STATs as a Novel Approach to Cancer Therapy

描述(由申请人提供)：信号转导和转录激活蛋白(STAT)家族最初是在细胞对细胞因子和生长因子的反应中发现的。在正常细胞中，STAT蛋白只被瞬时激活，这对于它们在细胞生长和分化、发育、炎症和生存等生理过程中发挥关键作用非常重要。然而，这个转录因子家族的某些成员的持续激活，特别是STAT3，已被发现伴随着恶性转化。在实体和血液肿瘤中，包括乳腺癌、前列腺癌、头颈部鳞状细胞癌、黑色素瘤和多发性骨髓瘤，这种持续的STAT3活性在肿瘤发生中的因果作用已经被确立，从而证实了STAT3是临床上发现抗癌药物的重要靶点。由于目前还没有STAT3的直接药理抑制剂，因此这一应用的目标是寻找有潜力用于癌症治疗的有效的小分子STAT3抑制剂。我们已经在鉴定一些选择性抑制STAT3信号的先导化合物方面取得了进展。这一应用的中心假设是，STAT3信号的小分子抑制剂将诱导肿瘤细胞的生长抑制和凋亡，从而阻止肿瘤生长。这一假设将通过以下具体目标来解决：(1)。开发STAT3二聚化、DNA结合和致癌信号转导的小分子抑制剂。将开发模拟多肽的方法来阻止STAT3蛋白通过其SH2结构域的二聚化。将采用基于结构的方法和组合方法将铅多肽转化为生物活性物质；目的：评价新型多肽类药物对STAT3的有效抑制作用及其在体外和全细胞中的生物学效应。在体外，DNA结合活性和基于细胞的报告分析将用于筛选化合物。软琼脂生长、原位末端标记法、Annexin V-FITC染色检测化合物的生物学效应；目的：评价上述有效化合物在小鼠人肿瘤模型中的抗肿瘤作用。研究将评估这些化合物的毒性和抗肿瘤效果的程度。拟议的研究将提炼和进一步开发先导化合物，使其成为具有抗肿瘤活性的有效的STAT3抑制剂，最终应用于临床。

DESCRIPTION (provided by applicant): Signal Transducer and Activator of Transcription (STAT) family of proteins were originally discovered in context of cellular responses to cytokines and growth factors. In normal cells, STAT proteins are only transiently activated, which is important for their key roles in physiological process, including cell growth and differentiation, development, inflammation and survival. However, persistent activation of certain members of this family of transcription factors, particularly Stat3, has been found to accompany malignant transformation. In both solid and hematological tumors, including breast cancer, prostate cancer, head and neck squamous cell carcinomas, melanoma and multiple myeloma, a causal role for this persistent Stat3 activity in oncogenesis has been established, thereby validating Stat3 as a clinically important target for cancer drug discovery. Since currently there are no direct pharmacological inhibitors of Stat3, the goal of this application is to identify potent small molecule Stat3 inhibitors with the potential to be used as cancer therapeutics. We have already made progress in identifying a number of lead compounds selective for inhibition of Stat3 signaling. The central hypothesis of this application is that small-molecule inhibitors of Stat3 signaling will induce growth inhibition and apoptosis in malignant cells, and thereby block tumor growth. The hypothesis will be addressed by the following Specific Aims: (1). To develop small-molecule inhibitors of Stat3 dimerization, DNA-binding and oncogenic signaling. Peptidomimetic approaches will be developed to block dimerization of Stat3 proteins though their SH2 domains. Structure-based and combinatorial methods will be used to convert lead peptides into biologically active agents; (2). To evaluate novel peptidomimetics for potent inhibitory effects against Stat3 and its biological effects in vitro and in whole cells. In vitro DNA binding activity and cell-based reporter assays will be used for screening of compounds. Soft-agar growth, TUNEL assay, and Annexin V-FITC staining will measure biological effects of compounds; (3). To evaluate the antitumor effects of potent compounds identified above in human tumor models in mice. Studies will assess toxicity and degree of efficacy of these compounds against tumors. The proposed studies will refine and further develop lead compounds as potent Stat3 inhibitors with antitumor activities for eventual clinical applications