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）：前列腺癌是最常诊断的癌症之一，也是美国男性癌症死亡的第二大原因。目前对雄激素非依赖性前列腺癌的治疗尚未显示出生存率的明确增加。用于晚期和转移性前列腺癌患者的治疗选择是有限的。 Stat3 是致癌信号传导的关键介质，在 82% 的前列腺癌以及许多其他癌症中活跃。然而，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、有效的 Stat3 抑制剂作为前列腺癌的治疗药物。开发一种新颖且有前景的前列腺癌治疗方法无论是在单药治疗还是作为联合治疗的一部分方面都将非常有帮助。我们提出了一种抑制 Stat3 的新策略，这对于前列腺癌治疗的开发非常有用，并且开发了 G 四联寡脱氧核苷酸 (GQ-ODN) T40214，作为先导化合物，优先抑制 Stat3 的 DNA 结合激活STAT 蛋白成员中的 Stat3 可抑制癌细胞中的抗凋亡基因 bcl-x 和 Mcl-1。我们还构建了 GQ-ODN 与 Stat3a 二聚体结合的模型，用于合理的药物设计。分子模型表明，Stat3 二聚体的两个 SH2 结构域之间的 GQ-ODN 插入导致同源二聚体不稳定。我们进一步表明，当通过静脉内或腹膜内注射给予T40214及其衍生物T40231时，T40214及其衍生物T40231对裸鼠体内前列腺癌的生长具有显着的体内作用，显着延缓肿瘤生长并显着增加生存时间。 GQ-ODN 还大大增加了肿瘤中凋亡细胞的数量，表明该药物利用细胞凋亡来消除肿瘤细胞。为实现这一目标而设计的具体目标概述如下。 (1) 开发一种有效的Stat3抑制剂来抑制细胞培养物中前列腺癌细胞的生长。实现这一具体目标的策略包含三个部分：(i) 合理药物设计，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) Stat3 体外活性测定。 (2) 开发最有效的 GQ-ODN 细胞内和核内递送系统。为此，我们将使用我们的新型药物递送系统来确定 G-四联体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对体内Stat3活性和前列腺肿瘤生长的影响。通过裸鼠肿瘤异种移植试验，我们将确定GQ-ODN、T40214及其衍生物是否可以阻断或控制异种移植小鼠中前列腺肿瘤的生长； GQ-ODN 的抗肿瘤作用是否同时影响非雄激素和雄激素反应； GQ-ODN 对肿瘤生长的抑制是否是通过增强肿瘤细胞的凋亡来介导的。