The roles of the TAK1-Pim-2 pathway in drug resistance and bone destruction in multiple myeloma and development of novel agents to conquer them

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K08329
• 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: The University of Tokushima
• Principal Investigator: ABE Masahiro 徳島大学, 大学院医歯薬学研究部(医学域), 教授 (80263812)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 多発性骨髄腫 / 骨髄微小環境 / 薬剤耐性 / 骨破壊 / TAK1 / PIM2 / 阻害薬

Outline of Final Research Achievements

PIM2 is over-expressed in bone marrow stromal cells and osteoclasts as well as multiple myeloma (MM) cells as a common mediator for MM tumor progression and bone destruction. We subsequently identified TAK1 as an upstream mediator responsible for PIM2 up-regulation in these cells. The PIM inhibitor SMI-16a or the TAK1 inhibitor LLZ1640-2 effectively suppressed MM tumor growth and prevented bone destruction in mouse MM models. Of note, these treatments were able to stimulate osteoblastogenesis and restore bone formation. Therefore, TAK1 and PIM2 appear to be pivotal targets for vicious interaction between MM cells and the bone marrow microenvironment in MM to ameliorate bone destruction while reducing MM tumor survival potential. We synthesized a series of new compounds targeting TAK1 and PIM2 based on structure-activity relationships of SMI-16a and LLZ1640-2, and obtained promising inhibitors for PIM2 and TAK1.

Free Research Field

血液内科

Academic Significance and Societal Importance of the Research Achievements

多発性骨髄腫の治療では、薬剤耐性の克服と骨喪失部に骨を再生させる治療薬の開発が喫緊の臨床課題として残されたままである。本研究で開発したTAK1阻害薬やPIM阻害薬は、骨破壊性病変部で骨吸収の抑制とともに骨形成の回復をもたらすため、新たなクラスの治療薬としての展望がある。さらに、骨髄腫の進展および生命予後と相関が判明したTAK1の活性化に着目し選出したTAK1依存性骨髄腫細胞由来分泌蛋白は、骨髄腫の難治性と予後を反映する血清バイオマーカーになる可能性がある。また、これらの分泌蛋白は病態を形成する責任因子の可能性もあり、今後貧血などの骨髄腫に伴う臓器障害形成の分子機序の解明にも資する。