| Project/Area Number |
18K16101
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Kyushu University (2020)
National Cancer Center Japan (2018-2019) |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| 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)
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| Keywords | EZH1/2 / 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 |
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| 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.
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| 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。
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