Development of novel anti-myeloma agents with potent bone anabolic actions and induction of anti-MM niche through bone cells

2021 Fiscal Year Final Research Report

• Project/Area Number: 17KK0169
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Okayama University (2020-2021); The University of Tokushima (2017-2019)
• Principal Investigator: Teramachi Jumpei 岡山大学, 医歯薬学域, 准教授 (20515986)
• Project Period (FY): 2018 – 2021
• Keywords: 骨髄腫 / TAK1 / IGF1 / 破骨細胞 / 骨芽細胞

Outline of Final Research Achievements

Multiple myeloma (MM) is largely incurable, and is characterized by devastating bone destruction caused by increased osteoclast (OCL) differentiation and bone resorption in more than 85% of MM patients. OCLs in MM not only promote bone resorption but also increase MM cell growth and drug resistance. Despite recent advances in anti-myeloma treatment, development of anti-MM drug resistance is a major limitation of MM therapy. We demonstrate that TAK1 is constitutively phosphorylated though PP2A inactivation. TAK1 inhibition suppressed osteoclastogenesis, and restored osteoblastic differentiation suppressed by MM and thereby induction of anti-MM niche.
IGF1 is a crucial factor for tumor cell growth and survival of malignant cells. We found that OCL-derived IGF1 plays a critical role in MM drug resistance and bone destruction.

Free Research Field

腫瘍生物学

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、今まで困難と考えられていた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。さらに、骨髄腫骨病変内に豊富に存在する骨髄間質細胞を骨芽細胞に分化誘導させることにより、骨欠損病変部に骨の再生とともに骨形成環境が生み出す腫瘍排他的ニッチを誘導するという革新的な再生・細胞治療法への展開が期待できる。