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

• 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
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
• 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.

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。

Research Products

• [Int'l Joint Research] インディアナ大学(米国) (2019)
• [Journal Article] Aberrant upregulation of the endogenous PP2A inhibitor CIP2A is vital for myeloma cell growth and survival (2022)
  • 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
  • Journal Title: International Journal of Myeloma Volume: 12 Pages: 14-23
  • Peer Reviewed
• [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 expression (2022)
  • 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
  • Journal Title: Clinical & Translational Immunology Volume: 11 Issue: 1
  • DOI: 10.1002/cti2.1371
  • Peer Reviewed / Open Access
• [Journal Article] Mechanical unloading aggravates bone destruction and tumor expansion in myeloma (2022)
  • 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
  • Journal Title: Haematologica Volume: 107 Issue: 3 Pages: 744-749
  • DOI: 10.3324/haematol.2021.278295
  • Peer Reviewed / Open Access
• [Journal Article] Myeloma-Bone Interaction: A Vicious Cycle via TAK1-PIM2 Signaling (2021)
  • Author(s): 1. Harada T, Hiasa M, Teramachi J, Abe M
  • Journal Title: Cancers Volume: 13 Issue: 17 Pages: 4441-4441
  • DOI: 10.3390/cancers13174441
  • Peer Reviewed / Open Access
• [Journal Article] Reveromycin A, a novel acid-seeking agent, ameliorates bone destruction and tumor growth in multiple myeloma. (2020)
  • Author(s): Keiichiro Watanabe、Ariunzaya Bat-Erdene、Hirofumi Tenshin、Qu Cui、Jumpei Teramachi、Masahiro Hiasa、Asuka Oda、Takeshi Harada、Hirokazu Miki、Kimiko Sogabe、Masahiro Oura、Ryohei Sumitani、Yukari Mitsui、Itsuro Endo、Eiji Tanaka、Makoto Kawatani、Hiroyuki Osada、Toshio Matsumoto、Masahiro Abe
  • Journal Title: Haematologica Volume: 106 Issue: 4 Pages: 1172-1177
  • DOI: 10.3324/haematol.2019.244418
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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.
  • Journal Title: Cancers (Basel) Volume: 12 Issue: 4 Pages: 929-929
  • DOI: 10.3390/cancers12040929
  • NAID: 120006894611
  • Peer Reviewed / Open Access
• [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.
  • Journal Title: Haematologica Volume: haematol.2019 Issue: 5 Pages: 1401-1413
  • DOI: 10.3324/haematol.2019.234476
  • NAID: 120007180361
  • Peer Reviewed / Open Access
• [Journal Article] Osteoclast-derived IGF1 is required for pagetic lesion formation in vivo (2020)
  • Author(s): Miyagawa Kazuaki、Ohata Yasuhisa、Delgado-Calle Jesus、Teramachi Jumpei、Zhou Hua、Dempster David D.、Subler Mark A.、Windle Jolene J.、Chirgwin John M.、Roodman G. David、Kurihara Noriyoshi
  • Journal Title: JCI Insight Volume: 5 Issue: 6
  • DOI: 10.1172/jci.insight.133113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ. (2019)
  • Author(s): Iwasa Masami、Harada Takeshi、Oda Asuka、Bat-Erdene Ariunzaya、Teramachi Jumpei、Tenshin Hirofumi、Ashtar Mohannad、Oura Masahiro、Sogabe Kimiko、Udaka Kengo、Fujii Shiro、Nakamura Shingen、Miki Hirokazu、Kagawa Kumiko、Ozaki Shuji、Abe Masahiro
  • Journal Title: Oncotarget Volume: 10 Issue: 20 Pages: 1903-1917
  • DOI: 10.18632/oncotarget.26726
  • Peer Reviewed / Open Access
• [Journal Article] Persistent activation of calcium-sensing receptor suppresses bone turnover, increases microcracks and decreases bone strength (2019)
  • 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.
  • Journal Title: JBMR Plus Volume: inpress Issue: 7
  • DOI: 10.1002/jbm4.10182
  • Peer Reviewed / Open Access
• [Journal Article] Class 1 HDAC and HDAC6 inhibition inversely regulates CD38 induction in myeloma cells via interferon-α and ATRA (2018)
  • Author(s): Bat-Erdene Ariunzaya、Nakamura Shingen、Oda Asuka、Iwasa Masami、Teramachi Jumpei、Ashtar Mohannad、Harada Takeshi、Miki Hirokazu、Tenshin Hirofumi、Hiasa Masahiro、Fujii Shiro、Sogabe Kimiko、Oura Masahiro、Udaka Kengo、Kagawa Kumiko、Yoshida Sumiko、Aihara Ken-ichi、Kurahashi Kiyoe、Endo Itsuro、Abe Masahiro
  • Journal Title: British Journal of Haematology Volume: 印刷中 Issue: 5 Pages: 969-974
  • DOI: 10.1111/bjh.15673
  • Peer Reviewed / Open Access
• [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.
  • Journal Title: British Journal of Haematology Volume: 180(2) Issue: 2 Pages: 246-258
  • DOI: 10.1111/bjh.15033
  • Peer Reviewed
• [Journal Article] Reduction of protein phosphatase 2A Cα promotes in vivo bone formation and adipocyte differentiation (2017)
  • Author(s): Yoshida Kaya、Teramachi Jumpei、Uchibe Kenta、Ikegame Mika、Qiu Lihong、Yang Di、Okamura Hirohiko
  • Journal Title: Molecular and Cellular Endocrinology Volume: 印刷中 Pages: 251-258
  • DOI: 10.1016/j.mce.2017.11.005
  • Peer Reviewed / Int'l Joint Research
• [Presentation] TAK1阻害は骨髄腫増殖と骨破壊を惹起する細胞間コミュニケーションを改善する (2021)
  • Author(s): 寺町順平、清水宗、天真寛文、原田武志、日浅雅博、小田明日香、沢禎彦、遠藤逸朗、松本俊夫、安倍正博
  • Organizer: 第39回日本骨代謝学会学術集会
• [Presentation] 骨髄腫細胞の生存・増殖と破骨細胞形成におけるTAK1CIP2A経路の重要な役割 (2021)
  • Author(s): 清水宗、寺町順平、原田武志、小田明日香、天真寛文、日浅雅博、田中栄二、松本俊夫、安倍正博
  • Organizer: 第39回日本骨代謝学会学術集会
• [Presentation] 活性酸素種（ROS）産生による脂肪細胞分化と骨芽細胞分化の制御機構と抗肥満、骨粗鬆症薬の開発 (2021)
  • Author(s): 比嘉佳基、日浅雅博、天真寛文、谷本幸多郎、清水宗、寺町順平、原田武志、遠藤逸朗、田中栄二、松本俊夫、安倍正博
  • Organizer: 第39回日本骨代謝学会学術集会
• [Presentation] 力学的除荷は骨髄腫の骨破壊と骨髄外進展を加速させる (2021)
  • Author(s): 谷本幸多郎、日浅雅博、天真寛文、清水宗、比嘉佳基、寺町順平、原田武志、遠藤逸朗、田中栄二、松本俊夫、安倍正博
  • Organizer: 第39回日本骨代謝学会学術集会
• [Presentation] TAK1 inhibition ameliorates skewed intercellular communication to elicit MM growth and bone loss (2021)
  • Author(s): 寺町順平、清水宗、天真寛文、原田武志、日浅雅博、小田明日香、沢禎彦、遠藤逸朗、松本俊夫、安倍正博
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] TAK1阻害は骨髄腫増殖と骨破壊を惹起する細胞間コミュニケーションを改善する (2021)
  • Author(s): 寺町順平、沢禎彦
  • Organizer: 第75回 日本解剖学会中国・四国支部学術集会
• [Presentation] TAK1はPP2A阻害因子CIP2A発現を誘導し骨髄腫細胞の生存シグナルを増強する (2020)
  • Author(s): 寺町順平
  • Organizer: 第62回歯科基礎医学会学術大会
• [Presentation] The mechanism of constitutive TAK1 activation via PP2A inhibitor CIP2A expression in MM cells (2020)
  • Author(s): Shimizu S, Teramachi J, Tenshin H, Hiasa M, Tanimoto K, Higa Y, Tanaka E, Matsumoto T, Abe M.
  • Organizer: 第38回日本骨代謝学会学術集会
• [Presentation] Critical role of TAK1-mediated CIP2A upregulation in tumorigenesis and survival in MM (2020)
  • Author(s): Shimizu S, Teramachi J, Harada T, Tenshin H, Oda A, Hiasa M, Endo I, Matsumoto T, Tanaka E, Abe M.
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 多発性骨髄腫の骨破壊と腫瘍進展の分子病態の解明と新規治療法の開発 (2019)
  • Author(s): 寺町順平
  • Organizer: 第37回日本骨代謝学会
  • Invited
• [Presentation] Pivotal Role of OCL-Derived IGF1 in Drug Resistance and Bone Destruction in MM. (2019)
  • Author(s): Teramachi J, Miyagawa K, Jesus DC, Windle JJ, Kurihara N, Roodman GD.
  • Organizer: American Society of Hematology 2019 Annual Meeting
  • Int'l Joint Research
• [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
  • Int'l Joint Research
• [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
  • Int'l Joint Research
• [Presentation] 骨髄腫細胞における脱リン酸化酵素PP2Aの活性抑制機構 (2019)
  • Author(s): 寺町順平
  • Organizer: 令和元年度がん研究開発費（大江班・骨髄腫小班）・AMED（丸山班）合同班会議
• [Presentation] TAK1阻害は腫瘍と微小環境との相互作用を遮断し腫瘍進展・骨破壊病変形成を抑制する (2019)
  • Author(s): 寺町順平
  • Organizer: 第124回日本解剖学会総会・全国学術集会
• [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
• [Presentation] TAK1阻害は腫瘍と微小環境との相互作用を遮断し腫瘍進展・骨破壊病変形成を抑制する (2019)
  • Author(s): 寺町順平, 天真寛文, 日浅雅博, 安倍正博
  • Organizer: 第124回日本解剖学会総会・全国学術集会
• [Presentation] Therapeutic impact of TAK1 inhibition on myeloma tumor progression and bone destruction (2018)
  • 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
  • Int'l Joint Research
• [Presentation] Disruption of a progressive vicious cycle between myeloma tumor growth and bone destruction by TAK1 inhibition (2018)
  • 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
  • Int'l Joint Research
• [Presentation] TAK1阻害は骨髄腫細胞と骨髄相互作用を抑制し、腫瘍進展と骨病変形成を抑制する (2018)
  • Author(s): 寺町順平, 天真寛文, 日浅雅博, 遠藤逸朗, 松本俊夫, 安倍正博
  • Organizer: 第36回日本骨代謝学会学術集会
• [Presentation] Mechanisms of TAK1 over-activation in myeloma cells and TAK1-mediated myeloma growth and bone destruction (2018)
  • 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
• [Presentation] 骨髄腫特異的抗腫瘍活性と骨再生をもたらす新規分子標的薬の開発 (2018)
  • Author(s): 寺町順平, 天真寛文, 日浅雅博, 遠藤逸朗, 松本俊夫, 安倍正博
  • Organizer: 2018 先端医学交流セミナー
  • Invited
• [Patent(Industrial Property Rights)] PIM2阻害剤 (2021)
  • Inventor(s): 徳島大学
  • Industrial Property Rights Holder: 徳島大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-014411
  • Filing Date: 2021
• [Patent(Industrial Property Rights)] 新規イノン化合物及びその用途 (2019)
  • Inventor(s): 徳島大学
  • Industrial Property Rights Holder: 徳島大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Acquisition Date: 2019
  • Overseas