Development of novel anti-myeloma agents with potent bone anabolic actions

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K11504
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: The University of Tokushima
• Principal Investigator: TERAMACHI Jumpei 徳島大学, 大学院医歯薬学研究部(歯学域), 講師 (20515986)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: 骨髄腫 / 骨病変 / 破骨細胞 / 骨芽細胞 / TAK1

Outline of Final Research Achievements

Multiple myeloma (MM) has a unique propensity to develop and expand almost exclusively in the bone marrow and generates destructive bone disease. We demonstrate that TGF-β-activated kinase-1 (TAK1) is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition induce apoptosis in MM cells. TAK1 phosphorylation was also induced along with upregulation of VCAM-1 in bone marrow stromal cells (BMSCs) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor RANKL expression by BMSCs. Furthermore, TAK1 inhibition suppressed osteoclastogenesis, and restored osteoblastic differentiation suppressed by MM. Treatment with the TAK1 inhibitor suppressed MM growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM.

Free Research Field

骨代謝

Academic Significance and Societal Importance of the Research Achievements

本研究は、現在も尚重大な臨床課題として残されている腫瘍細胞と骨髄微小環境との細胞間相互作用がもたらす薬剤耐性を克服し、骨破壊性悪性腫瘍における骨形成の回復・骨再生という患者QOLの改善に向けた新規治療法の開発に繋がる点に特色と意義がある。TAK1は骨髄腫だけでなく他の種々の悪性腫瘍においても標的分子となりうることが考えられ、TAK1を標的とした治療法の開発は癌全般の新規治療法の開発にも波及することが期待できる。TAK1の抑制は直接的に破骨細胞分化を抑制し、骨芽細胞分化を惹起させるため腫瘍性骨喪失のみならず炎症性骨喪失、薬剤性骨喪失に対する新規骨形成療法の開発への新たな道を拓くことが予想される。