Establishment of novel therapeutic strategies against cancers via identification of neosubstrate of IMiDs

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K21617
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: Kyushu University
• Principal Investigator: Kikushige Yoshikane 九州大学, 大学病院, 講師 (40619706)
• Co-Investigator(Kenkyū-buntansha): 赤司 浩一 九州大学, 医学研究院, 教授 (80380385)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Keywords: IMiDs / thrombosis

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.

Free Research Field

血液内科学

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。