL

      https://localhost/en/publications/2b3aef4e-f8ff-43b6-8c64-a850cda7e82d

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IDH-Mutant Astrocytoma With Chromosome 19q13 Deletion Manifesting as an Oligodendroglioma-Like Morphology.2021

    • Author(s)
      Miyake Y, Fujii K, Nakamaura T, Ikegaya N, Matsushita Y, Gobayashi Y, Iwashita H, Udaka N, Kumagai J, Murata H, Takemoto Y, Yamanaka S, Ichimura K, Tateishi K, Yamamoto T.
    • Journal Title

      J Neuropathol Exp Neurol.

      Volume: 80 Issue: 3 Pages: 247-253

    • DOI

      10.1093/jnen/nlaa161

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] GLI3?Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma2021

    • Author(s)
      Natsumeda Manabu、Miyahara Hiroaki、Yoshimura Junichi、Nakata Satoshi、Tsukamoto Yoshihiro、Okada Masayasu、Oishi Makoto、Hirato Junko、Wataya Takafumi、Tateishi Kensuk、Rodriguez Fausto J、Hovestadt Volker、Suva Mario L、Taylor Michael D、Eberhart Charles G、Fujii Yukihiko、et al.
    • Journal Title

      Journal of Neuropathology & Experimental Neurology

      Volume: 80 Issue: 2 Pages: 129-136

    • DOI

      10.1093/jnen/nlaa141

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma2020

    • Author(s)
      Tateishi Kensuke、Miyake Yohei、Kawazu Masahito、Sasaki Nobuyoshi、Nakamura Taishi、Sasame Jo、Yoshii Yukie、Ueno Toshihide、Miyake Akio、Matsushita Yuko、Shiba Norio、Udaka Naoko、Ohki Kentaro、Fink Alexandria L.、Tummala Shilpa S.、Natsumeda Manabu、Miller Julie J.、Fujii Yukihiko、et al
    • Journal Title

      Cancer Research

      Volume: 80 Issue: 23 Pages: 5330-5343

    • DOI

      10.1158/0008-5472.can-20-2425

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Poly(ADP-ribose) glycohydrolase inhibition sequesters NAD<sup>+</sup> to potentiate the metabolic lethality of alkylating chemotherapy in IDH-mutant tumor cells2020

    • Author(s)
      Nagashima Hiroaki、Lee Christine K.、Tateishi Kensuke、Higuchi Fumi、Subramanian Megha、Rafferty Seamus、Melamed Lisa、Miller Julie J.、Wakimoto Hiroaki、Cahill Daniel P.
    • Journal Title

      Cancer Discovery

      Volume: 10 Issue: 11 Pages: 1673

    • DOI

      10.1158/2159-8290.cd-20-0226

    • URL

      https://pure.teikyo.jp/en/publications/06bcfc39-c5b2-4a32-8257-6e5dbfd648c2

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Redox reaction and clinical outcome of primary diffuse large B-cell lymphoma of the central nervous system2020

    • Author(s)
      Tsuchiya Junichi、Yoneyama Tomohiro、Ohtake Makoto、Tateishi Kensuke、Bae Hyeyeol、Kishino Mitsuhiro、Tateishi Ukihide
    • Journal Title

      Nuclear Medicine Communications

      Volume: 41 Issue: 6 Pages: 567-574

    • DOI

      10.1097/mnm.0000000000001197

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] BRAF V600E mutation mediates FDG-methionine uptake mismatch in polymorphous low-grade neuroepithelial tumor of the young2020

    • Author(s)
      Tateishi Kensuke、Ikegaya Naoki、Udaka Naoko、Sasame Jo、Hayashi Takahiro、Miyake Yohei、Okabe Tetsuhiko、Minamimoto Ryogo、Murata Hidetoshi、Utsunomiya Daisuke、Yamanaka Shoji、Yamamoto Tetsuya
    • Journal Title

      Acta Neuropathologica Communications

      Volume: 8 Issue: 1 Pages: 139-139

    • DOI

      10.1186/s40478-020-01023-3

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] PI3K/AKT/mTOR pathway alterations promote malignant progression and xenograft formation in oligodendroglial tumors.2019

    • Author(s)
      Tateishi K, Nakamura T, Juratli TA, Williams EA, Matsushita Y, Miyake S, Nishi M, Miller JJ, Ryo A, Yamanaka S, Curry WT, Dias-Santagata D, Yamamoto T, Ichimura K, Batchelor T, Chi AS, Iafrate AJ, Wakimoto H, Cahill DP, et al.
    • Journal Title

      Clin Cancer Res.

      Volume: 印刷中 Issue: 14 Pages: 4375-4387

    • DOI

      10.1158/1078-0432.ccr-18-4144

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular genetics and therapeutic targets of pediatric low-grade gliomas2019

    • Author(s)
      Tateishi Kensuke、Nakamura Taishi、Yamamoto Tetsuya
    • Journal Title

      Brain Tumor Pathology

      Volume: 36 Issue: 2 Pages: 74-83

    • DOI

      10.1007/s10014-019-00340-3

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Genome-wide DNA Methylation Profiling Shows Molecular Heterogeneity of Anaplastic Pleomorphic Xanthoastrocytoma2019

    • Author(s)
      Nakamura T, Fukuoka K, Nakano Y, Yamasaki K, Matsushita Y, Yamashita S, Ikeda J, Udaka N, Tanoshima R, Shiba N, Tateishi K, Yamanaka S, Yamamoto T, Hirato J, Ichimura K.
    • Journal Title

      Cancer Sci.

      Volume: 110 Issue: 2 Pages: 828-832

    • DOI

      10.1111/cas.13903

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 悪性脳腫瘍に対する橋渡し研究のためのプラットフォーム構築.2021

    • Author(s)
      立石健祐, 三宅勇平, 中村大志, 笹目丈, 大島聡人, 本間博邦, 池谷直樹, 末永潤, 村田英俊, 山本哲哉
    • Organizer
      第39回日本脳腫瘍学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 悪性脳腫瘍に対する橋渡し研究のためのプラットフォーム構築.2021

    • Author(s)
      立石健祐, 三宅勇平, 中村大志, 笹目丈, 大島聡人, 本間博邦, 池谷直樹, 末永潤, 村田英俊, 山本哲哉
    • Organizer
      第80回日本脳神経外科学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 中枢神経原発悪性リンパ腫の病態と遺伝子異常2021

    • Author(s)
      立石健祐
    • Organizer
      第59回日本癌治療学会学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] トランスレーショナルアプローチにて見えた中枢神経原発悪性リンパ腫の進展機序と治療標的.2021

    • Author(s)
      立石健祐, 三宅勇平, 本間博邦, 河津正人, 佐々木重嘉, 吉井幸恵, 脇本浩明, 永根基雄, 市村幸一, 山本哲哉
    • Organizer
      第21回分子脳神経外科学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] BRAF変異脳腫瘍の臨床像と分子標的治療の展望2021

    • Author(s)
      立石健祐
    • Organizer
      第62回日本神経病理学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 独創的モデルを通じた中枢神経原発悪性リンパ腫の進展機序同定と治療標的の解明.2020

    • Author(s)
      立石健祐, 三宅勇平, 河津正人, 佐々木重嘉, 笹目丈, 吉井幸恵, 脇本浩明, 永根基雄, 市村幸一, 山本哲哉
    • Organizer
      第38回日本脳腫瘍学会学術総会 (シンポジウム)
    • Related Report
      2020 Research-status Report
  • [Presentation] 脳腫瘍治療の現在と未来展望2020

    • Author(s)
      立石健祐
    • Organizer
      第79回日本脳神経外科学会学術総会 Green Project
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] -kB経路の活性化はPCNSLの中枢神経浸潤を促進させる2020

    • Author(s)
      立石健祐, 三宅勇平, 河津正人, 佐々木重嘉, 吉井幸恵, 笹目丈, 永根基雄, 市村幸一
    • Organizer
      第38回日本脳腫瘍病理学会 (シンポジウム),
    • Related Report
      2020 Research-status Report
  • [Presentation] 研究成果がもたらす脳腫瘍分生物学の進展と課題2020

    • Author(s)
      立石健祐, 山本哲哉
    • Organizer
      第40回日本脳神経外科コングレス
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] ヒト由来中枢神経原発悪性リンパ腫細胞株を用いた腫瘍発生進展機構の解明、治療法探求のためのトランスレーショナル研究2019

    • Author(s)
      立石健祐, 佐々木重嘉, 河津正人, 三宅勇平, 中村大志, 吉井幸恵, 松下裕子, 山中正二, 山本哲哉, 脇本浩明, 永根基雄, 市村幸一
    • Organizer
      第37回日本脳腫瘍学会学術総会(シンポジウム, Top Scoring Abstract)
    • Related Report
      2019 Research-status Report
  • [Presentation] PI3 kinase pathway alterations promote tumor progression and xenograft formation in oligodendroglial tumors2019

    • Author(s)
      Tateishi K, Nakamura T, Juratli TA, Miyake S, Yamanaka S, Yamamoto T, Ichimura K, Wakimoto H, Cahill DP
    • Organizer
      ASNO meeting
    • Related Report
      2019 Research-status Report
  • [Presentation] ヒト由来脳腫瘍細胞株を用いた前臨床研究-多施設共同研究の進捗状況について2019

    • Author(s)
      立石健祐, 三宅茂太, 三宅勇平, 笹目丈, 中村大志, 山本哲哉
    • Organizer
      神奈川脳神経外科懇話会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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