2019 Fiscal Year Final Research Report
Optimization of treatment for multiple myeloma with HDAC inhibitors
Project/Area Number |
17K09916
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Hematology
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Research Institution | The University of Tokyo |
Principal Investigator |
IMAI YOICHI 東京大学, 医科学研究所, 准教授 (10345209)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Keywords | 多発性骨髄腫 / HDAC阻害 / AKT阻害 / ADCC / NKG2D / GSK-3 / IKZF1 |
Outline of Final Research Achievements |
We focused on the effect of histone deacetylase (HDAC) inhibitors in MM resistant to lenalidomide. We found that the HDAC inhibitors could activate NK cell activity by enhancing the expression of natural killer group 2D ligands (NKG2DLs) initiating an immune response against the target cells. Thus, HDAC inhibitors strengthen antibody-dependent cellular cytotoxicity (ADCC) of monoclonal antibodies (mAbs) irrespective of cereblon (CRBN), a primary target for lenalidomide. Resistance to lenalidomide is also caused by enhanced phosphorylation of glycogen synthase kinase-3 (p-GSK-3). GSK-3 is known to degrade c-Myc and inactivated through phosphorylation by PI3K/Akt. Thus, enhanced p-GSK-3 by Akt leads to stabilization of c-Myc and elongated survival of MM cells. Akt inhibitor, blocked p-GSK-3 and this inhibition was enhanced by addition of HDAC inhibitors. Combination of HDAC and Akt inhibitors had a synergistic effect in terms of cell cytotoxicity and c-Myc suppression.
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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 |
多発性骨髄腫は、プロテアソーム阻害薬・IMiDs (immunomodulatory drugs)などの新規薬剤の導入により、生存率の改善がみられている。一方で、プロテアソーム阻害薬・IMiDsの両方に抵抗性を示すdouble refractory症例に対する治療は困難なことが多く有効な治療法の開発が急務となっている。悪性腫瘍の再発・難治化には腫瘍免疫からの回避(escape)が深く関与する。本研究によって得られた知見は、HDAC阻害薬を含む低分子化合物により細胞内シグナル修飾などによる抗腫瘍効果と免疫賦活化の両面から造血器腫瘍の難治性を克服する新規治療法の開発の基盤を形成すると考えられる。
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