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.
Successful completion of the proposed research will provide novel mechanisms and targets for therapeutic strategies to suppress ovarian cancer progression and metastasis. Further, drug re-purposing of Niclosamide could be a rapidly-distributed, potential therapy for the treatment of ovarian cancer patients.
|Stodden, G R; Lindberg, M E; King, M L et al. (2015) Loss of Cdh1 and Trp53 in the uterus induces chronic inflammation with modification of tumor microenvironment. Oncogene 34:2471-82|
|King, M L; Lindberg, M E; Stodden, G R et al. (2015) WNT7A/Î²-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer. Oncogene 34:3452-62|
|Yoshioka, Shin; King, Mandy L; Ran, Sophia et al. (2012) WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/Î²-catenin pathway. Mol Cancer Res 10:469-82|