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Development of individualized therapy by elucidation of molecular mechanisms for hypermutation phenotype induced by treatment with alkylating agents in glioma

Research Project

Project/Area Number 18K09004
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

Noguchi Akio  杏林大学, 医学部, 准教授 (30311971)

Co-Investigator(Kenkyū-buntansha) 永根 基雄  杏林大学, 医学部, 教授 (60327468)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords神経膠腫 / 遺伝子異常 / 高度点変異誘導 / アルキル化剤 / 薬剤耐性 / 個別化治療
Outline of Final Research Achievements

This study aimed to elucidate molecular mechanisms for developing hypermutation after treatment with temozolomide (TMZ) or ACNU in glioma. Human glioma, MGMT-null cell lines, U251 and LNZ308, MGMT-forced expressing subline were used. TMZ- or ACNU-resistant sublines were also developed by continuous dose-elevating exposure of cells to the drugs. Both TMZ and ACNU resistant cells expressed MGMT whereas their expressions of mismatch repair proteins were not altered. MLPA and Cancer Gene Panel analyses disclosed no additional or new genetic alterations identified in any of resistant sublines. More efforts need to be pursued to clarify the hypermutation phenotype in future studies.

Academic Significance and Societal Importance of the Research Achievements

本研究では、TMZ及びACNUなどの薬剤による神経膠腫細胞におけるhypermutator形質の発生度や分子機序を解析し、薬剤の種類や腫瘍細胞の背景形質や遺伝子異常のパターンによる相違を明らかにすることで、TMZ治療におけるhypermutator化の危険因子を探索し、TMZ治療の良好な対象群を解明することを目的とした。今回の一連の実験では薬剤耐性獲得とhypermutationの一義的な関連は検証できず、IDH変異の有無を考慮に入れるなど別角度での実験系構築が必要であることが示唆された。本機序が明らかとなれば、神経膠腫治療に新たな指標が導入され、治療向上に寄与することが期待される。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report

Research Products

(17 results)

All 2021 2020 2019 2018

All Journal Article (10 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 9 results,  Open Access: 7 results) Presentation (7 results) (of which Int'l Joint Research: 5 results,  Invited: 2 results)

  • [Journal Article] Reduced H3K27me3 levels in diffuse gliomas: association with 1p/19q codeletion and difference from H3K27me3 loss in malignant peripheral nerve sheath tumors2021

    • Author(s)
      Kitahama K, Iijima S, Sumiishi A, Hayashi A, Nagahama K, Saito K, Sasaki N, Kobayashi K, Shimizu S, Nagane M, Shibahara J
    • Journal Title

      Brain Tumor Pathol

      Volume: 38 Pages: 23-29

    • DOI

      10.1007/s10014-020-00382-y

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Survival in patients with glioblastoma at a first progression does not correlate with isocitrate dehydrogenase (IDH)1 gene mutation status2021

    • Author(s)
      Tabei Y, Kobayashi K, Saito K, Shimizu S, Suzuki K, Sasaki N, Shiokawa Y, Nagane M
    • Journal Title

      Jpn J Clin Oncol

      Volume: 51 Pages: 45-53

    • DOI

      10.1093/jjco/hyaa162

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TERT promoter mutation confers favorable prognosis regardless of 1p/19q status in adult diffuse gliomas with IDH1/2 mutations2020

    • Author(s)
      Arita H, Matsushita Y, Machida R et al.
    • Journal Title

      Acta Neuropathol Com

      Volume: 8 Pages: 1-11

    • DOI

      10.1186/s40478-020-01078-2

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone.2020

    • Author(s)
      Natsume A, Aoki K, Ohka F, Maeda S, Hirano M, Adilijiang A, Motomura K, Sumi M, Nishikawa R, Narita Y, Muragaki Y, Maruyama T, Ito T, Beppu T, Nakamura H, Kayama T, Sato S, Nagane M, Mishima K, Nakasu Y, Kurisu K, Yamasaki F, Sugiyama K, Onishi T, Iwadate Y, Terasaki M, Kobayashi H, Matsumura A, Ishikawa E, Sasaki H, Mukasa A, Matsuo T, Hirano H, Kumabe T, Shinoura N, Hashimoto N, Aoki T, Asai A, Abe T, Yoshino A, Arakawa Y, Asano K, Yoshimoto K, Shibui S, Okuno Y, Wakabayashi T ; and Members of Japan Clinical Oncology Group Brain Tumor Study Group (JCOG-BTSG)
    • Journal Title

      J Neurooncol.

      Volume: May 4 Issue: 1 Pages: 17-27

    • DOI

      10.1007/s11060-020-03505-9

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Clinical and molecular genetic feature of cerebellar glioblastoma2019

    • Author(s)
      Iijima S, Saito K, Shimizu S, Kobayashi K, Shimada D, Matsumoto Y, Shiokawa Y, Nagane M
    • Journal Title

      Neuro-Oncology Advances

      Volume: 1

    • DOI

      10.1093/noajnl/vdz039.170

    • Related Report
      2019 Research-status Report
    • Open Access
  • [Journal Article] Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas2019

    • Author(s)
      Guerreiro Stucklin AS, Ichimura K, Nagane M, Bouffet E, Taylor M, Tabori U, Hawkins C, et al.
    • Journal Title

      Nature Communications

      Volume: 10(1) Pages: 4343-4343

    • DOI

      10.1038/s41467-019-12187-5

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Safety and effectiveness of bevacizumab in Japanese patients with malignant glioma: a post-marketing surveillance study2019

    • Author(s)
      Nagane M, Hayashi Y, Shimizu A, Ura M, Nishikawa R
    • Journal Title

      Jpn J Clin Oncol

      Volume: 49 Pages: 1016-1023

    • DOI

      10.1093/jjco/hyz125

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Reduced Neoantigen Expression Revealed by Longitudinal Multiomics as a Possible Immune Evasion Mechanism in Glioma.2019

    • Author(s)
      Nejo T, Matsushita H, Karasaki T, Nomura M, Saito K, Tanaka S, Takayanagi S, Hana T, Takahashi S, Kitagawa Y, Koike T, Kobayashi Y, Nagae G, Yamamoto S, Ueda H, Tatsuno K, Narita Y, Nagane M, Ueki K, Nishikawa R, Aburatani H, Mukasa A, Saito N, Kakimi K.
    • Journal Title

      Cancer Immunol Res.

      Volume: in press Pages: 1148-1161

    • DOI

      10.1158/2326-6066.cir-18-0599

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] DNA demethylation is associated with malignant progression of lower-grade gliomas2019

    • Author(s)
      Nomura Masashi、Saito Kuniaki、Aihara Koki、Nagae Genta、Yamamoto Shogo、Tatsuno Kenji、Ueda Hiroki、Fukuda Shiro、Umeda Takayoshi、Tanaka Shota、…、Narita Yoshitaka、Nagane Motoo、Nishikawa Ryo、Ueki Keisuke、Saito Nobuhito、Aburatani Hiroyuki、Mukasa Akitake
    • Journal Title

      Sci Rep

      Volume: 9 Pages: 1903-1903

    • DOI

      10.1038/s41598-019-38510-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma.2019

    • Author(s)
      Narita Y, Arakawa Y, Yamasaki F, Nishikawa R, Aoki T, Kanamori M, Nagane M, Kumabe T, Hirose Y, Ichikawa T, Kobayashi H, Fujimaki T, Goto H, Takeshima H, Ueba T, Abe H, Tamiya T, Sonoda Y, Natsume A, Kakuma T, Sugita Y, Komatsu N, Yamada A, Sasada T, Matsueda S, Shichijo S, Itoh K, Terasaki M.
    • Journal Title

      Neuro-Oncology

      Volume: 21 Pages: 348-359

    • DOI

      10.1093/neuonc/noy200

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 膠芽腫の治療開発:Temozolomideと課題2020

    • Author(s)
      永根基雄
    • Organizer
      第38回日本脳腫瘍学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Challenges in optimization of MGMT promoter methylation assays for development of companion diagnosis in glioblastoma2019

    • Author(s)
      Motoo Nagane, Kuniaki Saito, Keiichi Kobayashi, Saki Shimizu, Nobuyoshi Sasaki, Yuki Yamagishi, Yoshiaki Shiokawa
    • Organizer
      24th Annual Meeting of the Society for Neuro-Oncology
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 膠芽腫に対するコンパニオン診断法としてのMGMT遺伝子メチル化の解析法最適化における課題2019

    • Author(s)
      永根基雄,齊藤 邦昭,小林 啓一,清水 早紀,島田 大輔,松本 淑恵,佐々木 重嘉,久米 賢,飯島 昌平,山岸 夢希,塩川 芳昭
    • Organizer
      日本脳神経外科学会 第78回 学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Phase 1/2 study of depatuxizumab mafodotin (ABT-414) monotherapy or combination with temozolomide in Japanese patients with/without EGFR-amplified recurrent glioblastoma2019

    • Author(s)
      Yoshitaka Narita, Yoshihiro Muragaki, Takashi Maruyama, Naoki Kagawa, Katsunori Asai, Junichiro Kuroda, Kazuhiko Kurozumi, Motoo Nagane, Masahid Matsuda, Keisuke Ueki, Christopher Joseph Ocampo, Ikiru Matsumoto, Reiko Odagawa, Yasuko Nishimura, Kazuhiko Mishima
    • Organizer
      2019 ASCO Annual Meeting
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Mutation change after temozolomide treatment in primary glioblastoma2018

    • Author(s)
      Motoo Nagane, Kuniaki Saito, Keiichi Kobayashi, Saki Shimizu, Yoshiaki Shiokawa
    • Organizer
      The 15th Meeting of the Asian Society for Neuro-Oncology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Detailed analysis of mutation change after treatment in glioblastoma2018

    • Author(s)
      Nagane M, Saito K, Shimizu S, Nozaki E, Kobayashi K, Kume S, Chiba T, Shibahara J, Shiokawa Y
    • Organizer
      13th European Association of Neuro-Oncology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] IDH gene mutation status plays no impact on survival in patients with glioblastoma at a first progression2018

    • Author(s)
      Motoo Nagane, Yusuke Tabei, Keiichi Kobayashi, Kuniaki Saito, Saki Shimizu, Yoshiaki Shiokawa
    • Organizer
      22nd International Conference on Brain Tumor Research and Therapy
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited

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Published: 2018-04-23   Modified: 2022-01-27  

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