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.

我们证明了一种新型 STAT 抑制剂 OPB-31121 可以强烈抑制 STAT3 和 STAT5 磷酸化，而不抑制上游激酶，并在各种造血恶性细胞中诱导显着的生长抑制。对各种细胞系的研究表明，OPB-31121 对含有 BCR-ABL、FLT3/ITD 和 JAK2 V617F 的白血病细胞特别有效，致癌激酶的致癌性取决于 STAT3/5。利用免疫缺陷小鼠移植系统，我们还展示了 OPB-31121 对含有异常激酶的原代人白血病细胞的显着抗肿瘤作用以及对正常人脐带血的安全性。

项目成果

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

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

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

Mast cells promote the growth of Hodgkin's lymphoma cell tumor by modifying the tumor microenvironment that can be perturbed by bortezomib

• DOI: 10.1038/leu.2012.81
• 发表时间: 2012-10-01
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Mizuno, H.;Nakayama, T.;Naoe, T.
• 通讯作者: Naoe, T.

CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737

• DOI: 10.1016/j.exphem.2012.05.007
• 发表时间: 2012-09-01
• 期刊: EXPERIMENTAL HEMATOLOGY
• 影响因子: 2.6
• 作者: Shimada, Kazuyuki;Tomita, Akihiro;Naoe, Tomoki
• 通讯作者: Naoe, Tomoki