The role of FoxM1 in 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6个月。胰腺癌是非常致命的，因为它对常规治疗有抵抗力，并迅速扩散到淋巴系统和远端器官。因此，它是重要的，以确定新的药物，目标的PC生长的潜在分子事件和干扰PC的发展，通过阻断细胞分裂和选择性诱导肿瘤细胞凋亡。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定基因是叉头盒M1（FoxM 1）。FoxM 1是一种转录因子，调节参与细胞周期调节和转移的许多基因的表达。在我们的初步研究中，我们确定了抗生素噻唑化合物Siomycin A和硫链丝菌素作为FoxM 1的有效抑制剂。该提案的目的是研究FoxM 1在胰腺癌发展中的作用，并确定Siomycin A/thiostrepton对FoxM 1和胰腺癌的分子作用机制。在第一个具体目标中，我们将确定Siomycin A/硫链丝菌素如何抑制FoxM 1的转录活性和表达，并且我们将测试FoxM 1的下调是导致Siomycin A/硫链丝菌素诱导的PC细胞凋亡的关键事件的假设。为了评估FoxM 1抑制剂作为体内抗癌剂的功效，我们将使用它们对抗由人胰腺癌细胞系在无胸腺小鼠中形成的异种移植肿瘤，所述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/硫链丝菌素处理对FoxM 1表达和异种移植肿瘤生长的影响。这些数据不仅有助于开发治疗胰腺癌的新药，还有助于更好地理解FoxM 1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进一步临床开发胰腺癌的潜力。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6个月。胰腺癌是非常致命的，因为它对常规治疗有抵抗力，并迅速扩散到淋巴系统和远端器官。因此，重要的是确定癌症治疗的新靶点，这将有助于通过阻断细胞分裂和选择性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度表达而引起关注的一个特定基因是叉头盒M1（FoxM 1）。FoxM 1是一种转录因子，调节参与细胞增殖和转移的许多基因的表达。在我们的初步研究中，我们确定了抗生素噻唑化合物Siomycin A和硫链丝菌素作为FoxM 1的有效抑制剂。该提案的目的是研究FoxM 1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。这些数据不仅有助于开发治疗胰腺癌的新药，还有助于更好地了解FoxM 1在胰腺癌病因学中的作用。

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.