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Development of novel stem cell-targeted therapy for multiple myeloma based on dual inhibition of EZH1/2

Research Project

Project/Area Number 18K16101
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionKyushu University (2020)
National Cancer Center Japan (2018-2019)

Principal Investigator

Nakagawa Makoto  九州大学, 大学病院, 学術研究員 (20808878)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsEZH1/2 / 骨髄腫幹細胞 / Side population / WNT/β-catenin / PRC2 / WNT/β-cateninシグナル / 多発性骨髄腫 / 癌幹細胞 / ヒストンメチル化酵素
Outline of Final Research Achievements

By examining cell lines and mouse models, we found that the EZH1/2 dual inhibitor is appropriate as a therapy targeting myeloma stem cells. In addition, the myeloma cell lines and a PDX model showed high sensitivity to this inhibitor. Regarding the molecular mechanism of this inhibitor, we focused on WNT/β-catenin signaling, which is important for maintenance of stem cell, and clarified that these genes are direct targets of EZH1/2. Furthermore, we found that increased expression of WNT-related genes results in a decrease in self-renewal ability and suppression of cell proliferation. Through this research, we were able to elucidate the molecular biological function of EZH1/2 and obtain a nonclinical Proof of Concept for the EZH1/2 dual inhibitor under development.

Academic Significance and Societal Importance of the Research Achievements

本研究を通じて、多発性骨髄腫におけるEZH1/2の機能について解明を進めた。研究代表者は、EZH2だけではなくEZH1/2のいずれもが幹細胞性の維持に重要であることを見出し、実際にEZH1/2二重阻害剤を投与することで幹細胞性が失われることを証明している。また、研究代表者らが共同開発したEZH1/2二重阻害剤は、既存のEZH2特異的阻害剤と比較して極めて治療効果が高く、明確な優位性がある。この阻害剤は骨髄腫幹細胞を標的とすることから、再発・難治例に対しても治癒を見込める有効な治療となる可能性があり、今後は企業治験や医師主導治験を通じた臨床応用が期待される。

Report

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

    (5 results)

All 2021 2019 2018

All Journal Article (4 results) (of which Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (1 results)

  • [Journal Article] CDKN1C‐mediated growth inhibition by an EZH1/2 dual inhibitor overcomes resistance of mantle cell lymphoma to ibrutinib2021

    • Author(s)
      Kagiyama Yuki、Fujita Shuhei、Shima Yutaka、Yamagata Kazutsune、Katsumoto Takuo、Nakagawa Makoto、Honma Daisuke、Adachi Nobuaki、Araki Kazushi、Kato Ayako、Inaki Koichiro、Ono Yoshimasa、Fukuhara Suguru、Kobayashi Yukio、Tobinai Kensei、Kitabayashi Issay
    • Journal Title

      Cancer Science

      Volume: 印刷中 Issue: 6 Pages: 2314-2324

    • DOI

      10.1111/cas.14905

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 造血器腫瘍におけるEZH1/2を標的とした新規治療2019

    • Author(s)
      中川 亮, 北林 一生
    • Journal Title

      腫瘍内科

      Volume: 24 Pages: 704-710

    • NAID

      40022108694

    • Related Report
      2019 Research-status Report
  • [Journal Article] Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma2018

    • Author(s)
      Nakagawa Makoto、Fujita Shuhei、Katsumoto Takuo、Yamagata Kazutsune、Ogawara Yoko、Hattori Ayuna、Kagiyama Yuki、Honma Daisuke、Araki Kazushi、Inoue Tatsuya、Kato Ayako、Inaki Koichiro、Wada Chisa、Ono Yoshimasa、Yamamoto Masahide、Miura Osamu、Nakashima Yasuharu、Kitabayashi Issay
    • Journal Title

      Cancer Science

      Volume: 110 Issue: 1 Pages: 194-208

    • DOI

      10.1111/cas.13840

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies2018

    • Author(s)
      Nakagawa Makoto、Kitabayashi Issay
    • Journal Title

      Cancer Science

      Volume: 109 Issue: 8 Pages: 2342-2348

    • DOI

      10.1111/cas.13655

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma2018

    • Author(s)
      Makoto Nakagawa, Takuo Katsumoto, Kazutsune Yamagata, Yoko Ogawara, Ayuna Hattori, Yukiko Aikawa, Daisuke Honma, Kazushi Araki, Tatsuya Inoue, Ayako Kato, Koichiro Inaki, Chisa Wada, Yoshimasa Ono, Yasuharu Nakashima, Issay Kitabayashi
    • Organizer
      第16回幹細胞シンポジウム
    • Related Report
      2018 Research-status Report

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

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