Elucidation of the mechanism of resistance to proteasome inhibitors and search for novel molecular targets to overcome resistance

• Project/Area Number: 16K07179
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Nagoya City University
• Principal Investigator: RI MASAKI 名古屋市立大学, 医薬学総合研究院(医学), 講師 (00567539)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 多発性骨髄腫 / プロテアソーム阻害剤 / 耐性 / 感受性 / 薬剤耐性機序 / ボルテゾミブ / カルフィルゾミブ / RNAシークエンス / cfDNA / 耐性機序 / 分子標的治療 / 薬剤耐性

Outline of Final Research Achievements

This study aimed to elucidate the mechanism of drug resistance of proteasome inhibitors at the clinical level using the samples, including myeloma cells and peripheral blood serum: small RNA, collected before and after the administration of proteasome inhibitors in myeloma patients. As a result, several serum microRNAs sensitive to the proteasome inhibitor treatment were identified. In addition, several gene mutations related to the acquired resistance of the proteasome inhibitor could be identified. Finally, a common gene showing an alterated expression level after the drug resistance was not identified.

Academic Significance and Societal Importance of the Research Achievements

本研究により、ボルテゾミブの感受性に関わる因子（マイクロRNAおよび遺伝子変異）を、細胞株を用いた検証でなく臨床検体から直接同定しえたことは意義が大きいと考えられる。本研究成果により、患者さんの骨髄腫治療において、プロテアソーム阻害剤の感受性や耐性パターンに応じたバイオマーカー開発に寄与し、至適な治療法を確率することが可能となりうることで、難治性の骨髄腫患者の予後改善におおいに寄与できると考えている。