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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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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Keywords | 多発性骨髄腫 / HDAC阻害 / AKT阻害 / ADCC / NKG2D / GSK-3 / IKZF1 / 抗体療法 / HDAC阻害剤 / MICA / AKT / 内科 / 癌 |
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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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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Report
(4 results)
Research Products
(25 results)
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[Journal Article] SLAMF3-mediated signaling via ERK pathway activation promotes aggressive myeloma behaviors in multiple myeloma.2020
Author(s)
Ishibashi M, Takahashi R, Tsubota A, Sasaki M, Handa H, Imai Y, Tanaka N, Tsukune Y, Tanosaki S, Ito S, Asayama T, Sunakawa M, Kaito Y, Kuribayashi-Hamada Y, Kondo-Onodera A, Moriya K, Komatsu N, Tanaka J, Odajima T, Sugimori H, Inokuchi K, and Tamura H.
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Journal Title
Molecular Cancer Research
Volume: 18
Issue: 4
Pages: 632-643
DOI
Related Report
Peer Reviewed
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[Journal Article] Safety of lenalidomide, dexamethasone, and cyclophosphamide in elderly Japanese patients with relapsed and refractory multiple myeloma: results of phase 1 study.2019
Author(s)
Tsukune Y, Sasaki M, Isoda A, Ando J, Koike M, Matsumoto M, Sawamura M, Tamura H, Handa H, Imai Y, Yahata Y, and Komatsu N.
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Journal Title
International Journal of Myeloma
Volume: 9
Pages: 1-6
Related Report
Peer Reviewed
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[Journal Article] Nested polymerase chain reaction with specific primers for Mucorales in the serum of patients with hematological malignancies.2019
Author(s)
Hirano M, Ota Y, Koibuchi T, Takei T, Takeda R, Kawamata T, Yokoyama K, Uchimaru K, Yotsuyanagi H, Imai Y, Tojo A.
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Journal Title
The Japanese Journal of Infectious Diseases
Volume: 印刷中
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Clinical impact of serum soluble SLAMF7 in multiple myeloma.2018
Author(s)
Ishibashi M, Soeda S, Sasaki M, Hand H, Imai Y, Tanaka N, Tanosaki S, Ito S, Odajima T, Sugimori H, Asayama T, Sunakawa M, Kaito Y, Kinoshita R, Kuribayashi Y, Onodera A, Moriya K, Tanaka J, Tsukune Y, Komatsu N, Inokuchi K and Tamura H.
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Journal Title
Oncotarget
Volume: 9
Pages: 34784-34793
Related Report
Peer Reviewed / Open Access
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[Journal Article] Different clonal evolution of chronic myeloid leukemia between bone marrow and the central nervous system.2017
Author(s)
Ogawa M, Yokoyama K, Hirano M, Jimbo K, Ochi K, Kawamata T, Ohno N, Shimizu E, Yokoyama N, Yamaguchi R, Imoto S, Uchimaru K, Miyano S, Imai Y*, Tojo A.
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Journal Title
Related Report
Peer Reviewed
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[Journal Article] Chronic inflammatory demyelinating polyneuropathy in adult T-cell leukemia-lymphoma patients following allogeneic stem cell transplantation.2017
Author(s)
Hirano M, Jimbo K, Ogawa M, Ochi K, Makiyama J, Kawamata T, Yokoyama K, Tanaka T, Inamoto Y, Yamano Y, Fukuda T, Uchimaru K, Imai Y, Tojo A.
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Journal Title
Bone Marrow Transplantation
Volume: -
Related Report
Peer Reviewed
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[Presentation] Combined Inhibition of HDAC and AKT As a Strategy to Overcome Multi-Drug Resistance in Patients with Multiple Myeloma.2019
Author(s)
Hirano H, Imai Y, Murayama T, Sato K, Yamamoto J, Takumi Ito, Futami M, Ri M, Yasui H, Gotoh N, Iida S, Ishida T, Handa H, Tojo A.
Organizer
61th American Society of Hematology Annual meeting
Related Report
Int'l Joint Research
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[Presentation] A Novel Mutant WASp in X-linked Neutropenia Partially Recapitulates Defective Neutrophil Production through its Expression in WASP-deficient NB4 Cells.2017
Author(s)
Kobayashi M, Chanda B, Futami M, Yamashita M, Hirano M, Yokoyama K, Imai Y, Shimizu E, Yusa N, Yamaguchi R, Imoto S, Miyano S, Tojo A.
Organizer
The 59th Annual Meeting of American Society of Hematology
Related Report
Int'l Joint Research
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[Presentation] The new immunoreceptor SLAMF3 promotes aggressive biological and clinical characteristics in multiple myeloma.2017
Author(s)
Ishibashi M, Tamura H, Asayama T, Kuribayashi-hamada Y, Onodera A, Moriya K, Sasaki M, Handa H, Imai Y, Tanaka N, Tanaka J, Tanosaki S, Ito S, Komatsu N, Inokuchi K.
Organizer
The 59th Annual Meeting of American Society of Hematology, 2017
Related Report
Int'l Joint Research
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[Presentation] Chronic inflammatory demyelinating polyneuropathy in ATL patients after allo-SCT.2017
Author(s)
Hirano M, Imai Y, Jimbo K, Ogawa M, Ochi K, Kawamata T, Yokoyama K, Ohno N, Yamano Y, Fukuda T, Uchimaru K, Tojo A.
Organizer
第79回日本血液学会学術集会
Related Report
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[Presentation] Viral infections in acute myeloid leukemia accompanied with adult T-cell leukemia/lymphoma.2017
Author(s)
Jimbo K, Imai Y, Ogawa M, Hirano M, Ochi K, Kawamata T, Yokoyama K, Yasui H, Ohno N, Uchimaru K, Tojo A.
Organizer
第79回日本血液学会学術集会
Related Report
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