Elucidation of the molecular mechanism of synergistic anti-myeloma effects of dexamethasone and IMiDs

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08741
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: Yamamoto Junichi 東京工業大学, 生命理工学院, 助教 (40748472)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 多発性骨髄腫 / IMiDs / デキサメタゾン / CRBN

Outline of Final Research Achievements

In this study, we performed a comprehensive search for proteins that bind to CRBN in multiple myeloma cell lines in a pomalidomide-dependent manner in response to dexamethasone treatment and identified three proteins that met the criteria. One of these proteins was found to be unaffected by the two drugs at the transcriptional level and to be important for survival and growth of multiple myeloma lines, suggesting that it is a promising substrate for mediating the efficacy of dexamethasone and pomalidomide combination therapy. In addition, transcriptome analysis identified target genes and pathways where interactions were observed in expression changes upon the combination of dexamethasone and pomalidomide.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

デキサメタゾンと免疫調節薬の併用は、多発性骨髄腫の標準治療の一角を占めているが、その詳細な相乗効果の分子メカニズムは不明である。本研究で同定された、デキサメタゾン処理条件下で特異的に分解が誘導された標的タンパク質は、その薬効を媒介する有力な候補である。標的タンパク質の同定と作用機序の分子レベルの解明は、より効果的な治療薬の開発や適切な治療法の確立に寄与する。