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

• 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
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• 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 / 破骨細胞 / 骨形成 / 骨髄腫 / TAK-1 / 骨病変 / TAK１ / Pim-2 / 骨髄間質細胞

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.

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。

Research Products

• [Journal Article] A Genome-Wide Association Study Predicts the Onset of Dysgeusia Due to Anti-cancer Drug Treatment (2022)
  • Author(s): Takei M, Okada N, Nakamura S, Kagawa K, Fujii S, Miki H, Ishizawa K, Abe M, Sato Y.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 45 Issue: 1 Pages: 114-117
  • DOI: 10.1248/bpb.b21-00745
  • NAID: 130008139002
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2022-01-01
  • 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] Basal insulin requirement in patients with type 1 diabetes depends on the age and body mass index (2022)
  • Author(s): Mitsui Y, Kuroda A, Ishizu M, Mori H, Kurahashi K, Kondo T, Yoshida S, Akehi Y, Aihara KI, Endo I, Abe M, Matsuhisa M
  • Journal Title: J Diabetes Investig Volume: 13 Issue: 2 Pages: 292-298
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  • NAID: 120007181368
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• [Journal Article] Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span (2021)
  • Author(s): Takashi Y, Sawatsubashi S, Endo I, Ohnishi Y, Abe M, Matsuhisa M, Kawanami D, Matsumoto T, Fukumoto S
  • Journal Title: Biochem Biophys Rep Volume: 27 Pages: 101-107
  • NAID: 120007146085
  • Peer Reviewed
• [Journal Article] Management of bone metastasis and cancer treatment-induced bone loss during the COVID-19 pandemic: An international perspective and recommendations (2021)
  • Author(s): Brown JE, Wood SL, Confavreux C, Abe M, Weilbaecher K, Hadji P, Johnson RW, Rhoades JA, Edwards CM, Croucher PI, Juarez P, El Badri S, Ariaspinilla G, D'Oronzo S, Guise TA, Van Poznak C
  • Journal Title: J Bone Oncol Volume: 29 Pages: 100375-100375
  • DOI: 10.1016/j.jbo.2021.100375
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Plasma heparin cofactor II activity is inversely associated with albuminuria and its annual deterioration in patients with diabetes. (2021)
  • Author(s): Hara T, Uemoto R, Sekine A, Mitsui Y, Masuda S, Kurahashi K, Yoshida S, Otoda T, Yuasa T, Kuroda A, Ikeda Y, Endo I, Honda S, Yoshimoto K, Kondo A, Tamaki T, Matsumoto T, Matsuhisa M, Abe M, Aihara KI
  • Journal Title: J Diabetes Investig Volume: 12 Pages: 2172-2182
  • NAID: 120007182107
  • Peer Reviewed / Open Access
• [Journal Article] Development of a novel antioxidant based on a dimeric dihydroisocoumarin derivative (2021)
  • Author(s): Nakayama A, Nakamura T, Ara T, Fukuta T, Karanjit S, Harada T, Oda A, Sato H, Abe M, Kogure K, Namba K
  • Journal Title: Tetrahedron Letter Volume: 22 Pages: 153176-153176
  • DOI: 10.1016/j.tetlet.2021.153176
  • 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] Pathogenesis and treatment of multiple myeloma bone disease (2021)
  • Author(s): 2. Hiasa M, Harada T, Tanaka E, Abe M
  • Journal Title: Jpn Dent Sci Rev Volume: 57 Pages: 164-173
  • DOI: 10.1016/j.jdsr.2021.08.006
  • NAID: 210000172895
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of oral bacteria and oral immunity as risk factors for chemotherapy-induced fever with neutropenia in patients with hematological cancer (2020)
  • Author(s): Sogawa Yuka、Fukui Makoto、Nakamura Shingen、Sogabe Kimiko、Sumitani Ryohei、Yoshioka Masami、Abe Masahiro、Hinode Daisuke
  • Journal Title: International Journal of Hematology Volume: 112 Issue: 6 Pages: 851-859
  • DOI: 10.1007/s12185-020-02975-x
  • Peer Reviewed / Open Access
• [Journal Article] Clinical utility of target capture‐based panel sequencing in hematological malignancies: A multicenter feasibility study (2020)
  • Author(s): Yasuda T, Sanada M, Nishijima D, Kanamori T, Iijima Y, Hattori H, Saito A, Miyoshi H, Ishikawa Y, Asou N, Usuki K, Hirabayashi S, Kato M, Abe M.
  • Journal Title: Cancer Science Volume: 111 Issue: 9 Pages: 3367-3378
  • DOI: 10.1111/cas.14552
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 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] Polyclonal immunoglobulin recovery after autologous stem cell transplantation is an independent prognostic factor for survival outcome in patients with multiple myeloma (2019)
  • Author(s): Ozaki S, Harada T, Yagi H, Sekimoto E, Shibata H, Shigekiyo T, Fujii S, Nakamura S, Miki H, Kagawa K, Abe M
  • Journal Title: Cancers Volume: 12 Issue: 1 Pages: 12-12
  • DOI: 10.3390/cancers12010012
  • NAID: 120006894614
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• [Journal Article] Effect of serum concentration and concomitant drugs on vancomycin-induced acute kidney injury in haematologic patients: a single-centre retrospective study (2019)
  • Author(s): Okada N, Chuma M, Azuma M, Nakamura S, Miki H, Hamano H, Goda M, Takechi K, Zamami Y, Abe M, Ishizawa K
  • Journal Title: Eur J Clin Pharmacol Volume: 75 Issue: 12 Pages: 1695-1704
  • DOI: 10.1007/s00228-019-02756-4
  • Peer Reviewed
• [Journal Article] Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation (2019)
  • Author(s): Takashi Y, Kosako H, Sawatsubashi S, Kinoshita Y, Ito N, Tsoumpra MK, Nangaku M, Abe M, Matsuhisa M, Kato S, Matsumoto T, Fukumoto S
  • Journal Title: Proc Natl Acad Sci U S A Volume: 116 Issue: 23 Pages: 11418-11427
  • DOI: 10.1073/pnas.1815166116
  • NAID: 120006715989
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Correlation between high serum alkaline phosphatase levels and denosumab-related hypocalcemia in patients with multiple myeloma. (2019)
  • Author(s): Miki H, Nakamura S, Oura M, Hamano H, Ikuta K, Okada N, Okamoto Y, Sogabe K, Takahashi M, Iwasa M, Udaka K, Harada T, Kurahashi K, Fujii S, Yoshida S, Kagawa K, Endo I, Aihara KI, Abe M.
  • Journal Title: British Journal of Haematology Volume: in press Issue: 2 Pages: 355-358
  • DOI: 10.1111/bjh.15837
  • Peer Reviewed / Open Access
• [Journal Article] JSH practical guidelines for hematological malignancies, 2018: III. Myeloma-1. Multiple myeloma (MM) (2019)
  • Author(s): Iida S, Ishida T, Murakami H, Ozaki S, Abe M, Hata H, Shimazaki C
  • Journal Title: Int J Hematol Volume: 109 Issue: 5 Pages: 509-538
  • DOI: 10.1007/s12185-019-02636-8
  • Peer Reviewed
• [Journal Article] JSH practical guidelines for hematological malignancies, 2018: III. Myeloma-2. Related disorders of multiple myeloma. (2019)
  • Author(s): Iida S, Shimazaki C, Abe M, Nakaseko C
  • Journal Title: Int J Hematol Volume: 109 Issue: 6 Pages: 633-640
  • DOI: 10.1007/s12185-019-02640-y
  • Peer Reviewed
• [Journal Article] PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ (2019)
  • Author(s): Iwasa M, Harada T, Oda A, Bat-Erdene A, Teramachi J, TenshinT, Ashtar M, Oura M, Sogabe K, Udaka K, Fujii S, Nakamura S, Miki H, Kagawa K, Ozaki S and Abe M
  • Journal Title: Oncotarget Volume: 10 Pages: 1903-1917
  • 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
• [Presentation] 教育講演：多発性骨髄腫に対する治療の進歩と分子標的療法の開発 (2020)
  • Author(s): 安倍正博
  • Organizer: 第24回日本がん分子標的治療学会学術集会
  • Invited
• [Presentation] 合同シンポジウム 6 癌と骨代謝 骨髄腫骨病変と腫瘍進展 (2019)
  • Author(s): 安倍 正博
  • Organizer: 第37回日本骨代謝学会学術集会
  • Invited
• [Presentation] シンポジウム２ 骨髄腫骨病変治療の進歩と展望 (2019)
  • Author(s): 安倍 正博
  • Organizer: 第44回日本骨髄腫学会学術集会
  • Invited
• [Presentation] Management of patients with MGUS or multiple myeloma (2018)
  • Author(s): Masahiro Abe
  • Organizer: The 45th Congress of the European Calcified Tissue Society
  • Int'l Joint Research / Invited
• [Presentation] Development of novel therapeutic approaches targeting myeloma-bone marrow interplay (2018)
  • Author(s): Masahiro Abe
  • Organizer: 2018 Taiwan Society of Blood and Marrow Transplantation and the Hematology Society of Taiwan Joint Annual Congress
  • Invited
• [Patent(Industrial Property Rights)] ＰＩＭ２阻害剤 (2022)
  • Inventor(s): 寺町順平、中尾允泰、佐野茂樹、安倍正博、原田武志
  • Industrial Property Rights Holder: 徳島大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2022
  • Overseas