Mechanisms of WNT7A-FGF1 signaling and their therapeutic potential in ovarian can

描述（申请人提供）：卵巢癌是最致命的妇科恶性肿瘤。高死亡率主要是由于发病时病情进展较晚。在过去的20年里，卵巢癌的总体存活率并没有显著提高。由于没有很好的标志物来检测早期疾病，因此确定改善当前卵巢癌治疗的治疗靶点，以防止肿瘤生长和进展，以及卵巢肿瘤向继发器官的扩散（转移）是很重要的。我们最近的研究结果支持WNT7A在WNT/？连环蛋白通路。我们进一步的研究表明FGF1是WNT7A/？-catenin信号靶基因，具有致癌活性，通过下调卵巢癌中CDH1介导上皮-间质转化（EMT）。此外，奈洛沙胺被选为抑制wnt7a依赖性TCF/LEF报告细胞活性、FGF1水平和细胞活力以及体内肿瘤进展的最有效药物。因此，本提案的目的是研究WNT7A-FGF1信号传导的机制，具体来说，研究FGF1是否是WNT7A/？-catenin信号，以及WNT7A-FGF1信号是否具有促进肿瘤进展、传播和/或转移的活性。此外，我们将通过抑制WNT7A/?来确定氯硝柳胺是否可以成为卵巢癌治疗的有效药物。-catenin-FGF1信号。目的1，我们将评估FGF1是否是WNT7A/？-连环蛋白信号。我们还将研究WNT和FGF级联在卵巢癌中的影响，确定FGF1是否激活PI3K/Akt信号，导致Snail-EMT级联促进转移进展，其激活依赖于WNT7A。目的2，我们将评估氯硝柳胺对WNT7A/？-catenin-FGF1信号。我们还将确定奈洛沙胺对卵巢癌临床前细胞功能、肿瘤进展和转移的影响。此外，我们将研究氯硝柳胺对化疗耐药卵巢癌的影响，以确定氯硝柳胺是否能诱导化疗耐药细胞死亡。由于迫切需要新的药物来治疗这种毁灭性的疾病，如果确定在临床前环境中有希望，氯硝柳胺可能在临床环境中对卵巢癌患者的生活产生巨大的影响。

DESCRIPTION (provided by applicant): Ovarian cancer is the most lethal gynecological malignancy. The high mortality is primarily due to the advanced stage of the disease at presentation. The overall survival rate of ovarian cancer has not been significantly increased over the last 20 years. Because there are no good markers to detect early disease, it is important to identify therapeutic targets that improve current ovarian cancer treatment in order to prevent tumor growth and progression, as well as ovarian tumor dissemination to secondary organs (metastasis). Our recent findings support the idea that WNT7A plays a critical role in ovarian cancer tumor progression mediated by the WNT/?-catenin pathway. Our further studies indicate that FGF1 is a WNT7A/?-catenin signaling target gene that possesses oncogenic activity leading to epithelial-mesenchymal transition (EMT) through the down-regulation of CDH1 in ovarian carcinomas. Further, Niclosamide is selected as the most efficient drug to inhibit the activity of WNT7A-dependent TCF/LEF reporter, FGF1 level and cell viability as well as in vivo tumor progression. Therefore, the goal of this proposal is to examine the mechanisms of WNT7A-FGF1 signaling, specifically, addressing whether FGF1 is a downstream target of WNT7A/?-catenin signaling, and whether WNT7A-FGF1 signaling has activity to promote tumor progression, dissemination and/or metastasis. Further, we will determine whether Niclosamide can be a useful drug for ovarian cancer treatment through inhibition of WNT7A/?-catenin-FGF1 signaling. Aim1, we will assess whether FGF1 is a transcriptional target of WNT7A/?- catenin signaling. We will also examine the impact of the WNT and FGF cascade in ovarian cancer, determining whether FGF1 activates PI3K/Akt signaling leading to Snail-EMT cascade to promote metastatic progression, and its activation is dependent on WNT7A. Aim2, we will assess the target mechanisms of Niclosamide on WNT7A/?-catenin-FGF1 signaling. We will also determine the effect of Niclosamide on cell function, and tumor progression and metastasis in ovarian cancer pre-clinical settings. Further, we will examine the impact of Niclosamide on chemoresistant ovarian carcinomas to determine whether Niclosamide can induce death in chemoresistant cells. Because new drugs are desperately needed to treat this devastating disease, if determined to be promising in a pre-clinical setting, Niclosamide may have a tremendous impact on the lives of ovarian cancer patients in the clinical setting.