Establishment of novel therapeutic strategies against cancers via identification of neosubstrate of IMiDs
| Project/Area Number |
20K21617
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
赤司 浩一 九州大学, 医学研究院, 教授 (80380385)
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| Project Period (FY) |
2020-07-30 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2021: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
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| Keywords | IMiDs / thrombosis / アロマターゼ |
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| Outline of Research at the Start |
臨床的にIMiDsは骨髄腫治療において血小板減少を高頻度に生じ、治療中断の重要な原因である。我々は、IMiDsによる血小板減少の原因解明に取り組み、Aromatase(AROM)がその原因となるneo-substrateであることを見出した。本研究は、AROM分解メカニズム解明を進めると同時に、IMiDsによるAROM分解が閉経後乳癌治療へ応用可能か検討し、新規乳癌治療法開発につなげることを目的とする。
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| Outline of Final Research Achievements |
We have identified aromatase as a neo substrate of cereblon responsible for thrombocytopenia induced by IMiDs; IMiDs promote the recruitment of aromatase to cereblon, resulting in the degradation of aromatase in a proteasome-dependent manner, and the degradation of aromatase lead to the inhibition of proplatelet formation (PPF), an essential step for platelet production in human. Since aromatase represents a critical therapeutic target for postmenopausal breast cancer, we sought to establish a novel therapeutic strategy against breast cancer using IMiDs as a degrader of aromatase. Furthermore, we also tried to identify another neo substrate of cereblon to explain the pleiotropic effect of IMiDs, and identified “molecule X” as a neo substrate of cereblon responsible for IMiDs-induced thrombosis.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の遂行によりIMiDsによる血小板減少症の原因としてアロマターゼの分解が生じること、さらにIMiDsによる血栓症リスク上昇の原因として、巨核球、血小板において分子Xの蓄積が生じることを明らかにした。これらの結果からIMiDsによるメジャーな副作用の分子学的メカニズムを明らかとすることができた。さらにIMiDsによるアロマターゼ分解を閉経後乳癌の治療への応用の可能性を評価する研究を行い、今後応用のための基盤的研究としての重要な意義があると考えられた。
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Report
(3 results)
Research Products
(8 results)
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[Journal Article] A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.2022
Author(s)
Miyawaki K, Kato K, Sugio T, Sasaki K, Miyoshi H, Semba Y, Kikushige Y, Mori Y, Kunisaki Y, Iwasaki H, Miyamoto T, Kuo FC, Aster JC, Ohshima K, Maeda T, Akashi K.
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Journal Title
Blood Adv.
Volume: 6
Issue: 7
Pages: 2388-2402
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Aromatase is a novel neo-substrate of cereblon responsible for immunomodulatory drugs-induced thrombocytopenia. Tochigi T, Miyamoto T, Hatakeyama K, Sakoda T, Ishihara D, Irifune H, Shima T, Kato K, Maeda T, Ito T, Handa H, Akashi K, Kikushige Y.2020
Author(s)
Tochigi T, Miyamoto T, Hatakeyama K, Sakoda T, Ishihara D, Irifune H, Shima T, Kato K, Maeda T, Ito T, Handa H, Akashi K, Kikushige Y.
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Journal Title
Blood.
Volume: -
Issue: 24
Pages: 2146-2158
DOI
Related Report
Peer Reviewed / Open Access
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