シグナル伝達・転写活性化因子を標的とした画期的抗腫瘍剤の開発

• 研究課題/領域番号: 23659487
• 研究種目: 挑戦的萌芽研究
• 配分区分: 基金
• 研究分野: 血液内科学
• 研究機関: 名古屋大学
• 研究代表者: 直江 知樹 名古屋大学, 医学系研究科, 教授 (50217634)
• 研究期間 (年度): 2011 – 2012
• 研究課題ステータス: 完了 (2012年度)
• 配分額: 3,640千円 (直接経費: 2,800千円、間接経費: 840千円); 2012年度: 1,560千円 (直接経費: 1,200千円、間接経費: 360千円); 2011年度: 2,080千円 (直接経費: 1,600千円、間接経費: 480千円)
• キーワード: シグナル伝達 / STAT3 / STAT5 / FLT3 / FLT３

研究概要

In vitro で OPB-31121 の作用機序の解明を行い、本薬剤により JAK2 のリン酸化を阻害する事無く STAT3 のリン酸化が阻害されている事を確認した。多種類の細胞株で本薬剤の薬効を調べ、本薬剤が多彩な造血器悪性腫瘍に対し効果がある中でも、BCR-ABL、FLT3 変異、JAK2 変異を持つ腫瘍細胞は高率に本薬剤感受性である事を発見し、本薬剤適合癌種の選択を行った。更にこうした変異を持つ白血病の患者より採取した白血病細胞、および正常ヒト臍帯血を免疫不全マウスに移植したマウスモデルを作成し、これに対し OPB-31121 を投与し著明な腫瘍退縮効果(T/C: 4～58%)と正常造血細胞への安全性(T/C:99%)を確認した。

研究成果

• [雑誌論文] B Cell Receptor-ERK1/2 Signal Cancels PAX5-Dependent Repression of BLIMP1 through PAX5 Phosphorylation: A Mechanism of Antigen-Triggering Plasma Cell Differentiation (2012)
  • 著者名/発表者名: Yasuda T, Hayakawa F, Kurahashi S, Sugimoto K, Minami Y, Tomita A, Naoe T.
  • 雑誌名: J Immunol. 巻: 188 ページ: 6127-6134
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Shimada K, Tomita A, Minami Y, Abe A, Hind CK, Kiyoi H, Cragg MS, Naoe T
  • 雑誌名: Exp Hematol 巻: 40 ページ: 724-737
  • 査読あり
• [雑誌論文] Mast cells promote the growth of Hodgkin's lymphoma cell tumor by modifying the tumor microenvironment that can be perturbed by bortezomib (2012)
  • 著者名/発表者名: Mizuno H, Nakayama T, Miyata Y, Saito S, Nishiwaki S, Nakao N, Takeshita K, Naoe T
  • 雑誌名: Leukemia 巻: 26 ページ: 2269-2276
  • 査読あり
• [雑誌論文] Retrospective analysis of prognostic factors for angioimmunoblastic T-cell lymphoma: a multicenter cooperative study in Japan (2012)
  • 著者名/発表者名: 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
  • 雑誌名: Blood 巻: 119 ページ: 2837-2843
  • 査読あり
• [雑誌論文] B cell receptor-ERK1/2 signal cancels PAX5-dependent repression of BLIMP1 through PAX5 phosphorylation: a mechanism of antigen-triggering plasma cell differentiation (2012)
  • 著者名/発表者名: Takahiko Yasuda, Fumihiko Hayakawa, Shingo Kurahashi, Keiki Sugimoto , Yosuke Minami, Akihiro Tomita, Tomoki Naoe
  • 雑誌名: Journal of Immunology 巻: 188 号: 12 ページ: 6127-34
  • DOI: 10.4049/jimmunol.1103039
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Shimada K, Tomita A, Minami Y, Kiyoi H, Naoe T et al.
  • 雑誌名: Exp Hematol. 巻: 40 号: 9 ページ: 724-737
  • DOI: 10.1016/j.exphem.2012.05.007
  • 査読あり
• [雑誌論文] Retention of CD34(+) CML stem/progenitor cells during imatinib treatment and rapid decline after treatment with second-generation BCR-ABL inhibitors. (2012)
  • 著者名/発表者名: Minami Y, Abe A, Minami M, Kitamura K, Hiraga J, Mizuno S, Ymamoto K, Sawa M, Inagaki Y, Miyamura K, Naoe T.
  • 雑誌名: Leukemia 巻: 26 号: 9 ページ: 2142-2143
  • DOI: 10.1038/leu.2012.73
  • 査読あり
• [雑誌論文] Mast cells promote the growth of Hodgkin's lymphoma cell tumor by modifying the tumor microenvironment that can be perturbed by bortezomib (2012)
  • 著者名/発表者名: 水野 紘樹
  • 雑誌名: Leukemia 巻: 26 号: 10 ページ: 2269-2269
  • DOI: 10.1038/leu.2012.81
  • 査読あり
• [雑誌論文] B cell receptor-ERK1/2 signal cancels PAX5-dependent repression of BLIMP1 through PAX5 phosphorylation: a mechanism of antigen-triggering plasma cell differentiation. (2012)
  • 著者名/発表者名: Yasuda T, Hayakawa F, Kurahashi S, Sugimoto K, Minami Y, Tomita A, Naoe T.
  • 雑誌名: J Immunol. 巻: in press
  • 査読あり
• [雑誌論文] Retention of CD34(+) CML stem/progenitor cells during imatinib treatment and rapid decline after treatment with second-generation BCR-ABL inhibitors. (2012)
  • 著者名/発表者名: Minami Y, Abe A, Minami M, Kitamura K, Hiraga J, Mizuno S, Yamamoto K, Sawa M, Inagaki Y, Miyamura K, Naoe T.
  • 雑誌名: Leukemia 巻: in press
  • 査読あり
• [雑誌論文] Missense mutations in PML-RARA critical for the lack of responsiveness to arsenic trioxide treatment (2011)
  • 著者名/発表者名: Goto E, Tomita A, Hayakawa F, Atsumi A, Kiyoi H, Naoe T
  • 雑誌名: Blood 巻: 118 ページ: 1600-1609
  • 査読あり
• [雑誌論文] The mTOR inhibitor, everolimus (RAD001), overcomes resistanceto imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells (2011)
  • 著者名/発表者名: Kuwatsuka Y, Minami M, Minami Y, Sugimoto K, Hayakawa F, Miyata Y, Abe A, Goff DJ, Kiyoi H, Naoe T
  • 雑誌名: Blood Cancer J 巻: 1(5)
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Sakai K, Ishikawa Y, Mori Y, Kobayashi M, Iriyama C, Ozawa Y, Suzuki T, Minami Y,Ishikawa K, Kaneda N, Naoe T, Kiyoi H
  • 雑誌名: Int J Hematol 巻: 93 ページ: 237-242
  • NAID: 10029533322
  • 査読あり
• [雑誌論文] PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML (2011)
  • 著者名/発表者名: Kurahashi S, Hayakawa F, Miyata Y, Yasuda T, Minami Y, Tsuzuki S, Abe A, Naoe T
  • 雑誌名: Oncogene 巻: 30 ページ: 1822-1830
  • 査読あり
• [雑誌論文] PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML. (2011)
  • 著者名/発表者名: Kurahashi S, Hayakawa F, Miyata Y, Yasuda T, Minami Y, Tsuzuki S, Abe A, Naoe T.
  • 雑誌名: Oncogene 巻: 30 ページ: 1822-1830
  • 査読あり
• [雑誌論文] Expanded distribution of the T315I mutation among hematopoietic stem cells and progenitors in a chronic myeloid leukemia patient during imatinib treatment (2010)
  • 著者名/発表者名: Minami Y, Kajiguchi T, Abe A, Ohno T, Kiyoi H, Naoe T
  • 雑誌名: Int J Hematol 巻: 92 ページ: 664-666
  • NAID: 10027674164
  • 査読あり
• [雑誌論文] Selective KIT inhibitor KI-328 and HSP90 inhibitor show different potency against the type of KIT mutations recurrently identified in acute myeloid leukemia (2010)
  • 著者名/発表者名: Tsujimura A, Kiyoi H, Shiotsu Y, Ishikawa Y, Mori Y, Ishida H, Toki T, Ito E, Naoe T
  • 雑誌名: Int J Hematol 巻: 92 ページ: 624-633
  • NAID: 10027673999
  • 査読あり
• [学会発表] Wnt Signaling Is Associated with Anti-Apoptosis in the Interaction Between Acute Myeloid Leukemia Cells and Stromal Cells (2012)
  • 著者名/発表者名: Yosuke Minami, Yosuke Niwa, Akihiro Abe, Fumihiko Hayakawa, and Tomoki Naoe
  • 学会等名: The American Society of Hematology 54th Annual Meeting
  • 発表場所: Atlanta (USA).
  • 年月日: 2012-12-08
• [学会発表] Drug Development Targeting Microenvironment for Malignant Lymphoma ASH Annual Meeting Abstracts 2012 120:1661 (2012)
  • 著者名/発表者名: Keiki Sugimoto, Fumihiko Hayakawa, Takahiko Yasuda, and Tomoki Naoe
  • 学会等名: The American Society of Hematology 54th Annual Meeting
  • 発表場所: Atlanta (USA)
  • 年月日: 2012-12-08
• [学会発表] Wnt Signaling Is Associated with Anti-Apoptosis in the Interaction Between Acute Myeloid Leukemia Cells and Stromal Cells. (2012)
  • 著者名/発表者名: Minami Y, Niwa Y, Abe A, Hayakawa F, and Naoe T.
  • 学会等名: 第54回アメリカ血液学会
  • 発表場所: Atlanta (USA)
• [学会発表] Drug Development Targeting Microenvironment for Malignant Lymphoma ASH Annual Meeting Abstracts 2012 120:1661 (2012)
  • 著者名/発表者名: Sugimoto K, Hayakawa F, Yasuda T, and Naoe T.
  • 学会等名: 第54回アメリカ血液学会
  • 発表場所: Atlanta (USA)
• [学会発表] 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)
  • 著者名/発表者名: Hayakawa F, Sugimoto K, Kurahashi S, Sumida T, Naoe T.
  • 学会等名: The American Society of Hematology 53th Annual Meeting
  • 発表場所: San Diego, USA
  • 年月日: 2011-12-10
• [学会発表] Retention of Slow-Cycling CD34+ cells During Imatinib Treatment and Rapid Decline After 2ndABL-TKI Treatment in Ph+ Leukemia Cells (2011)
  • 著者名/発表者名: Minami Y, Abe A, Minami M, Kuwatsuka Y, Fukushima N, Kitamura K, Hiraga J, Yamamoto K, Jamieson C, Naoe T
  • 学会等名: The American Society of Hematology 53th Annual Meeting
  • 発表場所: San Diego, USA
  • 年月日: 2011-12-10
• [学会発表] 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)
  • 著者名/発表者名: Hayakawa F, Sugimoto K, Kurahashi S, Sumida T, Naoe T.
  • 学会等名: The American Society of Hematology 53th Annual Meeting
  • 発表場所: San Diego, USA
• [学会発表] RhoH Downregulates Rac Through RhoGAP Family Protein. (2011)
  • 著者名/発表者名: Katsumi A, Kobayashi M, Matsushita T, Kiyoi H, Kojima T, Maruyama M, Kaibuchi K, Naoe T.
  • 学会等名: The American Society of Hematology 53th Annual Meeting
  • 発表場所: San Diego, USA
• [学会発表] Retention of Slow-Cycling CD34+ cells During Imatinib Treatment and Rapid Decline After 2nd ABL-TKI Treatment in Ph+ Leukemia Cells. (2011)
  • 著者名/発表者名: Minami Y, Abe A, Minami M, Kuwatsuka Y, Fukushima N, Kitamura K, Hiraga J, Yamamoto K, Jamieson C, Naoe T.
  • 学会等名: The American Society of Hematology 53th Annual Meeting
  • 発表場所: San Diego, USA