Mechanism of action of a novel STAT3 inhibitor and its effect on leukemic stem cell

• Project/Area Number: 23591381
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Nagoya University
• Principal Investigator: HAYAKAWA Fumihiko 名古屋大学, 医学部附属病院, 助教 (30402580)
• 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: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: STAT阻害剤 / 分子標的薬 / ヒト化マウス / 白血病 / STAT3 / 抗癌剤 / 白血病モデルマウス / 抗がん剤

Research Abstract

STAT proteins are transcription factors that mediate cell proliferation and differentiation. Aberrant signals of STAT are strongly involved in cancer. We demonstrated that a novel STAT inhibitor, OPB-31121, strongly inhibited STAT3 and STAT5 phosphorylation, and induced significant growth inhibition in various hematopoietic malignant cells. OPB-31121 was particularly effective against leukemia harboring BCR-ABL, FLT3/ITD, and JAK2 V617F. We showed the significant anti-tumor effect of OPB-31121 against human leukemia cells using patient-derived xenograft model.

Research Products

• [Journal Article] A novel STAT inhibitor, OPB-31121, has a significant anti-tumor effect on leukemia with STAT-addictive oncokinases (2013)
  • Author(s): Hayakawa F他6名
  • Journal Title: Blood Cancer Journal Volume: 3
  • Peer Reviewed
• [Journal Article] GATA2 zincfinger 2 mutation found in acute myeloid leukemia impairs myeloid differentiation (2013)
  • Author(s): Niimi K, Hayakawa F,他6名
  • Journal Title: Leuk. Res. Rep Volume: 2 Pages: 21-25
  • Peer Reviewed
• [Journal Article] A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases (2013)
  • Author(s): Fumihiko Hayakawa, Keiki Sugimoto, Yasuo Harada, Norikazu Hashimoto, Naoto Ohi, Shingo Kurahashi, Tomoki Naoe
  • Journal Title: Blood Cancer Journal Volume: 3 Issue: 11 Pages: e166-e166
  • DOI: 10.1038/bcj.2013.63
  • Peer Reviewed
• [Journal Article] GATA2 zincfinger2mutationfoundinacutemyeloidleukemia impairs myeloiddifferentiation (2013)
  • Author(s): Keiko Niimi, Hitoshi Kiyoi, Yuichi Ishikawa, Fumihiko Hayakawa, Shingo Kurahashi, Rika Kihara, Akihiro Tomita, Tomoki Naoe
  • Journal Title: Leukemia ResearchReports Volume: 2 Issue: 1 Pages: 21-25
  • DOI: 10.1016/j.lrr.2013.02.002
  • Peer Reviewed
• [Journal Article] B cell receptor-ERK1/2 signal cancels PAX5-dependent repression of BLIMP1 through PAX5 phosphorylation : a mechanism of antigen-triggering plasma cell differentiation (2012)
  • Author(s): Yasuda T,Hayakawa F,他6名
  • Journal Title: J Immunol Volume: 188 Pages: 6127-6134
  • Peer Reviewed
• [Journal Article] B cell receptor-ERK1/2 signal cancels PAX5-dependent repression of BLIMP1 through PAX5 phosphorylation: a mechanism of antigen-triggering plasma cell differentiation (2012)
  • Author(s): Takahiko Yasuda, Fumihiko Hayakawa, Shingo Kurahashi, Keiki Sugimoto , Yosuke Minami, Akihiro Tomita, Tomoki Naoe
  • Journal Title: Journal of Immunology Volume: 188 Issue: 12 Pages: 6127-34
  • DOI: 10.4049/jimmunol.1103039
  • Peer Reviewed
• [Journal Article] B cell receptor-ERK1/2 signal cancels PAX5-dependent repression of BLIMP1 through PAX5 phosphorylation: a mechanism of antigen-triggering plasma cell differentiation (2012)
  • Author(s): Takahiko Yasuda, Fumihiko Hayakawa, Shingo Kurahashi, Keiki Sugimoto , Yosuke Minami, Akihiro Tomita, Tomoki Naoe
  • Journal Title: Journal of Immunology Volume: in press
  • Peer Reviewed
• [Journal Article] Missense mutations in PML-RARA critical for the lack of responsiveness to arsenic trioxide treatment (2011)
  • Author(s): Goto E, Hayakawa F他7名
  • Journal Title: Blood Volume: 118 Pages: 1600-1609
• [Journal Article] The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Phpositiveacute lymphoblastic leukemia cells (2011)
  • Author(s): Kuwatsuka Y, Hayakawa F他8名
  • Journal Title: Blood Cancer J Volume: 1
• [Journal Article] The mTOR inhibitor, everolimus(RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells (2011)
  • Author(s): Kuwatsuka Y, Naoe T, et al
  • Journal Title: Blood Cancer Journal Volume: 1 Issue: 5 Pages: 1-7
  • DOI: 10.1038/bcj.2011.16
  • Peer Reviewed
• [Presentation] Feasibility and safety of pediatric-type therapy for acute lymphoblastic leukemia in adolescences and young adults : Interim analysis of JALSG ALL202-U (2012)
  • Author(s): Hayakawa F
  • Organizer: 25th Anniversary International Symposium of Japan Adult Leukemia Study Group
  • Place of Presentation: 東京都千代田区国際フォーラム
  • Year and Date: 2012-06-24
  • Invited
• [Presentation] Drug Development Targeting Microenvironment for Malignant Lymphoma (2012)
  • Author(s): Keiki Sugimoto, Fumihiko Hayakawa, Takahiko Yasuda, and Tomoki Naoe
  • Organizer: American Society of Hematology Annual Meeting
  • Place of Presentation: アトランタ 米国
• [Presentation] A novel STAT3 inhibitor OPB-31121 induces tumor-specific growth inhibition in a wide range of hematopoietic malignancies (2011)
  • Author(s): Fumihiko Hayakawa, Keiki Sugimoto, Shingo Kurahashi, Takumi Sumida, Tomoki Naoe
  • Organizer: 53rd Annual Meeting of the American Society of Hematology
  • Place of Presentation: 米国サンディエゴ
  • Year and Date: 2011-12-11
• [Presentation] Development of growth signal inhibitors for hematopoietic malignancies (2011)
  • Author(s): Hayakawa F
  • Organizer: 第70回日本癌学会学術総会腫瘍別シンポジウム
  • Place of Presentation: 名古屋白鳥国際会議場
  • Year and Date: 2011-11-10
  • Invited
• [Presentation] B cell receptor-ERK1/2 signal cancels PAX5-dependent repression of BLIMP1 through PAX5 phosphorylation: a mechanism of antigen-triggering plasma cell differentiation (2011)
  • Author(s): Takahiko Yasuda, Fumihiko Hayakawa, Shingo Kurahashi, Keiki Sugimoto , Tomoki Naoe
  • Organizer: 53rd Annual Meeting of the American Society of Hematology
  • Place of Presentation: San Diego, CA, USA
• [Presentation] A novel STAT3 inhibitor OPB-31121 induces tumor-specific growth inhibition in a wide range of hematopoietic malignancies (2011)
  • Author(s): Fumihiko Hayakawa, Keiki Sugimoto, Shingo Kurahashi, Takumi Sumida, Tomoki Naoe
  • Organizer: 53rd Annual Meeting of the American Society of Hematology
  • Place of Presentation: San Diego, CA, USA
• [Presentation] Development of growth signal inhibitors for hematopoietic malignancies (2011)
  • Author(s): Fumihiko Hayakawa, Keiki Sugimoto, Shingo Kurahashi, Takumi Sumida, Tomoki Naoe
  • Organizer: 第70回日本癌学会学術総会(招待講演)
  • Place of Presentation: 名古屋
• [Book] 専門医のための薬物療法Q&A (2011)
  • Author(s): 早川文彦 他
  • Total Pages: 394
  • Publisher: 中外医学社
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/medical/1639/1674/ketsuekishuyounaikagaku.html
• [Patent(Industrial Property Rights)] 悪性リンパ腫のインビトロ腫瘍細胞モデル及びその利用 (2012)
  • Inventor(s): 早川文彦 他4名
  • Industrial Property Rights Holder: 名古屋大学 他4名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-137462
  • Filing Date: 2012-06-19
  • Overseas