STAT3 in the Pathogenesis and Treatment of Pancreatic Cancer

描述（由申请人提供）：尽管胰腺癌是所有常见人类恶性肿瘤中病死率最高的，但其治疗进展相对较小。为了开发更有效、毒性更小的治疗方法，有必要了解癌细胞的关键分子异常，并专门针对这些异常。最近的证据表明，转录因子STAT3的不适当激活可能是胰腺癌细胞恶性行为的关键。我们已经确定了STAT3的直接靶点基因队列，这些基因在原发性人类胰腺癌中作为一组被激活。此外，鉴于STAT3在胰腺癌发病机制中的核心重要性，我们已经开发了一种高通量的基于细胞的筛选方法，可以抑制STAT3的功能。在目前的应用中，我们建议阐明这些STAT3靶基因在胰腺癌生物学中的作用，并评估我们已经确定的用于这种疾病的靶向治疗的分子。具体来说，我们将解决三个目标：确定STAT3靶基因在胰腺癌生物学中的作用；阐明STAT3靶向抑制剂对人胰腺癌细胞基因表达和表型的影响；以及确定STAT3抑制剂在小鼠胰腺癌模型中的活性。通过这项工作，我们的目标是提高我们对胰腺癌分子基础的理解，并开发针对这种疾病的靶向分子治疗。相关性：为了加强胰腺癌的治疗，本提案将重点了解关键转录因子STAT3的异常功能如何直接促进该疾病的发病机制。鉴于这种蛋白在胰腺癌生物学中的重要性，我们已经确定了能够特异性抑制STAT3功能的药物。我们将测试这些药物，以确定它们是否可以作为治疗这种疾病的一种新的靶向形式的原型。

DESCRIPTION (provided by applicant): Although pancreatic cancer has the highest case fatality rate of any common human malignancy, relatively little progress has been made in its treatment. To develop more effective and less toxic therapies it is necessary to understand the key molecular abnormalities of cancer cells, and to target these specifically. Recent evidence has indicated that inappropriate activation of the transcription factor STAT3 may be critical to the malignant behavior of pancreatic carcinoma cells. We have identified a cohort of genes that are immediate targets of STAT3, and which are activated as a group in primary human pancreatic cancers. In addition, given the central importance of STAT3 in pancreatic cancer pathogenesis, we have developed a high throughput cell based screen for small molecules that can inhibit the function of STAT3. In the present application we propose to elucidate the role that these STAT3 target genes play in pancreatic cancer biology, and evaluate the molecules we have identified as targeted therapies for this disease. Specifically, we will address three aims: To determine the role of STAT3 target genes in the biology of pancreatic cancer; to elucidate the effect of targeted STAT3 inhibitors on gene expression and phenotype of human pancreatic cancer cells; and, to determine the activity of STAT3 inhibitors in a murine model of pancreatic cancer. Through this work, we aim to enhance our understanding of the molecular underpinnings of pancreatic cancer, and to develop targeted molecular therapy for this disease. Relevance: To enhance the treatment of pancreatic cancer, this proposal will focus on understanding how the abnormal function of a key transcription factor, STAT3, directly contributes to the pathogenesis of this disease. Given the importance of this protein in the biology of pancreatic cancer, we have identified drugs that can specifically inhibit the function of STAT3. We will test these drugs to determine whether they can be prototypes for a novel targeted form of therapy for this disease.