Development of novel anti-myeloma agents with potent bone anabolic actions and induction of anti-MM niche through bone cells
Project/Area Number |
17KK0169
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Research Category |
Fund for the Promotion of Joint International Research (Fostering Joint International Research)
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Allocation Type | Multi-year Fund |
Research Field |
Pathobiological dentistry/Dental radiology
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Research Institution | Okayama University (2020-2021) The University of Tokushima (2017-2019) |
Principal Investigator |
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Project Period (FY) |
2018 – 2021
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Project Status |
Completed (Fiscal Year 2021)
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Budget Amount *help |
¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
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Keywords | 骨髄腫 / TAK1 / IGF1 / 破骨細胞 / 骨芽細胞 / NEO1 |
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.
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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。
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Report
(5 results)
Research Products
(38 results)
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[Journal Article] Aberrant upregulation of the endogenous PP2A inhibitor CIP2A is vital for myeloma cell growth and survival2022
Author(s)
SHIMIZU S, TERAMACHI J, HARADA T, HIASA M, TENSHIN H, ODA A, SEKI A, INOUE Y, TANIMOTO K, HIGA Y, OURA M, SOGABE K, HARA T, SUMITANI R, MARUHASHI T, YAMAGAMI H, SAWA Y, ENDO I, TSUNEYAMA K, MATSUMOTO T, TANAKA E, ABE M
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Journal Title
International Journal of Myeloma
Volume: 12
Pages: 14-23
Related Report
Peer Reviewed
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[Journal Article] TGF‐β‐activated kinase‐1 inhibitor LL‐Z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF‐α and RANKL expression2022
Author(s)
Tenshin H, Teramachi J, Ashtar M, Hiasa M, Inoue Y, Oda A, Tanimoto K, Shimizu S, Higa Yi, Harada T, Oura M, Sogabe K, Hara T, Sumitani R, Maruhashi T, Sebe M, Tsutsumi R, Sakaue H, Endo I, Matsumoto T, Tanaka E, Abe M
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Journal Title
Clinical & Translational Immunology
Volume: 11
Issue: 1
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Mechanical unloading aggravates bone destruction and tumor expansion in myeloma2022
Author(s)
Tanimoto K, Hiasa M, Tenshin H, Teramachi J, Oda A, Harada T, Higa Y, Sogabe K, Oura M, Sumitani R, Hara T, Endo I, Matsumoto T, Tanaka E, Abe M
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Journal Title
Haematologica
Volume: 107
Issue: 3
Pages: 744-749
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat.2020
Author(s)
1. Ashtar M, Tenshin H, Teramachi J, Bat-Erdene A, Hiasa M, Oda A, Tanimoto K, Shimizu S, Higa Y, Harada T, Oura M, Sogabe K, Nakamura S, Fujii S, Sumitani R, Miki H, Udaka K, Takahashi M, Kagawa K, Endo I, Tanaka E, Matsumoto T, Abe M.
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Journal Title
Cancers (Basel)
Volume: 12
Issue: 4
Pages: 929-929
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma.2020
Author(s)
2. Teramachi J, Tenshin H, Hiasa M, Oda A, Bat-Erdene A, Harada T, Nakamura S, Ashtar M, Shimizu S, Iwasa M, Sogabe K, Oura M, Fujii S, Kagawa K, Miki H, Endo I, Haneji T, Matsumoto T, Abe M.
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Journal Title
Haematologica
Volume: haematol.2019
Issue: 5
Pages: 1401-1413
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Persistent activation of calcium-sensing receptor suppresses bone turnover, increases microcracks and decreases bone strength2019
Author(s)
Bingzi Dong, Itsuro Endo, Yukiyo Ohnishi, Yukari Mitsui, Kiyoe Kurahashi, Mai Kanai, Masahiro Hiasa, Jumpei Teramachi, Hirofumi Tenshin, Seiji Fukumoto, Masahiro Abe, Toshio Matsumoto.
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Journal Title
JBMR Plus
Volume: inpress
Issue: 7
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity.2018
Author(s)
Fujii S, Nakamura S, Oda A, Miki H, Tenshin H, Teramachi J, Hiasa M, Bat-Erdene A, Maeda Y, Oura M, Takahashi M, Iwasa M, Endo I, Yoshida S, Aihara KI, Kurahashi K, Harada T, Kagawa K, Nakao M, Sano S, Abe M.
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Journal Title
British Journal of Haematology
Volume: 180(2)
Issue: 2
Pages: 246-258
DOI
Related Report
Peer Reviewed
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[Presentation] A progressive auto-amplification loop in TAK1 expression and activation in MM cells.2019
Author(s)
Teramachi J, Shimizu S, Harada T, Tenshin H, Oda A, Bat-Erdene A, Hiasa M, Tanimoto K, Endo I, Haneji T, Matsumoto T, Tanaka E, Abe M.
Organizer
International Myeloma Workshop 2019
Related Report
Int'l Joint Research
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[Presentation] A progressive auto-amplification loop in TAK1 expression and activation in MM cells.2019
Author(s)
Teramachi J, Shimizu S, Tenshin H, Bat-Erdene A, Hiasa M, Oda A, Harada T, Ashter M, Tanimoto K, Endo I, Matsumoto T, Tanaka E, Abe M.
Organizer
American Society for Bone and Mineral Research 2019 Annual Meeting
Related Report
Int'l Joint Research
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[Presentation] 骨髄腫におけるTAK1の発現および活性化の自己増幅2019
Author(s)
寺町 順平, 清水 宗, 天真 寛文, Ariunzaya Baterdene, 小田 明日香, 日浅 雅博, 原田 武志, 谷本 幸多朗, Mohannad Ashter, 田中 栄二, 安倍 正博
Organizer
第82回日本血液学会学術集会
Related Report
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[Presentation] Therapeutic impact of TAK1 inhibition on myeloma tumor progression and bone destruction2018
Author(s)
Jumpei Teramachi, Hirofumi Tenshin, Masahiro Hiasa, Asuka Oda, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Akihito Yamamoto, Tatsuji Haneji, Toshio Matsumoto, Masahiro Abe
Organizer
8th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone and other Musculoskeletal Diseases and Cancer and Bone Society 2018 Meeting
Related Report
Int'l Joint Research
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[Presentation] Disruption of a progressive vicious cycle between myeloma tumor growth and bone destruction by TAK1 inhibition2018
Author(s)
Jumpei Teramachi, Hirofumi Tenshin, Masahiro Hiasa, Asuka Oda, Ariunzaya Bat-Erdene, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Toshio Matsumoto, Masahiro Abe
Organizer
American Society for Bone and Mineral Research 2018 Annual Meeting
Related Report
Int'l Joint Research
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[Presentation] Mechanisms of TAK1 over-activation in myeloma cells and TAK1-mediated myeloma growth and bone destruction2018
Author(s)
Jumpei Teramachi, Hirofumi Tenshin, Masahiro Hiasa, Asuka Oda, Ariunzaya Bat-Erdene, Takeshi Harada, Masami Iwasa, Shiro Fujii, Kimiko Sogabe, Shingen Nakamura, Hirokazu Miki, Masahiro Oura, Kumiko Kagawa, Itsuro Endo, Toshio Matsumoto, Masahiro Abe
Organizer
第80回日本血液学会学術集会
Related Report
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