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

开发针对信号转导子和转录激活子的创新抗肿瘤药物

• 批准号: 23659487
• 负责人: NAOE Tomoki
• 金额: $ 2.33万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23659487/
• 关键词: シグナル伝達; STAT3; STAT5; FLT3; FLT３

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.

我们证明了一种新的STAT抑制剂OPB-31121，在没有上游激酶抑制的情况下，强烈抑制STAT3和STAT5的磷酸化，并诱导了多种造血恶性细胞的显著生长抑制。对多种细胞系的研究表明，OPB-31121对携带BCR-ABL、FLT3/ITD和JAK2 V617F的白血病细胞特别有效，这些致癌激酶的致癌性依赖于STAT3/5。通过免疫缺陷小鼠移植系统，我们也证实了OPB-31121对含有这些异常激酶的人白血病细胞有显著的抗肿瘤作用，并且对正常人脐带血具有安全性。

项目成果

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

• DOI: 10.1007/s12185-011-0766-2
• 发表时间: 2011-02-01
• 期刊: INTERNATIONAL JOURNAL OF HEMATOLOGY
• 影响因子: 2.1
• 作者: Sakai, Katsuya;Ishikawa, Yuichi;Kiyoi, Hitoshi
• 通讯作者: Kiyoi, Hitoshi

Retention of slow-cycling CD34^+ cells during imatinib treatment and rapid decline after 2nd ABL-TKI treatment in Ph^+ leukemia cells

Ph^ 白血病细胞在伊马替尼治疗期间保留慢周期 CD34^ 细胞，并在第 2 次 ABL-TKI 治疗后快速下降

• 发表时间: 2011
• 作者: Yoshiki Omatsu;Tatsuki Sugiyama;Hiroshi Kohara;Gen Kondoh;Nobutaka Fujii N;Kenji Kohno;and Takashi Nagasawa;福島健太郎 ほか;Y Minami
• 通讯作者: Y Minami

B Cell Receptor-ERK1/2 Signal Cancels PAX5-Dependent Repression of BLIMP1 through PAX5 Phosphorylation: A Mechanism of Antigen-Triggering Plasma Cell Differentiation

• DOI: 10.4049/jimmunol.1103039
• 发表时间: 2012-06
• 期刊: The Journal of Immunology
• 作者: T. Yasuda;F. Hayakawa;S. Kurahashi;K. Sugimoto;Y. Minami;A. Tomita;T. Naoe

Wnt signaling is associated with anti-apoptosis in the interaction between acute myeloid leukemia cells and stromal cells

Wnt信号传导与急性髓系白血病细胞和基质细胞相互作用中的抗凋亡相关

• 发表时间: 2012
• 作者: Minami Y;Naoe T;et al
• 通讯作者: et al

Missense mutations in PML-RARA critical for the lack of responsiveness to arsenic trioxide treatment

PML-RARA 的错义突变对于三氧化二砷治疗缺乏反应至关重要

• 发表时间: 2011
• 期刊: Blood
• 影响因子: 20.3
• 作者: Goto E;Hayakawa F他7名
• 通讯作者: Hayakawa F他7名