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Study to develop nucleic acid analog to inhibit transcription network to maintain glioma stemness

Research Project

Project/Area Number 19K22685
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
Research InstitutionKyoto University

Principal Investigator

Miyamoto Susumu  京都大学, 医学研究科, 教授 (70239440)

Co-Investigator(Kenkyū-buntansha) 荒川 芳輝  京都大学, 医学研究科, 講師 (20378649)
杉山 弘  京都大学, 理学研究科, 教授 (50183843)
上久保 靖彦  京都大学, 医学研究科, 特定教授 (60548527)
Project Period (FY) 2019-06-28 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2020: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Keywordsがん幹細胞 / グリオーマ / ステムネス / マスター転写因子 / SOX2 / 転写ネットワーク / 転写活性制御 / 核酸類似化合物 / 腫瘍幹細胞
Outline of Research at the Start

本研究では、グリオーマのステムネス維持を制御するマスター転写因子であるPOU3F2, SOX2, SALL2, OLIG2を標的とした転写因子のシスエレメントに結合することで転写活性を制御(スイッチ)する核酸類似化合物の開発を行い、グリオーマのがん幹細胞のステムネスを崩壊させる新規治療化合物を確立する。さらに、開発されたがん幹細胞を標的とした化合物を用いた新しい治療ストラテジーの確立を目指す。

Outline of Final Research Achievements

Gliomas inevitably recur after chemoradiation therapy. Gliomas possess cancer stem cells with chemoresistance and radioresistance. As transcription factors for stemness, POU3F2, SOX2, SALL2, OLIG2 are identified. In this study, a small molecule was developed to regulate transcription factors for stemness. Chb-SOX2 was identified to inhibit SOX2 functions. Chb-SOX2 inhibits glioma growth and sphere formation. In the analysis of gene expression, Chb-SOX2 induced apoptosis and dysregulate cell cycle. These results suppose that Chb-SOX2 may be a novel drug to treat gliomas targeting cancer stem cells.

Academic Significance and Societal Importance of the Research Achievements

グリオーマの中で最も悪性度の高い膠芽腫は、手術、放射線治療、化学療法を行っても、生存期間中央値は16-18か月と非常に予後の悪い脳腫瘍である。有効な治療薬はテモゾロミと1剤であり、その効果も限定的である。グリオーマは進行すると運動障害、言語障害を生じるため、予後不要に加えて生活の質が著しく悪化しやすい。本研究では、有望な治療法がないグリオーマに対して、特に治療困難な腫瘍成分であるがん幹細胞を標的とする治療薬となりうることを示した。本研究成果からグリオーマに対する新たな創薬が進むことが期待される。

Report

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

    (6 results)

All 2020 2019

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

  • [Journal Article] Temozolomide and etoposide combination for the treatment of relapsed osteosarcoma2020

    • Author(s)
      Akazawa Ryo、Umeda Katsutsugu、Saida Satoshi、Kato Itaru、Hiramatsu Hidefumi、Sakamoto Akio、Arakawa Yoshiki、Sumiyoshi Shinji、Okamoto Takeshi、Moritake Hiroshi、Adachi Souichi、Takita Junko
    • Journal Title

      Japanese Journal of Clinical Oncology

      Volume: 50 Issue: 8 Pages: 948-952

    • DOI

      10.1093/jjco/hyaa070

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone2020

    • Author(s)
      Natsume A, Nagane M, Wakabayashi T, et al.
    • Journal Title

      J Neurooncol

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

    • DOI

      10.1007/s11060-020-03505-9

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Hierarchical Cluster and Region of Interest Analyses Based on Mass Spectrometry Imaging of Human Brain Tumours2020

    • Author(s)
      Hiratsuka Takuya、Arakawa Yoshiki、Yajima Yuka、Kakimoto Yu、Shima Keisuke、Yamazaki Yuzo、Ikegami Masahiro、Yamamoto Takushi、Fujiwake Hideshi、Fujimoto Koichi、Yamada Norishige、Tsuruyama Tatsuaki
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 1-11

    • DOI

      10.1038/s41598-020-62176-8

    • NAID

      120006823932

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Human Pluripotent Stem Cell-Derived Tumor Model Uncovers the Embryonic Stem Cell Signature as a Key Driver in Atypical Teratoid/Rhabdoid Tumor2019

    • Author(s)
      Terada Yukinori、Jo Norihide、Arakawa Yoshiki、Sakakura Megumi、Yamada Yosuke、Ukai Tomoyo、Kabata Mio、Mitsunaga Kanae、Mineharu Yohei、Ohta Sho、Nakagawa Masato、Miyamoto Susumu、Yamamoto Takuya、Yamada Yasuhiro
    • Journal Title

      Cell Reports

      Volume: 26 Issue: 10 Pages: 2608-2621

    • DOI

      10.1016/j.celrep.2019.02.009

    • NAID

      120006578965

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Suppression of glioblastoma through novel drug based on “Gene Switch Technology”2020

    • Author(s)
      Etsuko Yamamoto Hattori, Yoshiki Arakawa, Youhei Mineharu, Masamitsu Mikami, Yasuzumi Matsui, Hiroshi Sugiyama, Souichi Adachi,Yasuhiko Kamikubo
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 遺伝子スイッチ法を用いた、glioblastoma に対する新規治療戦略の構築2020

    • Author(s)
      山本悦子、荒川芳輝、峰晴陽平、三上真充、松井恭澄、杉山 弘、足立壯一、上久保靖彦
    • Organizer
      第38回日本脳腫瘍学会学術集会
    • Related Report
      2020 Annual Research Report

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Published: 2019-07-04   Modified: 2022-01-27  

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