Development of innovative anti-tumor agents that target signal transducers and activator of transcription

• Project/Area Number: 23659487
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Nagoya University
• Principal Investigator: NAOE Tomoki 名古屋大学, 医学系研究科, 教授 (50217634)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: シグナル伝達 / STAT3 / STAT5 / FLT3 / FLT３

Research Abstract

We demonstrated that a novel STAT inhibitor, OPB-31121, strongly inhibited STAT3 and STAT5 phosphorylation without upstream kinase inhibition, and induced significant growth inhibition in various hematopoietic malignant cells. Investigation among various cell lines indicated that OPB-31121 is particularly effective on leukemia cells harboring BCR-ABL, FLT3/ITD and JAK2 V617F, oncogenic kinases depended their oncogenicities on STAT3/5. Using immunodeficient mice transplantation system, we also showed the significant anti-tumor effect of OPB-31121 on primary human leukemia cells harboring those aberrant kinases and the safety on normal human cord blood.

Research Products

• [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, Kurahashi S, Sugimoto K, Minami Y, Tomita A, Naoe T.
  • Journal Title: J Immunol. Volume: 188 Pages: 6127-6134
  • Peer Reviewed
• [Journal Article] CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737 (2012)
  • Author(s): Shimada K, Tomita A, Minami Y, Abe A, Hind CK, Kiyoi H, Cragg MS, Naoe T
  • Journal Title: Exp Hematol Volume: 40 Pages: 724-737
  • Peer Reviewed
• [Journal Article] Mast cells promote the growth of Hodgkin's lymphoma cell tumor by modifying the tumor microenvironment that can be perturbed by bortezomib (2012)
  • Author(s): Mizuno H, Nakayama T, Miyata Y, Saito S, Nishiwaki S, Nakao N, Takeshita K, Naoe T
  • Journal Title: Leukemia Volume: 26 Pages: 2269-2276
  • Peer Reviewed
• [Journal Article] Retrospective analysis of prognostic factors for angioimmunoblastic T-cell lymphoma: a multicenter cooperative study in Japan (2012)
  • Author(s): Tokunaga T, Shi mada K, Yamamoto K, Chihara D, Ichihashi T, Oshima R, Tanimoto M, Iwasaki T, Isoda A, Sakai A, Kobayashi H, Kitamura K, Matsue K, Taniwaki M, Tamashima S, Saburi Y, Masunari T, Naoe T, Nakamura S, Kinoshita T
  • Journal Title: Blood Volume: 119 Pages: 2837-2843
  • 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] CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737. (2012)
  • Author(s): Shimada K, Tomita A, Minami Y, Kiyoi H, Naoe T et al.
  • Journal Title: Exp Hematol. Volume: 40 Issue: 9 Pages: 724-737
  • DOI: 10.1016/j.exphem.2012.05.007
  • Peer Reviewed
• [Journal Article] Retention of CD34(+) CML stem/progenitor cells during imatinib treatment and rapid decline after treatment with second-generation BCR-ABL inhibitors. (2012)
  • Author(s): Minami Y, Abe A, Minami M, Kitamura K, Hiraga J, Mizuno S, Ymamoto K, Sawa M, Inagaki Y, Miyamura K, Naoe T.
  • Journal Title: Leukemia Volume: 26 Issue: 9 Pages: 2142-2143
  • DOI: 10.1038/leu.2012.73
  • Peer Reviewed
• [Journal Article] Mast cells promote the growth of Hodgkin's lymphoma cell tumor by modifying the tumor microenvironment that can be perturbed by bortezomib (2012)
  • Author(s): 水野 紘樹
  • Journal Title: Leukemia Volume: 26 Issue: 10 Pages: 2269-2269
  • DOI: 10.1038/leu.2012.81
  • 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, Kurahashi S, Sugimoto K, Minami Y, Tomita A, Naoe T.
  • Journal Title: J Immunol. Volume: in press
  • Peer Reviewed
• [Journal Article] Retention of CD34(+) CML stem/progenitor cells during imatinib treatment and rapid decline after treatment with second-generation BCR-ABL inhibitors. (2012)
  • Author(s): Minami Y, Abe A, Minami M, Kitamura K, Hiraga J, Mizuno S, Yamamoto K, Sawa M, Inagaki Y, Miyamura K, Naoe T.
  • Journal Title: Leukemia 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, Tomita A, Hayakawa F, Atsumi A, Kiyoi H, Naoe T
  • Journal Title: Blood Volume: 118 Pages: 1600-1609
  • Peer Reviewed
• [Journal Article] The mTOR inhibitor, everolimus (RAD001), overcomes resistanceto imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells (2011)
  • Author(s): Kuwatsuka Y, Minami M, Minami Y, Sugimoto K, Hayakawa F, Miyata Y, Abe A, Goff DJ, Kiyoi H, Naoe T
  • Journal Title: Blood Cancer J Volume: 1(5)
  • Peer Reviewed
• [Journal Article] A novel insertion mutation of K294RGG within BCR-ABL kinase domain confers imatinib resistance: sequential analysis of the clonal evolution in a patient with chronic myeloid leukemia in blast crisis (2011)
  • Author(s): Sakai K, Ishikawa Y, Mori Y, Kobayashi M, Iriyama C, Ozawa Y, Suzuki T, Minami Y,Ishikawa K, Kaneda N, Naoe T, Kiyoi H
  • Journal Title: Int J Hematol Volume: 93 Pages: 237-242
  • NAID: 10029533322
  • Peer Reviewed
• [Journal Article] PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML (2011)
  • Author(s): Kurahashi S, Hayakawa F, Miyata Y, Yasuda T, Minami Y, Tsuzuki S, Abe A, Naoe T
  • Journal Title: Oncogene Volume: 30 Pages: 1822-1830
  • Peer Reviewed
• [Journal Article] PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML. (2011)
  • Author(s): Kurahashi S, Hayakawa F, Miyata Y, Yasuda T, Minami Y, Tsuzuki S, Abe A, Naoe T.
  • Journal Title: Oncogene Volume: 30 Pages: 1822-1830
  • Peer Reviewed
• [Journal Article] Expanded distribution of the T315I mutation among hematopoietic stem cells and progenitors in a chronic myeloid leukemia patient during imatinib treatment (2010)
  • Author(s): Minami Y, Kajiguchi T, Abe A, Ohno T, Kiyoi H, Naoe T
  • Journal Title: Int J Hematol Volume: 92 Pages: 664-666
  • NAID: 10027674164
  • Peer Reviewed
• [Journal Article] Selective KIT inhibitor KI-328 and HSP90 inhibitor show different potency against the type of KIT mutations recurrently identified in acute myeloid leukemia (2010)
  • Author(s): Tsujimura A, Kiyoi H, Shiotsu Y, Ishikawa Y, Mori Y, Ishida H, Toki T, Ito E, Naoe T
  • Journal Title: Int J Hematol Volume: 92 Pages: 624-633
  • NAID: 10027673999
  • Peer Reviewed
• [Presentation] Wnt Signaling Is Associated with Anti-Apoptosis in the Interaction Between Acute Myeloid Leukemia Cells and Stromal Cells (2012)
  • Author(s): Yosuke Minami, Yosuke Niwa, Akihiro Abe, Fumihiko Hayakawa, and Tomoki Naoe
  • Organizer: The American Society of Hematology 54th Annual Meeting
  • Place of Presentation: Atlanta (USA).
  • Year and Date: 2012-12-08
• [Presentation] Drug Development Targeting Microenvironment for Malignant Lymphoma ASH Annual Meeting Abstracts 2012 120:1661 (2012)
  • Author(s): Keiki Sugimoto, Fumihiko Hayakawa, Takahiko Yasuda, and Tomoki Naoe
  • Organizer: The American Society of Hematology 54th Annual Meeting
  • Place of Presentation: Atlanta (USA)
  • Year and Date: 2012-12-08
• [Presentation] Wnt Signaling Is Associated with Anti-Apoptosis in the Interaction Between Acute Myeloid Leukemia Cells and Stromal Cells. (2012)
  • Author(s): Minami Y, Niwa Y, Abe A, Hayakawa F, and Naoe T.
  • Organizer: 第54回アメリカ血液学会
  • Place of Presentation: Atlanta (USA)
• [Presentation] Drug Development Targeting Microenvironment for Malignant Lymphoma ASH Annual Meeting Abstracts 2012 120:1661 (2012)
  • Author(s): Sugimoto K, Hayakawa F, Yasuda T, and Naoe T.
  • Organizer: 第54回アメリカ血液学会
  • Place of Presentation: Atlanta (USA)
• [Presentation] A Novel STAT3 Inhibitor OPB-31121 Induces Tumor-Specific Growth Inhibition in a Wide Range of Hematopoietic Malignancies without Growth Suppression of Normal Hematopoietic Cells (2011)
  • Author(s): Hayakawa F, Sugimoto K, Kurahashi S, Sumida T, Naoe T.
  • Organizer: The American Society of Hematology 53th Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2011-12-10
• [Presentation] Retention of Slow-Cycling CD34+ cells During Imatinib Treatment and Rapid Decline After 2ndABL-TKI Treatment in Ph+ Leukemia Cells (2011)
  • Author(s): Minami Y, Abe A, Minami M, Kuwatsuka Y, Fukushima N, Kitamura K, Hiraga J, Yamamoto K, Jamieson C, Naoe T
  • Organizer: The American Society of Hematology 53th Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2011-12-10
• [Presentation] A Novel STAT3 Inhibitor OPB-31121 Induces Tumor-Specific Growth Inhibition in a Wide Range of Hematopoietic Malignancies without Growth Suppression of Normal Hematopoietic Cells. (2011)
  • Author(s): Hayakawa F, Sugimoto K, Kurahashi S, Sumida T, Naoe T.
  • Organizer: The American Society of Hematology 53th Annual Meeting
  • Place of Presentation: San Diego, USA
• [Presentation] RhoH Downregulates Rac Through RhoGAP Family Protein. (2011)
  • Author(s): Katsumi A, Kobayashi M, Matsushita T, Kiyoi H, Kojima T, Maruyama M, Kaibuchi K, Naoe T.
  • Organizer: The American Society of Hematology 53th Annual Meeting
  • Place of Presentation: San Diego, USA
• [Presentation] Retention of Slow-Cycling CD34+ cells During Imatinib Treatment and Rapid Decline After 2nd ABL-TKI Treatment in Ph+ Leukemia Cells. (2011)
  • Author(s): Minami Y, Abe A, Minami M, Kuwatsuka Y, Fukushima N, Kitamura K, Hiraga J, Yamamoto K, Jamieson C, Naoe T.
  • Organizer: The American Society of Hematology 53th Annual Meeting
  • Place of Presentation: San Diego, USA