The role of FoxM1 in pancreatic cancer

描述(申请人提供)：胰腺癌(PC)是美国癌症死亡的主要原因之一，中位生存期不到6个月。胰腺癌非常致命，因为它对常规治疗具有抵抗力，而且它会迅速扩散到淋巴系统和远处的器官。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地诱导肿瘤细胞凋亡来干扰PC发展的新型药物是非常重要的。近年来，由于其在许多癌症中的重要性而受到关注的一个特定基因是叉头盒M1(FOXM1)。FOXM1是一种转录因子，可调节参与细胞周期调控和转移的多个基因的表达。在我们的初步研究中，我们确定了抗生素噻唑类化合物西奥霉素A和硫代链球菌素是FOXM1的有效抑制剂。本研究的目的是探讨FOXM1在胰腺癌发生发展中的作用，并确定西奥霉素A/硫代链球菌素抗FOXM1和胰腺癌的分子机制。在第一个特定的目标中，我们将确定西霉素A/硫链霉菌如何抑制FOXM1的转录活性和表达，并验证FOXM1下调是导致西霉素A/硫链霉菌诱导PC细胞凋亡的关键事件的假说。为了评价FOXM1抑制剂作为体内抗癌药物的有效性，我们将其用于体外抑制对噻唑类抗生素敏感的人胰腺癌细胞株在裸鼠体内的移植瘤。将在这些小鼠中检测西霉素A/硫链霉菌治疗对FOXM1表达和异种移植瘤生长的影响。这些数据不仅有助于开发针对胰腺癌的新药，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作用，并能使小鼠胰腺癌消退，那么这些化合物可能具有进一步开发抗胰腺癌临床应用的潜力。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6个月。胰腺癌非常致命，因为它对常规治疗具有抵抗力，而且它会迅速扩散到淋巴系统和远处的器官。因此，寻找新的肿瘤治疗靶点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预胰腺癌的发展。近年来，由于在许多癌症中过度表达而引起关注的一个特定基因是Forkhead Box M1(FOXM1)。FOXM1是一种转录因子，调节与细胞增殖和转移有关的多个基因的表达。在我们的初步研究中，我们确定了抗生素噻唑类化合物西奥霉素A和硫代链球菌素是FOXM1的有效抑制剂。本研究的目的是探讨FOXM1在胰腺癌发生发展中的作用，并确定西奥霉素A/硫代链球菌素在体内外是否能够抑制胰腺癌的生长。这些数据不仅可能有助于开发针对胰腺癌的新药，还将有助于更好地了解FOXM1在胰腺癌病因中的作用。

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.