The role of FoxM1 in pancreatic cancer

FoxM1在胰腺癌中的作用

基本信息

批准号：
7638585
负责人：
ANDREI L GARTEL
金额：
$ 24.73万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-16 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7638585
关键词：
Animal Model Animals Antibiotics Antineoplastic Agents Apoptosis Apoptosis Promoter Attention Binding Boxing Cancer Etiology Cancer cell line Cell Culture Techniques Cell Cycle Regulation Cell Proliferation Cell division Cessation of life Clinical Data Development Dose Down-Regulation Drug Delivery Systems Duct (organ) structure Erinaceidae Etiology Event Exhibits FDA approved Family Genes Goals Growth Head of pancreas Human Human Activities In Vitro Induction of Apoptosis Lead Liver Lung Lymphatic System Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Mammalian Cell Matrix Metalloproteinases Maximum Tolerated Dose Mediating Molecular Molecular Mechanisms of Action Mus Neoplasm Metastasis Normal Cell Nude Mice Oncogenes Oncogenic Organ Parasitic infection Pathway interactions Pattern Pharmaceutical Preparations Principal Investigator Resistance Ribosomal RNA Role Structure Testing Thiazoles Thiostrepton Tissues Toxic effect Translations Tumor Suppressor Proteins United States Xenograft procedure anticancer activity antitumor drug cancer cell cancer therapy cell growth cell motility conventional therapy efficacy testing gemcitabine in vivo inhibitor/antagonist innovation killings migration mouse model neoplastic cell novel novel therapeutics overexpression pancreatic neoplasm programs public health relevance research study response siomycin A transcription factor treatment strategy tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is one of the leading causes of cancer death in the United States with a median survival shorter than six months. Pancreatic cancer is very deadly, because it is resistant to conventional treatments and it rapidly disseminates to the lymphatic system and remote organs. Hence, it is important to identify novel drugs that target the underlying molecular events of PC growth and interfere with PC development by blocking cell division and selectively inducing tumor cell apoptosis. One particular gene that has gained attention in recent years due to its importance in a number of cancers is Forkhead Box M1 (FoxM1). FoxM1 is a transcription factor that regulates the expression of a number of genes that are involved in cell cycle regulation and metastasis. In our preliminary studies, we identified the antibiotic thiazole compounds Siomycin A and thiostrepton as potent inhibitors of FoxM1. The goal of this proposal is to investigate the role of FoxM1 in the development of pancreatic cancer and to determine the molecular mechanisms of action of Siomycin A/thiostrepton against FoxM1 and pancreatic cancer. In the first specific aim we will determine how Siomycin A/thiostrepton inhibit the transcriptional activity and expression of FoxM1 and we will test the hypothesis that downregulation of FoxM1 is the key event that leads to Siomycin A/thiostrepton-induced apoptosis in PC cells. To evaluate the efficacy of FoxM1 inhibitors as anticancer agents in vivo, we will use them against xenograft tumors developed in athymic mice by human pancreatic cancer cell lines, which are sensitive to thiazole antibiotics in vitro. The effect of Siomycin A/thiostrepton treatment on FoxM1 expression and growth of xenograft tumors will be examined in these mice. These data may not only help to develop new drugs against pancreatic cancer, but they will also facilitate better understanding of the role of FoxM1 in the etiology of PC. If the thiazole antibiotics have low toxicity and lead to pancreatic tumor regression in mice, we will conclude that these compounds may have a potential for further clinical development against pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is one of the leading causes of cancer death in the United States with a median survival shorter than six months. Pancreatic cancer is very deadly, because it is resistant to conventional treatments and it rapidly disseminates to the lymphatic system and remote organs. Therefore, it is important to identify novel targets for cancer therapy that will help to interfere with development of pancreatic cancer by blocking cell division and selectively inducing tumor cell apoptosis. One particular gene that has gained attention in recent years due to its overexpression in a number of cancers is Forkhead Box M1 (FoxM1). FoxM1 is a transcription factor that regulates the expression of a number of genes that are involved in cell proliferation and metastasis. In our preliminary studies, we identified the antibiotic thiazole compounds Siomycin A and thiostrepton as potent inhibitors of FoxM1. The goal of this proposal is to investigate the role of FoxM1 in the development of pancreatic cancer and to determine if Siomycin A/thiostrepton will be able to inhibit growth of pancreatic tumors in vitro and vivo. These data may not only help to develop new drugs against pancreatic cancer, but they will also facilitate better understanding of the role of FoxM1 in the etiology of pancreatic cancer.

描述（由申请人提供）：胰腺癌（PC）是美国癌症死亡的主要原因之一，中位生存期短于六个月。胰腺癌非常致命，因为它对常规治疗有抵抗力，并且会迅速扩散到淋巴系统和远端器官。因此，寻找针对 PC 生长的潜在分子事件并通过阻断细胞分裂和选择性诱导肿瘤细胞凋亡来干扰 PC 发育的新药物非常重要。 Forkhead Box M1 (FoxM1) 是近年来因其在多种癌症中的重要性而受到关注的一个特殊基因。 FoxM1 是一种转录因子，可调节许多参与细胞周期调节和转移的基因的表达。在我们的初步研究中，我们确定抗生素噻唑化合物 Siomycin A 和硫链丝菌素是 FoxM1 的有效抑制剂。该提案的目的是研究 FoxM1 在胰腺癌发展中的作用，并确定 Siomycin A/thiostrepton 对抗 FoxM1 和胰腺癌的分子机制。在第一个具体目标中，我们将确定 Siomycin A/thiostrepton 如何抑制 FoxM1 的转录活性和表达，并且我们将测试 FoxM1 的下调是导致 Siomycin A/thiostrepton 诱导 PC 细胞凋亡的关键事件的假设。为了评估 FoxM1 抑制剂作为体内抗癌药物的功效，我们将使用它们来对抗由人类胰腺癌细胞系在无胸腺小鼠中产生的异种移植肿瘤，这些细胞系在体外对噻唑类抗生素敏感。将在这些小鼠中检查 Siomycin A/thiostrepton 治疗对 FoxM1 表达和异种移植肿瘤生长的影响。这些数据不仅可能有助于开发抗胰腺癌的新药，而且还将有助于更好地了解 FoxM1 在 PC 病因学中的作用。如果噻唑类抗生素具有低毒性并导致小鼠胰腺肿瘤消退，我们将得出结论，这些化合物可能具有针对胰腺癌的进一步临床开发的潜力。公共卫生相关性：胰腺癌是美国癌症死亡的主要原因之一，中位生存期不到六个月。胰腺癌非常致命，因为它对常规治疗有抵抗力，并且会迅速扩散到淋巴系统和远端器官。因此，确定癌症治疗的新靶标非常重要，这些靶标将通过阻止细胞分裂和选择性诱导肿瘤细胞凋亡来帮助干扰胰腺癌的发展。 Forkhead Box M1 (FoxM1) 是近年来因其在多种癌症中过度表达而受到关注的一个特殊基因。 FoxM1 是一种转录因子，调节许多参与细胞增殖和转移的基因的表达。在我们的初步研究中，我们确定抗生素噻唑化合物 Siomycin A 和硫链丝菌素是 FoxM1 的有效抑制剂。该提案的目的是研究 FoxM1 在胰腺癌发展中的作用，并确定 Siomycin A/thiostrepton 是否能够在体外和体内抑制胰腺肿瘤的生长。这些数据不仅可能有助于开发抗胰腺癌的新药，而且还将有助于更好地了解 FoxM1 在胰腺癌病因学中的作用。