A Novel Inhibitor of Stat3 for Prostate Cancer Therapy

用于前列腺癌治疗的新型 Stat3 抑制剂

基本信息

批准号：
7350927
负责人：
NAIJIE JING
金额：
$ 28.09万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7350927
关键词：
Accounting American Androgens Apoptosis Apoptotic Binding Biological Assay Cancer Etiology Carcinoma Cell Proliferation Cells Cessation of life Clinical Clinical Research Clinical Trials Combined Modality Therapy Condition Cultured Cells DNA Binding DNA delivery Development Drug Delivery Systems Drug Design Drug Kinetics EMSA Effectiveness Electrophoretic Mobility Shift Assay Epithelial Cells G-Quartets Gene Expression Genes Goals Growth Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Intraperitoneal Injections Intravenous Lead Length Lipids Malignant Neoplasms Malignant neoplasm of prostate Mediating Mediator of activation protein Metastatic Prostate Cancer Modeling Mus Nude Mice Numbers Oligonucleotides Oncogenic Patients Pharmaceutical Preparations Prostate Cancer therapy Prostate carcinoma Prostatic Neoplasms Research Personnel STAT protein Second Primary Cancers Signal Transduction Structure Structure-Activity Relationship System Therapeutic Time Tissues Toxic effect United States Xenograft Model Antitumor Assays Xenograft procedure androgen independent prostate cancer antitumor agent base cancer cell cancer diagnosis cancer therapy design dimer in vitro Assay in vivo inhibitor/antagonist malignant breast neoplasm member men molecular modeling neoplastic cell novel novel strategies programs src Homology Region 2 Domain tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is one of the most frequently diagnosed cancers and the second leading cause of cancer death in American men. Current treatments for androgen-independent prostate cancer have not shown a definitive increase in survival. The treatment options employed for patients with advanced and metastatic prostate cancer are limited. Stat3 is a critical mediator of oncogenic signaling, which is active in 82% of prostate cancers as well as many other cancers. However, drugs targeting Stat3 have not been used to treat prostate cancer. Our goal is to develop a novel, potent inhibitor of Stat3 as a therapeutic drug for prostate cancer therapy. Developing a novel and promising treatment for prostate cancer will be greatly helpful both in terms of single agent treatment and as part of a combination therapy. We propose a novel strategy to inhibit Stat3, which could be very useful in development of prostate cancer therapy, and have developed a G-quartet oligodeoxynucleotide (GQ-ODN), T40214, as a lead compound that preferentially inhibits the DNA-binding activation of Stat3 among STAT protein members, resulting in the suppression of the anti-apoptotic genes, bcl-x and Mcl-1, in cancer cells. We also have constructed a model of GQ-ODN binding onto Stat3a dimer for rational drug design. The molecular model suggests that the GQ-ODN insert between the two SH2 domains of Stat3 dimer resulting in destabilization of the homodimers. We further show that T40214 and its derivative, T40231, have dramatic in vivo effects on prostate cancer growth in nude mice when the agent is given by intravenous or intraperitoneal injections, dramatically retarding tumor growth and significantly increasing the length of survival time. Also GQ-ODNs greatly increase the number of apoptotic cells in tumors, showing the agents using apoptosis to eliminate tumor cells. The Specific Aims designed to achieve this objective are outlined as below. (1) To develop a potent inhibitor of Stat3 to suppress the growth of prostate cancer cells in cell culture. The strategy to achieve this specific aim contains three parts: (i) rational drug design, which will include structure-based drug design and rational optimization, (ii) oligonucleotide synthesis, and (iii) Stat3 activity assays in vitro. (2) To develop an optimally effective intracellular and intranuclear delivery system for GQ-ODNs. In this aim, we will use our novel drug delivery system to determine the optimum conditions for intracellular delivery of G-quartet inhibitors, e.g. T40214 and its derivatives, in vivo. (3) To determine the effect of GQ-ODNs on Stat3 activity and the growth of prostate tumors in vivo. Using nude mice tumor xenograft assays, we will determine whether GQ-ODNs, T40214 and its derivatives, can block or control the growth of prostate tumors in xenografted mice; whether the anti-tumor effects of GQ-ODNs are on both non-androgen and androgen responsiveness; whether the suppression of tumor growth for GQ-ODNs is mediated by enhanced apoptosis of tumor cells.

描述（由申请人提供）：前列腺癌是美国男性最常见的癌症和癌症死亡的第二大原因之一。目前对雄激素非依赖性前列腺癌的治疗尚未显示出生存期的明确增加。晚期和转移性前列腺癌患者采用的治疗选择有限。 STAT3是致癌信号传导的关键介体，它在82％的前列腺癌以及许多其他癌症中都活跃。但是，针对STAT3的药物尚未用于治疗前列腺癌。我们的目标是开发一种新型的，有效的STAT3抑制剂，作为前列腺癌治疗的治疗药物。在单一药物治疗和组合疗法的一部分方面，开发一种新颖的前列腺癌治疗方法都将非常有帮助。 We propose a novel strategy to inhibit Stat3, which could be very useful in development of prostate cancer therapy, and have developed a G-quartet oligodeoxynucleotide (GQ-ODN), T40214, as a lead compound that preferentially inhibits the DNA-binding activation of Stat3 among STAT protein members, resulting in the suppression of the anti-apoptotic genes, bcl-x and Mcl-1, in癌细胞。我们还构建了一种在STAT3A二聚体上的GQ-ODN模型，以进行合理的药物设计。分子模型表明，在STAT3二聚体的两个SH2域之间插入GQ-ODN，从而导致同型二聚体的稳定。我们进一步表明，当该药物通过静脉注射或腹膜内注射给药时，T40214及其衍生物T40231对裸鼠的前列腺癌生长产生了巨大的体内影响，肿瘤的生长显着延迟，并显着增加了生存时间的长度。同样，GQ-ODN大大增加了肿瘤中凋亡细胞的数量，显示了使用凋亡来消除肿瘤细胞的药物。旨在实现此目标的具体目标如下所述。（1）开发一种有效的STAT3抑制剂来抑制细胞培养中前列腺癌细胞的生长。实现此特定目标的策略包含三个部分：（i）合理的药物设计，其中包括基于结构的药物设计和合理优化，（ii）寡核苷酸合成，以及（iii）体外STAT3活性测定。（2）为GQ-ODN开发最佳有效的细胞内和核内输送系统。在此目标中，我们将使用新型的药物输送系统来确定G Quartet抑制剂的细胞内递送的最佳条件，例如T40214及其衍生物，体内。（3）确定GQ-ODNS对Stat3活性和体内前列腺肿瘤生长的影响。使用裸鼠肿瘤异种移植分析，我们将确定GQ-ODNS，T40214及其衍生物是否可以阻止或控制异种移植小鼠前列腺肿瘤的生长。 GQ-ODNs的抗肿瘤作用是否对非源基因和雄激素反应性均为抗肿瘤； GQ-ODN肿瘤生长的抑制是否通过肿瘤细胞凋亡的增强介导。