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STAT3 in the Pathogenesis and Treatment of Pancreatic Cancer

STAT3在胰腺癌发病机制和治疗中的作用

基本信息

批准号：
7268155
负责人：
DAVID A. FRANK
金额：
$ 17.51万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-27 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7268155
关键词：
Address Animal Model Apoptosis Behavior Biological Assay Biology Cancer Biology Carcinoma Case Fatality Rates Cells Clinical Development Disease Family Family member Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Goals Human Knowledge Life Expectancy Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator of activation protein Modeling Molecular Molecular Abnormality Molecular Target Mus Numbers Pancreatic Adenocarcinoma Pancreatic carcinoma Pathogenesis Patients Pharmaceutical Preparations Phenotype Play Proteins Purpose Research Personnel Resistance Role STAT protein STAT3 gene Screening procedure Specimen System Therapeutic Toxic effect Transgenic Animals Tumorigenicity Work base cancer cell cancer therapy chemotherapeutic agent cohort cytotoxic drug testing inhibitor/antagonist insight malignant phenotype novel prototype research study small molecule transcription factor tumor tumorigenic

项目摘要

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.

描述（由申请人提供）：尽管胰腺癌在任何常见的人类恶性肿瘤中具有最高的病死率，但其治疗进展相对较小。为了开发更有效和毒性更小的治疗方法，有必要了解癌细胞的关键分子异常，并针对这些特异性。最近的证据表明，转录因子STAT 3的不适当激活可能是胰腺癌细胞恶性行为的关键。我们已经确定了一组基因，它们是STAT 3的直接靶点，并且在原发性人类胰腺癌中作为一组被激活。此外，鉴于STAT 3在胰腺癌发病机制中的核心重要性，我们已经开发了一种基于细胞的高通量筛选可以抑制STAT 3功能的小分子的方法。在本申请中，我们提出阐明这些STAT 3靶基因在胰腺癌生物学中发挥的作用，并评估我们已经鉴定为该疾病的靶向疗法的分子。具体而言，我们将解决三个目标：确定STAT 3靶基因在胰腺癌生物学中的作用;阐明靶向STAT 3抑制剂对人胰腺癌细胞基因表达和表型的影响;以及确定STAT 3抑制剂在胰腺癌小鼠模型中的活性。通过这项工作，我们的目标是提高我们对胰腺癌的分子基础的理解，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，该提案将重点关注关键转录因子STAT 3的异常功能如何直接导致这种疾病的发病机制。鉴于这种蛋白质在胰腺癌生物学中的重要性，我们已经确定了可以特异性抑制STAT 3功能的药物。我们将测试这些药物，以确定它们是否可以成为治疗这种疾病的新型靶向治疗形式的原型。