2020 Fiscal Year Final Research Report
Elucidation of acidic metabolism in multiple myeloma and the development of novel therapies targeting its acidic microenvironment.
Project/Area Number |
19K17858
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 54010:Hematology and medical oncology-related
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Research Institution | The University of Tokushima |
Principal Investigator |
FUJII Shiro 徳島大学, 病院, 助教 (00618473)
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Project Period (FY) |
2019-04-01 – 2021-03-31
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Keywords | 多発性骨髄腫 / 酸性環境 |
Outline of Final Research Achievements |
The present study was undertaken to clarify the mechanisms of multiple myeloma (MM) cell adaptation to acidic microenvironment in MM to confer drug resistance and to develop novel therapies targeting MM cells in acidic bone lesions. MM cells sense acid to activate their PI3K-Akt and PIM2 survival signaling pathways in response to acidic conditions at pH values as low as 6.4. The acidic conditions further upregulated their pH sensor expression while enhancing HDAC1-mediated repression of various genes, indicating epigenetic adaptation to acid and thereby drug resistance in MM cells. We found bendamustine, thiazolidine-2,4-dione-family compounds with PIM inhibition and monocarboxylate transporter inhibitors as novel drug candidates to target MM cells in acidic microenvironments.
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Free Research Field |
血液内科学
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Academic Significance and Societal Importance of the Research Achievements |
本研究では、多発性骨髄腫における骨病変が酸性環境下で進展し、治療抵抗性を獲得する機序を酸代謝の観点から分子生物学的に捉え、がん酸性環境を標的とした新たな治療薬(Akt阻害薬、PIM阻害薬、モノカルボン酸トランスポーター阻害薬)を見出した。本研究は、破壊性骨病変を特徴とし、難治性造血器疾患である多発性骨髄腫において新規治療薬の創出と開発に寄与するため、学術的意義、社会的意義は非常に大きいと考える。
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