Drug discovery based on novel concept for overcoming high-risk myeloma which is still intractable despite of recent progress in the treatment

• Project/Area Number: 26461432
• 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): 柳川 弘志 慶應義塾大学, 薬学部(芝共立), 訪問教授 (40327672) ; 木内 文之 慶應義塾大学, 薬学部(芝共立), 教授 (60161402) ; 須貝 威 慶應義塾大学, 薬学部(芝共立), 教授 (60171120) ; 山田 健人 埼玉医科大学, 医学部, 教授 (60230463)
• 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: 内科 / 薬学 / 多発性骨髄腫 / TP53 / TC11 / 免疫調節薬 / 髄外病変 / 上皮間葉系移行 / nucleophosmin-1

Outline of Final Research Achievements

Despite of the use of newly developed drugs, multiple myeloma (MM) with high-risk cytogenetic changes revealed significantly poor prognosis. Most patients acquired drug resistance and developed extra-medullary diseases.We found that N-cadherin and other mesenchymal genes were highly expressed in t(4;14)-positive high-risk MM patients, and E-cadherin and other epithelial genes were expressed in MM patients with normal karyotype. Those cadherin-positive MM cells demonstrated tumorigenicity to SCID mice.We also developed a new immunomudulatory drug (IMiDs), TC11, which showed anti-tumor activity via cereblon-independent pathway unlike previously developed IMiDs.In addition, we tried structural modification of TC11 and succeeded in significantly increasing water-solublity of TC11.

Research Products

• [Journal Article] 分子標的療法サリドマイド 多発性骨髄腫学 (2016)
  • Author(s): 服部 豊
  • Journal Title: 日本臨床 Volume: 74(5) Pages: 316-320
• [Journal Article] A novel phthalimide derivative, TC11, has preclinical effects on high-risk myeloma cells and osteoclasts. (2015)
  • Author(s): Matsushita M, Yoshie Ozaki Y, Hasegawa Y, Terada F, Tabata N, Shiheido H, Yanagawa H, Oikawa T, Matsuo K, Du W, Yamada T, Hozumi M, Ichikawa D, and Hattori Y.
  • Journal Title: PLoS One Volume: 10(1)
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Komaroviquinone-derivatives, revealed anti-tumor effect on high-risk multiple myeloma cells in vitro as well as in vivo. (2016)
  • Author(s): Sato M, Kitabatake S, Ichikawa D, Suto Y, Iwasaki G, Kiuchi F, Yamaguchi T, Ueda A, Aida S, Matsushita M, & Hattori Y.
  • Organizer: 58th AMERICAN SOCIETY of HEMATOLOGY Annual Meeting and Exposition.
  • Place of Presentation: San Diego Convention Center, San Diego, CA., USA
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Novel Komaroviquinone derivatives with anti-protozoal activity inhibited growth of high-risk myeloma cells in vivo. (2016)
  • Author(s): Yamaguchi T, Ichikawa D, Ueda A, Aida S, Matsushita M, Hattori Y.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Drug Design for Overcoming High-Risk Myeloma and Identification of Novel Binding Proteins to Immune-Modulatory Drugs. (2015)
  • Author(s): Hozumi M, Ichikawa D, Matsushita M, Kamiyama E, Yanagawa H, Tabata N, Kitabatake S, Ueda A, Yamaguchi T, Sato M, Hattori Y.
  • Organizer: 57th AMERICAN SOCIETY of HEMATOLOGY Annual Meeting and Exposition.
  • Place of Presentation: Orlando, FL. (USA)
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Clinical significance of 11;14 translocation in myeloma, AL amyloidosis and mantle cell lymphoma. (2015)
  • Author(s): Kasuga M, Ikeda M, Shingaki S, Miyazaki K, Meshituka S, Yoshiki Y, Abe Y, Tsukada N, Hattori Y, Suzuki K.
  • Organizer: 第77回日本血液学会
  • Place of Presentation: 石川県立音楽堂（石川県・金沢市）
  • Year and Date: 2015-10-17
• [Presentation] Identification of New IMiDs-Binding Proteins and Nonteratogenic Drug Design for High-Risk Myeloma. (2015)
  • Author(s): Hozumi M, Matsushita M, Ichikawa D, Ozaki Y, Hasegawa Y, Terada F, Yanagawa H, Tabata N, Shiheido H, Oikawa T, Matsuo K, Yamada T, Wenlin Du W, Kitabatake S, Ueda A, Hattori Y.
  • Organizer: 第77回日本血液学会
  • Place of Presentation: 石川県立音楽堂（石川県・金沢市）
  • Year and Date: 2015-10-16
• [Presentation] ハイリスク多発性骨髄腫に対する新規治療薬の開発. (2015)
  • Author(s): 北畠翔太朗、松下麻衣子、市川大樹、尾崎由枝、長谷川由佳、寺田蕗子、柳川弘志、田畠典子、始平堂弘和、及川司、松尾光一、山田健人、杜雯林、穂積暢史、植田有美、 服部豊
  • Organizer: 第16回 Pharmaco-Hematologyシンポジウム（日本薬学会生物系薬学部会）
  • Place of Presentation: 日本薬学会長井記念館（東京）
  • Year and Date: 2015-06-13
• [Patent(Industrial Property Rights)] フェニルフタルイミド修飾体及びそれを有効成分とする抗癌剤 (2016)
  • Inventor(s): 服部豊、柳川弘志ほか
  • Industrial Property Rights Holder: 服部豊、柳川弘志ほか
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-10-21