Development of new anticancer drugs based on the novel post-translational modification UBL3

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07159
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Fujita Health University
• Principal Investigator: Ageta Hiroshi 藤田医科大学, 医科学研究センター, 講師 (40416649)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: UBL3 / MVB / エクソソーム

Outline of Final Research Achievements

Exosomes are nano-sized vesicles that are released from almost all organs. The applicant identified a novel post-translational UBL3 modification and found that the UBL3 modification regulates protein sorting to exosomes (Ageta et al., Nat Commun 2018, Cell Mol Life Sci 2019). In cancer immunotherapy, PD-L1 on the surface of exosomes is known to impair the therapeutic effect. We found that PD-L1 is modified by UBL3 modification. Furthermore, we found that drug X, a clinically applied drug, has a potent inhibitory effect on UBL3 modification.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

免疫チェックポイント阻害薬は、従来の薬物療法に比べ副作用が少ない一方、奏効率が25%と少ないことが問題であり原因が不明であった。近年の研究から、PD-L1含有エクソソームの増大により免疫チェックポイント阻害薬の効果が損われることが報告されたが、PD-L1のエクソソームへの輸送機構に関しては不明であった。本研究は、免疫チェックポイント阻害薬に対してUBL3化阻害剤Xを新しい併用剤として提唱することに繋がる。