| Project/Area Number |
19K16805
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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 50020:Tumor diagnostics and therapeutics-related
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| Research Institution | University of Toyama (2020)
Sapporo Medical University (2019) |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 多発性骨髄腫 / アポトーシス / IAP / IAP阻害剤 |
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| Outline of Research at the Start |
本研究は多発性骨髄腫の細胞ストレス下における抗アポトーシス効果解除を主眼として，あらたに最近注目されているアポトーシス阻害因子（IAP）を応用した新規治療戦略の開発を目的とする．
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| Outline of Final Research Achievements |
Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling. A novel dimeric IAPi, AZD5582, have high binding potency to XIAP, enabling to simultaneous inhibit XIAP and cIAP1/2. AZD5582 monotherapy showed cell growth inhibition for all MM cell lines, MM1S, RPMI8226, U266 and KMS-5 and induced apoptosis. AZD5582 further showed anti-proliferation effect under the IL-6 additional condition. AZD5582 combined with carfilzomib therapy showed a synergistic effect. Enhanced apoptosis was also observed in combination therapy. Synergistic effect was further observed with other conventional therapeutics. Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy.
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| Academic Significance and Societal Importance of the Research Achievements |
根治困難な多発性骨髄腫診療において、あらたにIAP阻害剤の治療可能性を示した。治療標的としてのIAPにおいては、とくにXIAPが重要な治療標的であること示した。アポトーシス誘導は、ほか癌腫にも応用可能な有効な治療標的であり、IAPを標的としたあらたな治療薬開発の可能性を広げた。
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