Mechanisms of myeloma growth in bone marrow microenvironment and development of novel therapeutic options for myeloma

• Project/Area Number: 26461422
• 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, 大学院医歯薬学研究部(医学系), 教授 (80263812)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 骨髄腫 / 骨破壊病変 / 酸環境 / 骨形成 / 骨病変 / TRPV1 / Pim-2 / TAK-1 / 酸性環境 / 骨髄微小環境

Outline of Final Research Achievements

Acid activates the TRPV1-PI3K-Akt survival signaling in MM cells, which further upregulates the pH sensor TRPV1 while inducing HDAC-mediated gene repression, suggesting a positive feedback loop between acid sensing and the PI3K-Akt signaling. Cocultures of MM cells with bone marrow stromal cells (BMSCs) or osteoclasts (OCs) activate the TGF-β-activated kinase-1 (TAK-1)-Pim-2 pathway in these cells to enhance MM tumor progression and bone destruction. TAK-1 inhibition not only directly suppressed MM cell growth but also impaired MM cell adhesion to BMSCs to reduce BMSC support for MM cell growth. In addition, TAK-1 inhibition was able to restore osteoblastogenesis suppressed by MM cells and abolish RANKL-induced osteoclastogenesis. Thus, TAK1 may become an efficacious therapeutic target in MM to suppress tumor burden while restoring bone.

Research Products

• [Journal Article] Expansion of Th1-like Vgamma9Vdelta2T cells by new-generation IMiDs, lenalidomide and pomalidomide, in combination with zoledronic acid. (2017)
  • Author(s): 2. Harada T, Miki H, Cui Q, Oda A, Amachi R, Teramachi J, Bat-Erdene A, Sogabe K, Iwasa M, Fujii S, Nakamura S, Kagawa K, Yoshida S, Endo I, Aihara K, Ozaki S, Matsumoto T, Abe M.
  • Journal Title: Leukemia Volume: 31 Pages: 258-262
  • DOI: 10.1038/leu.2016.273
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Synergistic targeting of Sp1, a critical transcription factor for myeloma cell growth and survival, by panobinostat and proteasome inhibitors. (2016)
  • Author(s): Bat-Erdene A, Miki H, Oda A, Nakamura S, Teramachi J, Amachi R, Tenshin H, Hiasa M, Iwasa M, Harada T, Fujii S, Sogabe K, Kagawa K, Yoshida S, Endo I, Aihara K, Abe M.
  • Journal Title: Oncotarget Volume: 7 Pages: 79064-79075
  • DOI: 10.18632/oncotarget.12594
  • NAID: 120006576955
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A vicious cycle between acid sensing and survival seignaling in myeloma cells: acid-induced epigenetic alteration. (2016)
  • Author(s): Amachi R, Hiasa M, Teramachi J, Harada T, Oda A, Nakamura S, Hanson D, Watanabe K, Fujii S, Miki H, Kagawa K, Iwasa M, Endo I, Kondo T, Yoshida S, Aihara KI, Kurahashi K, Kuroda Y, Horikawa H, Tanaka E, Matsumoto T, Abe M
  • Journal Title: Oncotarget Volume: 7 Pages: 70447-70461
  • DOI: 10.18632/oncotarget.11927
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Susceptibility to bendamustine considerably varies among myeloma cells, but is enhanced in acidic conditions (2016)
  • Author(s): Nakamura S , Miki H, Oda A, Amachi R, Teramachi J, Sogabe K, Fujino H, Maruhashi T, Fujii S, Kagawa K , Abe M.
  • Journal Title: International Journal of Myeloma Volume: 6 Pages: 7-11
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation. (2015)
  • Author(s): 6. Hanson DJ, Nakamura S, Amachi R, Hiasa M, Oda A, Tsuji D, Itoh K, Harada T, Horikawa K, Teramachi J, Miki H, Matsumoto T, Abe M.
  • Journal Title: Oncotarget Volume: 6 Pages: 33568-33586
  • DOI: 10.18632/oncotarget.5598
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma (2015)
  • Author(s): Hiasa M, Jumpei T, Oda A, Amachi R, Harada T, Nakamura S, Miki H, 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: 29 Pages: 207-217
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Induction of endoplasmic reticulum stress by bortezomib sensitizes myeloma cells to DR5-mediated cell death (2015)
  • Author(s): Miki H, Nakamura S, Oda A, Amachi R, Watanabe K, Hanson D, Teramachi J, Hiasa M, Yagi H, Sogabe K, Takahashi M, Maruhashi T, Udaka K, Harada T, Fujii S, Nakano A, Kagawa K, Ri M, Iida S, Ozaki S, Matsumoto T, Abe M
  • Journal Title: International Journal of Myeloma Volume: 5 Pages: 1-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Risk factors for early-onset peripheral neuropathy caused by vincristine in patients with a first administration of R-CHOP or R-CHOP-like chemotherapy (2014)
  • Author(s): Okada N, Hanafusa T, Sakurada T, Kawazoe K, Teraoka K, Kujime T, Abe M, Shinohara Y, Minakuchi K
  • Journal Title: J Clin Med Res Volume: 6 Pages: 252-260
  • DOI: 10.14740/jocmr1856w
  • Peer Reviewed
• [Presentation] 多発性骨髄腫：QoLの改善に向けた治療の進歩 (2016)
  • Author(s): 安倍正博
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Invited
• [Presentation] Pivotal role of TAK-1 in tumor growth and bone destruction in myeloma: therapeutic impact of TAK-1 inhibition (2015)
  • Author(s): Jumpei Teramachi, Masahiro Hiasa, Asuka Oda, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe
  • Organizer: American Society for Bone and Mineral Research Annual Meeting
  • Place of Presentation: Seattle (USA)
  • Year and Date: 2015-10-08
• [Presentation] Up-regulation of the pH sensor TRPV1 in myeloma cells and their adaption to an acidic microenvironment (2015)
  • Author(s): Ryota Amachi, Masahiro Hiasa, Jumpei Teramachi, Asuka Oda, Keiichiro Watanabe, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto, Masahiro Abe
  • Organizer: American Society for Bone and Mineral Research Annual Meeting
  • Place of Presentation: Seattle (USA)
  • Year and Date: 2015-10-08
• [Presentation] 骨髄腫骨病変の管理：ゾレドロン酸かデノスマブか (2014)
  • Author(s): 安倍正博
  • Organizer: 第76回血液学会学学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-10-31
  • Invited
• [Presentation] 骨微小環境と骨髄腫の進展 (2014)
  • Author(s): 安倍正博
  • Organizer: 第32回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-07-24
  • Invited