molecular analysis and drug discovery targeting extramedullary disease in high-risk multiple myeloma

• Project/Area Number: 17K09940
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Keio University
• Principal Investigator: HATTORI Yutaka 慶應義塾大学, 薬学部(芝共立), 教授 (20189575)
• Co-Investigator(Kenkyū-buntansha): 木内 文之 慶應義塾大学, 薬学部(芝共立), 教授 (60161402) ; 山田 健人 埼玉医科大学, 医学部, 教授 (60230463)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 多発性骨髄腫 / リプログラミング遺伝子 / 上皮間葉系移行 / 薬剤耐性 / フタル酸 / TC11 / G2/M細胞周期停止 / 多発生骨髄腫 / ハイリスク多発性骨髄腫 / cadherin / PEG-TC11 / 内科 / 薬学

Outline of Final Research Achievements

In this project, we found overexpression of Oct4 gene in multiple myeloma (MM) cells and also established Oct4-overexpresed MM cell lines. In the overexpressed cells, expression of mesenchymal genes such as Snail was increased, and the EMT-like morphological change was observed. Expression of MRP1 transporter proteins was also increased, and Oct-4-overexpressed cells obtained the resistance to various anti-MM drugs.
We have also developed a novel phthalimide, TC11, and its optimized form, PEG-TC11. PEG-TC11 revealed strong growth inhibitory effects to MM cells in mice xenograft model. Even though TC11 and PEG-TC11 have structural similarity to thalidomide, they did not associated with the thalidomide-binding protein, cereblon, but with α-tubulin and nucleophosmin-1. By binding to α-tubulin and nucleophosmin-1, PEG-TC11 induced G2/M arrest without involvement of p53 and caused apoptosis of high-risk MM cells with p53 deletion.

Academic Significance and Societal Importance of the Research Achievements

白血病、悪性リンパ腫では、薬物治療の進歩により治癒する症例も多いが、多発性骨髄腫は治癒があり得ない難治性造血器腫瘍であった。近年の新規薬剤の開発により予後は改善したものの、ハイリスク骨髄腫はしばしば薬剤耐性の獲得や髄外病変の形成に至り、これらは治療の深刻な妨げとなる。本研究では、ハイリスク骨髄腫におけるリプログラミングや上皮間葉系移行(EMT)を司る遺伝子の異所性発現を見出し、さらにその下流因子を検索して臨床的悪性化の分子機構を追求した。さらに、各種化合物ライブラリーをスクリーニングし、新規治療薬の開発を行い、さらにそれらの標的分子の探索を推し進めた。

Research Products

• [Journal Article] A phenylphthalimide derivative, TC11, induces apoptosis by degrading MCL1 in multiple myeloma cells (2020)
  • Author(s): Ichikawa Daiju、Nakamura Misa、Murota Wakana、Osawa Sho、Matsushita Maiko、Yanagawa Hiroshi、Hattori Yutaka
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 521 Issue: 1 Pages: 252-258
  • DOI: 10.1016/j.bbrc.2019.10.119
  • Peer Reviewed
• [Journal Article] A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress. (2018)
  • Author(s): 1.Okayama M, Kitabatake S, Sato M, Fujimori K, Ichikawa D, Matsushita M, Suto Y, Iwasaki G, Yamada T, Kiuchi F, Hirao M, Kunieda H, Osada M, Okamoto S, Hattori Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 505 Issue: 3 Pages: 787-793
  • DOI: 10.1016/j.bbrc.2018.09.177
  • Peer Reviewed / Open Access
• [Journal Article] A novel phenylphthalimide derivative, pegylated TC11, improves pharmacokinetic properties and induces apoptosis of high-risk myeloma cells via G2/M cell-cycle arrest. (2017)
  • Author(s): Aida S, Hozumi M, Ichikawa D, Iida K, Yonemura Y, Tabata N, Yamada T, Matsushita M, Sugai T, Yanagawa H, Hattori Y
  • Journal Title: Biochem. Biophysic. Res. Commun. Volume: 493 Issue: 1 Pages: 514-520
  • DOI: 10.1016/j.bbrc.2017.08.159
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis and biological evaluation of the natural product komaroviquinone and related compounds aiming at a potential therapeutic lead compound for high-risk multiple myeloma. (2017)
  • Author(s): Suto Y, Sato M, Fujimori K, Kitabatake S, Okayama M, Ichikawa D, Matsushita M, Yamagiwa N, Iwasaki G, Kiuchi F, Hattori Y.
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 27 Issue: 19 Pages: 4558-4563
  • DOI: 10.1016/j.bmcl.2017.08.054
  • Peer Reviewed
• [Journal Article] CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients (2017)
  • Author(s): Matsushita M, Ozawa K, Suzuki T, Nakamura M, Nakano N, Kanchi S, Ichikawa D, Matsuki E, Sakurai M, Karigane D, Kasahara H, Tsukamoto N, Shimizu T, Mori T, Nakajima H, Okamoto S, Kawakami Y, Hattori Y
  • Journal Title: Blood Cancer J. Volume: 7 Issue: 9 Pages: 601-601
  • DOI: 10.1038/bcj.2017.84
  • Peer Reviewed / Open Access
• [Presentation] 骨髄腫細胞においてリプログラミング遺伝子による脱分化が薬剤抵抗性とクローン増殖性を増強する (2019)
  • Author(s): 辻宏樹、不藤 拓海, 佐俣 光一, 山元 智史, 市川 大樹, 松下 麻衣子, 服部 豊
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 多発性骨髄腫細胞のレナリドミド耐性に関する多様な分子メカニズム (2019)
  • Author(s): 不藤拓海、宇於崎 凉, 山口 高史, 山元 智史, 辻 宏樹, 佐俣 光一, 市川 大樹, 松下 麻衣子, 服部 豊
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] komaroviquinoneという天然物由来の新規化合物がin vivoにおいて抗MM活性を示す (2019)
  • Author(s): 佐俣光一、岡山幹夫、藤森宏太、山元智史、市川大樹、松下麻衣子、須藤豊、岩崎源司、山田健人、服部豊
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 天然物由来成分komaroviquinone及びその誘導体群はin vivoにおいて抗骨髄腫活性を示す (2019)
  • Author(s): 佐俣光一、岡山幹夫、藤森宏太、西山沙織、辻宏樹、不藤拓海、市川大樹、松下麻衣子、岩崎源司、須藤豊、山田健人、平尾磨樹、国枝尚子、長田眞、服部豊
  • Organizer: 日本薬学会生物系薬学部会第20回Pharmaco-Hematologyシンポジウム
• [Presentation] Characteristics of Cytotoxic T Cells against Myeloma Cells for Adoptive Immunotherapy. (2019)
  • Author(s): Saito S, Matsushita M, Mori K, Yokoe S, Ichikawa D, Hattori Y
  • Organizer: 10th Intenational symposium of Japanese Society of Hematology.
  • Int'l Joint Research
• [Presentation] Elucidation of the IMiDs-Resistant Mechanism and Development of the Overcoming Drugs Inducing CRBN Independent G2/M Cell Cycle Arrest in Myeloma Cells. (2018)
  • Author(s): Uozaki R, Aida S, Yamagughi T, Yamamoto T, Kashiwazaki S, Yanagawa H, Ichikawa D, Matsushita M and Hattori Y
  • Organizer: 60th AMERICAN SOCIETY of HEMATOLOGY Annual Meeting and Exposition. abst 4451 2018/12/03 San Diego CA.
  • Int'l Joint Research
• [Presentation] Understanding the Role of Extracellular Vesicles in Lenalidomide-Resistance Multiple Myeloma. (2018)
  • Author(s): Yamamoto T, Kosaka N, Ochiya T and Hattori Y
  • Organizer: 60th AMERICAN SOCIETY of HEMATOLOGY Annual Meeting and Exposition. abst 1887 2018/12/01 San Diego CA.
  • Int'l Joint Research
• [Presentation] 新規天然化合物コマロビキノン化合物の抗骨髄腫効果および構造展開 (2018)
  • Author(s): 岡山幹夫、北畠翔太朗、佐藤真梨子、藤森宏太、左俣光一、市川大樹、松下麻衣子、須藤豊、岩崎源司、山田健人、木内文之、岡本真一郎、服部 豊
  • Organizer: 第80回日本血液学会学術集会 大阪国際会議場 大阪市2018/10/14
• [Presentation] 多発性骨髄腫のIMIDs抵抗性メカニズムの解明 (2018)
  • Author(s): 宇於崎涼、市川大樹、松下麻衣子、服部豊
  • Organizer: 第77回日本癌学会学術集会 大阪国際会議場 大阪市2018/9/27
• [Presentation] 天然物コマロビキノン及び関連化合物の骨髄腫細胞 に対する抗腫瘍活性の評価 (2018)
  • Author(s): 須藤豊、佐藤真梨子、北畠翔太朗, 藤森 宏太, 岡山 幹夫, 市川 大樹, 松下 麻衣子, 山際教之, 岩崎 源司, 木内 文之, 服部 豊
  • Organizer: 日本薬学会第138年会
• [Presentation] Cereblon-independent anti-myeloma pathway of TC11, a novel compound of immunomodulatory drugs. (2017)
  • Author(s): Nakamura M, Ichikawa D, Aida S, Hashimoto N, Murota W, Uozaki R, Okayama M, Fujimori K, Yonemura Y, Noriko Tabata N, Yanagawa H, Matsushita M, Hattori Y.
  • Organizer: 79th Annual Meeting Japanese Society of Hematology
• [Presentation] Evaluation of a novel therapeutic target in hematological malignancies. (2017)
  • Author(s): Matsushita M, Yokoe S,Ozawa K, Kanchi S, Ichikawa D, Matsuki E, Mori T, Okamoto S, Hattori Y.
  • Organizer: AACR special conference Tumor Immunology and Immunotherapy
  • Int'l Joint Research
• [Presentation] 天然物由来の新規コマロビキノン誘導体はP53欠損多発性骨髄腫を克服する (2017)
  • Author(s): 藤森剛太、岡山 幹夫、市川 大樹、松下 麻衣子、服部 豊
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Establishment of KU-MEL9-specific cytotoxic T cells for the development of adoptive immunotherapy for multiple myeloma. (2017)
  • Author(s): Yokoe S, Matsushita M, Ozawa K, Uchiumi A, Kashiwazaki S, Ichikawa D, Hattori Y.
  • Organizer: The 8th International Symposium2017 by Japanese Society of Hematology
  • Int'l Joint Research
• [Presentation] PEG(E)-TC11, a novel polyehylene glycol-linked phthalimide derivative, inhibited high-risk MM cell growth in vivo and in vitro via cell cycle G2/M arrest in a CRBN-independent manner. (2017)
  • Author(s): Aida S, Ichikawa D, Iida K, Hozumi M, Nakamura M, Uozaki R, Hashimoto N, Okayama M, Yonemura Y, Tabata N, Yamada T, Matsushita M, Sugai T, Yanagawa H, Hattori Y.
  • Organizer: 2017 Annual meeting of American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] PEG(E)-TC11は、CRBN非依存的に細胞周期の調節を介してハイリスク骨髄腫の増殖を抑制する。 (2017)
  • Author(s): 會田 宗司, 市川 大樹, 中村 美沙, 宇於崎 涼, 飯田 和樹, 穂積 暢史, 岡山 幹夫, 藤森 宏太, 米村 裕子, 田畠 典子, 山田 健人, 松下 麻衣子, 須貝 威, 柳川 弘志, 服部 豊
  • Organizer: 第42回日本骨髄腫学会学術集会