The role of FoxM1 in pancreatic cancer

FoxM1在胰腺癌中的作用

• 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
• 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; 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

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。胰腺癌是非常致命的，因为它具有对常规治疗的抵抗力，并且迅速传播到淋巴系统和远程器官。因此，重要的是要确定针对PC生​​长的潜在分子事件的新型药物，并通过阻止细胞分裂并选择性地诱导肿瘤细胞凋亡来干扰PC发育。近年来由于其在许多癌症中的重要性而引起关注的一个特殊基因是Forkhead Box M1（FOXM1）。 FOXM1是一个转录因子，可调节细胞周期调节和转移涉及的许多基因的表达。在我们的初步研究中，我们确定抗生素噻唑化合物A siomycin A和硫代蛋白酶是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FOXM1和胰腺癌作用的分子机制。在第一个具体目的中，我们将确定siomycin a/thiostrepton如何抑制FOXM1的转录活性和表达，我们将测试以下假设：FOXM1的下调是导致Siomycin A/thiostrepton诱导PC细胞中细胞凋亡的关键事件。为了评估FOXM1抑制剂作为体内抗癌剂的疗效，我们将通过人胰腺癌细胞系在小鼠中开发的异种移植肿瘤，该肿瘤在体外对噻唑抗生素敏感。在这些小鼠中，将检查神霉素A/硫代蛋白酶治疗对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针对胰腺癌的新药，而且还将促进对FOXM1在PC病因中的作用的更好理解。如果噻唑抗生素的毒性低，导致小鼠的胰腺肿瘤消退，我们将得出结论，这些化合物可能具有进一步抗胰腺癌的临床发育的潜力。公共卫生相关性：胰腺癌是美国癌症死亡的主要原因之一，中位生存期短于六个月。胰腺癌是非常致命的，因为它具有对常规治疗的抵抗力，并且迅速传播到淋巴系统和远程器官。因此，重要的是要确定癌症治疗的新靶标，这将通过阻止细胞分裂并选择性地诱导肿瘤细胞凋亡来干扰胰腺癌的发展。近年来由于其在许多癌症中的过表达而引起关注的一个特定基因是叉子盒M1（FOXM1）。 FOXM1是一个转录因子，可调节与细胞增殖和转移有关的许多基因的表达。在我们的初步研究中，我们确定抗生素噻唑化合物A siomycin A和硫代蛋白酶是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针对胰腺癌的新药，而且还将促进对FOXM1在胰腺癌病因中的作用的更好理解。