Mechanisms of bone destruction and drug resistance in myeloma: a novel therapeutic strategy targeting a myeloma-bone marrow interaction

• Project/Area Number: 23591390
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: The University of Tokushima
• Principal Investigator: ABE Masahiro 徳島大学, ヘルスバイオサイエンス研究部, 准教授 (80263812)
• Co-Investigator(Kenkyū-buntansha): ENDO Itsuro 徳島大学, 大学病院, 講師 (10432759)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 血液腫瘍学 / 多発性骨髄腫 / 骨病変 / Pimキナーゼ / 骨髄腫 / 骨芽細胞 / 薬剤耐性 / アポトーシス

Research Abstract

Pim-2 kinase is up-regulated in both myeloma cells and bone marrow stromal cells through their mutual interaction in bone lesions in myeloma, and plays a pivotal role in tumor survival and the suppression of osteoblastogenesis with bone loss in myeloma. Treatment with Pim inhibitiors appears to induce myeloma cell death and restore its drug sensitivity through abrogating a drug efflux pump function. Further, Pim inhibitors induce bone formation suppressed in myeloma. Therefore, Pim-2 inhibition may become an important therapeutic option to target a myeloma-bone marrow interaction, which causes drug resistance and bone destruction.

Research Products

• [Journal Article] Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma (2014)
  • Author(s): Hiasa M, Jumpei T, Oda A, Amachi R, Harada T, Nakamura S, Miki S, Fujii S, Kagawa K, Watanabe K, Endo I, Kuroda Y, Yoneda T, Tsuji D, Nakao M, Tanaka E, Hamada K, Sano S, Itoh K, Matsumoto T, Abe M
  • Journal Title: Leukemia Volume: (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Defining and targeting myeloma stem cell-like cells (2014)
  • Author(s): Abe M, Harada T, Matsumoto T
  • Journal Title: Stem Cells Volume: 32 Issue: 5 Pages: 1067-1073
  • DOI: 10.1002/stem.1643
  • Peer Reviewed
• [Journal Article] Bench work for the targeted therapy to the microenvironment of myeloma bone disease. (2014)
  • Author(s): Abe M
  • Journal Title: Clin Lymphoma Myeloma Leuk Volume: 14 Issue: 1 Pages: 8-9
  • DOI: 10.1016/j.clml.2013.12.006
  • Peer Reviewed
• [Journal Article] Combination with a defucosylated anti-HM1.24 monoclonal antibody plus lenalidomide induces marked ADCC against myeloma cells and their progenitors (2013)
  • Author(s): T. Harada, S. Ozaki, A. Oda, D. Tsuji, A. Ikegame, M. Iwasa, K. Udaka, S. Fujii, S. Nakamura, H. Miki, K. Kagawa, Y. Kuroda, S. Kawai, K. Itoh, H. Yamada-Okabe, T. Matsumoto, M. Abe
  • Journal Title: PLoS One Volume: vol.26; 8(12) Issue: 12 Pages: e83905-e83905
  • DOI: 10.1371/journal.pone.0083905
  • Peer Reviewed
• [Journal Article] Phytohemagglutinin-induced IL2 mRNA in whole blood can predict bortezomib-induced peripheral neuropathy for multiple myeloma patients． (2013)
  • Author(s): Watanabe T, Mitsuhashi M, Sagawa M, Ri M, Suzuki K, Abe M, Ohmachi K, Nakagawa Y, Nakamura S, Chosa M, Iida S, and Kizaki M.
  • Journal Title: Blood Cancer Journal Volume: 3 Issue: 10 Pages: e150-e150
  • DOI: 10.1038/bcj.2013.47
  • Peer Reviewed
• [Journal Article] Microenvironment for myeloma growth and drug resistance (2013)
  • Author(s): Abe M
  • Journal Title: International Journal of Myeloma Volume: 3 Pages: 2-11
  • URL: http://www.jsm.gr.jp/journal.html
  • Peer Reviewed
• [Journal Article] Superparamagnetic nanoparticle clusters for cancer theranostics combining magnetic resonance imaging and hyperthermia treatment. (2013)
  • Author(s): Hayashi K, Nakamura M, Sakamoto W, Yogo T, Miki H, Ozaki S, Abe M, Matsumoto T, Ishimura K.
  • Journal Title: Theranostics Volume: 3 Issue: 6 Pages: 366-376
  • DOI: 10.7150/thno.5860
  • Peer Reviewed
• [Journal Article] Activating transcription factor 4, an ER stress mediator, is required for, but excessive ER stress suppresses osteoblastogenesis by bortezomib. (2013)
  • Author(s): Nakamura S, Miki H, Kido S, Nakano A, Hiasa M, Oda A, Amou H, Watanabe K, Harada T, Fujii S, Takeuchi K, Kagawa K, Ozaki S, Matsumoto T, Abe M.
  • Journal Title: Int J Hematol Volume: 98 Issue: 1 Pages: 66-73
  • DOI: 10.1007/s12185-013-1367-z
  • NAID: 10031189598
  • Peer Reviewed
• [Journal Article] Gold nanoparticle cluster-plasmon-enhanced fluorescent silica core-shell nanoparticles for X-ray computed tomography-fluorescence dual-mode imaging of tumors. (2013)
  • Author(s): Hayashi K, Nakamura M, Miki H, Ozaki S, Abe M, Matsumoto T, Ishimura K.
  • Journal Title: Chem Commun Volume: 49 Issue: 46 Pages: 5334-5336
  • DOI: 10.1039/c3cc41876f
  • Peer Reviewed
• [Journal Article] Association of Th1 and Th2 cytokines with transient inflammatory reaction during lenalidomide plus dexamethasone therapy in multiple myeloma. (2013)
  • Author(s): Harada T, Ozaki S, Oda A, Fujii S, Nakamura S, Miki H, Kagawa K, Takeuchi K, Matsumoto T, Abe M.
  • Journal Title: Int J Hematol Volume: 97 Issue: 6 Pages: 743-748
  • DOI: 10.1007/s12185-013-1321-0
  • NAID: 10031183730
  • Peer Reviewed
• [Journal Article] Serum carboxy-terminal telopeptide of type I collagen (ICTP) as a surrogate marker for vulnerable plaques in atherosclerotic patients: A pilot study (2013)
  • Author(s): Kato S, Endo I, Fujimura M, Kuriwaka-Kido R, Fujinaka Y, Aihara K, Iwase T, Inoue D, Akaike M, Abe M, Matsumoto T
  • Journal Title: Atherosclerosis Volume: 229 Issue: 1 Pages: 182
  • DOI: 10.1016/j.atherosclerosis.2013.03.030
  • URL: https://pure.teikyo.jp/en/publications/4a74b056-eff8-4d73-83d4-ed45b7e624ed
  • Peer Reviewed
• [Journal Article] Identification of the risk factors associated with hypocalcemia induced by denosumab. (2013)
  • Author(s): Okada N, Kawazoe K, Teraoka K, Kujime T, Abe M, Shinohara Y, Minakuchi K.
  • Journal Title: Biol Pharm Bull. Volume: 36 Pages: 1622-1626
  • NAID: 130003361547
  • Peer Reviewed
• [Journal Article] Serum carboxy-terminal telopeptide of type I collagen (ICTP) as a surrogate marker for vulnerable plaques in atherosclerotic patients: A pilot study. (2013)
  • Author(s): Kato S, Endo I, Fujimura M, Kuriwaka-Kido R, Fujinaka Y, Aihara K, Iwase T, Inoue D, Akaike M, Abe M, Matsumoto T.
  • Journal Title: Atherosclerosis Volume: 229 Pages: 182-185
  • Peer Reviewed
• [Journal Article] Microenvironment for myeloma growth and drug resistance. (2013)
  • Author(s): Abe M
  • Journal Title: International Journal of Myeloma Volume: 3 Pages: 2-11
  • Peer Reviewed
• [Journal Article] Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors (2012)
  • Author(s): Ikegame A, Ozaki S, Tsuji D, Harada T, Fujii S, Nakamura S, Miki H, Nakano A, Kagawa K, Takeuchi K, Abe M, Watanabe K, Hiasa M, Kimura N, Kikuchi Y, Sakamoto A, Habu K, Endo M, Itoh K, Yamada-Okabe H, MatsumotoT
  • Journal Title: Leukemia Volume: 26 Issue: 9 Pages: 2124-2134
  • DOI: 10.1038/leu.2012.78
  • Peer Reviewed
• [Journal Article] Autologous Peripheral Blood-Derived Mononuclear Cells Induced by Erythropoietin Improve Critical Ischemic Limbs (2012)
  • Author(s): Kanbara T
  • Journal Title: Annals of Vascular Diseases Volume: 5 Issue: 1 Pages: 52-60
  • DOI: 10.3400/avd.oa.11.00070
  • NAID: 130004695429
  • ISSN: 1881-641X, 1881-6428
  • Peer Reviewed
• [Journal Article] CD138-negative clonogenic cells are plasma cells but not B cells in some multiple myeloma patients (2012)
  • Author(s): Hosen N, Matsuoka Y, Kishida S, Nakata J, Mizutani Y, Hasegawa K, Mugitani A, Ichihara H, Aoyama Y, Nishida S, Tsuboi A, Fujiki F, Tatsumi N, Nakajima H, Hino M, Kimura T, Yata K, Abe M, Oka Y, Oji Y, Kumanogoh A, Sugiyama H.
  • Journal Title: Leukemia Volume: (in press) Issue: 9 Pages: 2135-2141
  • DOI: 10.1038/leu.2012.80
  • Peer Reviewed
• [Journal Article] TRAIL produced from multiple myeloma cell is associated with osteolytic markers (2012)
  • Author(s): Kawano Y, Ueno S, Abe M, Kikukawa Y, Yuki H, lyama K, Okuno Y, Mitsuya H, Hata H
  • Journal Title: Oncol Rep Volume: 27 Issue: 2 Pages: 39-44
  • DOI: 10.1371/journal.pone.0031594
  • Peer Reviewed
• [Journal Article] Up-regulation of hexokinaseII in myeloma cells: targeting myeloma cells with 3-bromopyruvate (2012)
  • Author(s): Nakano A, Miki H, Nakamura S, Harada T, Oda A, Amou H, Fujii S, Kagawa K, Takeuchi K, Ozaki 5, Matsumoto T, Abe M
  • Journal Title: J Bioenerg Biomembr Volume: 44 Issue: 1 Pages: 31-38
  • DOI: 10.1007/s10863-012-9412-9
  • Peer Reviewed
• [Journal Article] Inhibition of TACE activity enhances the susceptibility of myeloma cells to TRAIL (2012)
  • Author(s): Kagawa K, Nakano A, Miki H, Oda A, Amou H, Takeuchi K, Nakamura S, Harada T, Fujii S, Yata K, Ozaki S, Matsumoto T, Abe M
  • Journal Title: PLoS One Volume: 7 Issue: 11 Pages: e27222-e27222
  • DOI: 10.1371/journal.pone.0027222
  • Peer Reviewed
• [Journal Article] 骨免疫学―研究最前線 骨髄腫の骨破壊機序 (2012)
  • Author(s): 安倍正博
  • Journal Title: 医学のあゆみ Volume: 第242巻第9号 Pages: 697-702
• [Journal Article] 多発性骨髄腫―現状と進歩 骨髄腫の骨病変：骨破壊機序と骨病変に対する標的療法 (2012)
  • Author(s): 安倍正博
  • Journal Title: 医学のあゆみ Volume: 第242巻第13号 Pages: 1068-1073
• [Journal Article] 骨髄腫の分子病態 造血器腫瘍学―基礎と臨床の最新研究動向― (2012)
  • Author(s): 安倍正博
  • Journal Title: 日本臨床 Volume: 70 Pages: 577-583
• [Journal Article] Inhibition of TACE Activity Enhances the Susceptibility of Myeloma Cells to TRAIL. (2012)
  • Author(s): Kagawa K
  • Journal Title: PLoS One Volume: 7
  • Peer Reviewed
• [Journal Article] TRAIL produced from multiple myeloma cell is associated with osteolytic markers. (2012)
  • Author(s): 1. Kawano Y
  • Journal Title: Oncol Rep Volume: 27 Pages: 39-44
  • DOI: 10.3892/or.2011.1491
  • Peer Reviewed
• [Journal Article] Guest editorial: understanding the pathogenesis and the evolving treatment paradigm for multiple myeloma in the era of novel agents (2011)
  • Author(s): Abe M
  • Journal Title: Int J Hematol Volume: 94 Issue: 4 Pages: 307-309
  • DOI: 10.1007/s12185-011-0950-4
  • NAID: 10030264986
  • Peer Reviewed
• [Journal Article] Targeting the interplay between myeloma cells and the bone marrow microenvironment in myeloma (2011)
  • Author(s): Abe M
  • Journal Title: Int J Hematol Volume: 94 Issue: 4 Pages: 334-343
  • DOI: 10.1007/s12185-011-0949-x
  • NAID: 10030265135
  • Peer Reviewed
• [Journal Article] The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells (2011)
  • Author(s): Asano J, Nakano A, Oda A, Amou H, Hiasa M, Takeuchi K, Miki H, Nakamura S, Harada T, Fujii S, Kagawa K, Endo I, Yata K, Sakai A, Ozaki S, Matsumoto T, Abe M
  • Journal Title: Leukemia Volume: 25 Issue: 7 Pages: 1182-1188
  • DOI: 10.1038/leu.2011.60
  • Peer Reviewed
• [Journal Article] Delayed treatment with vitamin C and N-acetyl-cysteine protects Schwann cells without compromising the anti-myeloma activity of bortezomib (2011)
  • Author(s): Nakano A, Abe M, Oda A, Amou A, Hiasa M, Nakamura S, Miki H, Harada T, Fujii S, Kagawa K, Takeuchi K, Watanabe T, Ozaki S, Matsumoto T
  • Journal Title: Int J Hematol Volume: 93 Issue: 6 Pages: 727-735
  • DOI: 10.1007/s12185-011-0850-7
  • Peer Reviewed
• [Journal Article] Targeting myeloma-osteoclast interaction with V γ 9V 6 2 T cells (2011)
  • Author(s): Cui Q, Shibata H, Oda A, Amou H, Nakano A, Yata K, Hiasa M, Watanabe K, Nakamura S, Miki H, Harada T, Fujii S, Kagawa K, Takeuchi K, Ozaki S, Matsumoto T, Abe M
  • Journal Title: Int J Hematol Volume: 94 Issue: 1 Pages: 63-70
  • DOI: 10.1007/s12185-011-0885-9
  • Peer Reviewed
• [Journal Article] KRN5500, a spicamycin derivative, exerts anti-myeloma effects through impairing both myeloma cells and osteoclasts (2011)
  • Author(s): Miki H, Ozaki S, Nakamura S, Oda A, Amou H, Ikegame A, Watanabe K, Hiasa M, Cui Q, Harada T, Fujii S, Nakano A, Kagawa K, Takeuchi K, Yata K, Sakai A, Abe M, Matsumoto T
  • Journal Title: Br J Haematol Volume: 155 Issue: 3 Pages: 328-339
  • DOI: 10.1111/j.1365-2141.2011.08844.x
  • Peer Reviewed
• [Journal Article] Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells (2011)
  • Author(s): 2. Nakano A
  • Journal Title: PLoS One Volume: 6
  • Peer Reviewed
• [Journal Article] Targeting myeloma-osteoclast interaction with Vγ9Vδ2 T cells (2011)
  • Author(s): Cui Q
  • Journal Title: Int J Hematol Volume: 94 Pages: 63-70
  • Peer Reviewed
• [Journal Article] Transient inflammatory reaction during lenalidomide plus reduced-dose dexamethasone therapy in two patients with relapsed multiple myeloma (2011)
  • Author(s): 7. Ozaki S
  • Journal Title: Int J Hematol Volume: 93 Pages: 257-259
  • Peer Reviewed
• [Presentation] 骨髄腫骨病変と腫瘍免疫.シンポジウム5骨免疫と炎症性疾患 (2013)
  • Author(s): 安倍正博
  • Organizer: 第34回日本炎症・再生医学会
  • Place of Presentation: 京都国際会議場(京都府)
  • Year and Date: 2013-07-03
• [Presentation] Overview of the pathophysiology of MBD and acquired genetic events: Bench work for the targeted therapy to the microenvironmen of MBD. Session: Myeloma bone disease (2013)
  • Author(s): M Abe
  • Organizer: The 14th International Myeloma Workshop
  • Place of Presentation: 京都国際会議場(京都府)
  • Year and Date: 2013-04-04
• [Presentation] Overview of the pathophysiology of MBD and acquired genetic events: Bench work for the targeted therapy to the microenvironment of MBD (2013)
  • Author(s): M. Abe
  • Organizer: The 14th International Myeloma Workshop
  • Place of Presentation: 京都国際会議場（京都）
  • Invited
• [Presentation] 骨髄腫骨病変と腫瘍免疫 (2013)
  • Author(s): 安倍正博
  • Organizer: 第34回日本炎症・再生医学会
  • Place of Presentation: 京都国際会議場（京都）
  • Invited
• [Presentation] SY6-4 Targeting the interplay between myeloma cells and the bone marrow microenvironment (2012)
  • Author(s): M Abe
  • Organizer: Symposium 6: Multiple myeloma: Topics in basic science applicable to the development of novel therapies.第74回日本血液学会学術集会
  • Place of Presentation: 京都国際会議場(京都府)
  • Year and Date: 2012-10-21
• [Presentation] Multiple myeloma: Topics in basic science applicable to the development of novel therapies (2012)
  • Author(s): Masahiro Abe
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 国立京都国際会議場（京都府）
  • Invited
• [Presentation] Prevention of tumor growth and bone destruction in myeloma by Pim kinase inhibition (2012)
  • Author(s): Masahiro Abe
  • Organizer: 12th Int'l Meeting on Cancer Induced Bone Disease
  • Place of Presentation: CITE Centre de Congres (France)
  • Invited
• [Presentation] An Acidic Milieu Aggravates Myeloma Growth And Drug Resistance But Triggers Anti-myeloma Activity Of Reveromycin A, A Novel Anti-resorptive Agent (2011)
  • Author(s): Abe M
  • Organizer: 11th International Meeting on Cancer Induced Bone Disease
  • Place of Presentation: Chicago, Illinois, USA
• [Book] 骨髄腫Updating第２巻 (2013)
  • Author(s): 安倍正博
  • Total Pages: 303
  • Publisher: 医薬ジャーナル社
• [Book] 骨髄腫Updating第１巻 (2012)
  • Author(s): 安倍正博
  • Total Pages: 235
  • Publisher: 医薬ジャーナル社