Elucidation of acidic metabolism in multiple myeloma and the development of novel therapies targeting its acidic microenvironment.

• Project/Area Number: 19K17858
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: The University of Tokushima
• Principal Investigator: FUJII Shiro 徳島大学, 病院, 助教 (00618473)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 多発性骨髄腫 / 酸性環境 / pHセンサー / PIM2

Outline of Research at the Start

1) 骨髄腫細胞に特徴的な細胞外酸感知受容器と酸排出に関わるモノカルボン酸トランスポーター(MCT)の発現制御機構、酸感受の下流で活性化する生存シグナル経路やエピゲノミックな遺伝子異常発現機序を解明し、2) PI3K-AktおよびPIM2などの生存経路の阻害やMCT阻害による細胞内pHの低下がもたらす解糖系やミトコンドリアによるエネルギー産生やコレステロール合成系等の代謝経路、薬剤排出ポンプ発現への影響や自己複製能をもつ癌幹細胞やSP分画の生存に及ぼす効果を明らかにする。

Outline of Final Research Achievements

The present study was undertaken to clarify the mechanisms of multiple myeloma (MM) cell adaptation to acidic microenvironment in MM to confer drug resistance and to develop novel therapies targeting MM cells in acidic bone lesions. MM cells sense acid to activate their PI3K-Akt and PIM2 survival signaling pathways in response to acidic conditions at pH values as low as 6.4. The acidic conditions further upregulated their pH sensor expression while enhancing HDAC1-mediated repression of various genes, indicating epigenetic adaptation to acid and thereby drug resistance in MM cells. We found bendamustine, thiazolidine-2,4-dione-family compounds with PIM inhibition and monocarboxylate transporter inhibitors as novel drug candidates to target MM cells in acidic microenvironments.

Academic Significance and Societal Importance of the Research Achievements

本研究では、多発性骨髄腫における骨病変が酸性環境下で進展し、治療抵抗性を獲得する機序を酸代謝の観点から分子生物学的に捉え、がん酸性環境を標的とした新たな治療薬（Akt阻害薬、PIM阻害薬、モノカルボン酸トランスポーター阻害薬）を見出した。本研究は、破壊性骨病変を特徴とし、難治性造血器疾患である多発性骨髄腫において新規治療薬の創出と開発に寄与するため、学術的意義、社会的意義は非常に大きいと考える。

Research Products

• [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] 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
  • Peer Reviewed / Open Access
• [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] 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] Novel therapeutic rationale for targeting HDAC1 and PIM2 in multiple myeloma (2019)
  • Author(s): Takeshi Harada, Asuka Oda, Hiroto Ohguchi, Yohann Grondin, Hirofumi Tenshin, Masahiro Hiasa, Jumpei Teramachi, Masahiro Oura, Kimiko Sogabe, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Shuji Ozaki, Teru Hideshima, Kenneth C. Anderson, Masahiro Abe
  • Organizer: 61th ASH Annual Meeting & Exposition
• [Presentation] Targeting myeloma metabolisms regulated by HDAC1-IRF4 axis can be a novel therapeutic strategy (2019)
  • Author(s): Takeshi Harada, Asuka Oda, Hirofumi Tenshin, Jumpei Teramachi, Masahiro Oura, Kimiko Sogabe, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Shuji Ozaki, Teru Hideshima, Kenneth C. Anderson, Masahiro Abe
  • Organizer: 17th International Myeloma Workshop
• [Presentation] Synergistic targeting of Sp1 in myeloma cells with hyperthermia plus proteasome inhibitors (2019)
  • Author(s): Hirokazu Miki, Shingen Nakamura, Ariunzaya Bat-Erdene, Hirofumi Tenshin, Jumpei Teramachi, Asuka Oda, Shiyori Kawata, Taiki Hori, Jumpei Murai, Ryouhei Sumitani, Masahiro Oura, Kimiko Sogabe, Mamiko Takahashi, Kengo Udaka, Takeshi Harada, Shiro Fujii, Kumiko Kagawa, Masahiro Abe
  • Organizer: 17th International Myeloma Workshop