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

WNT7A-FGF1 信号传导机制及其在卵巢癌中的治疗潜力

基本信息

批准号：
8572502
负责人：
KANAKO HAYASHI
金额：
$ 44.25万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8572502
关键词：
Address CDH1 gene Cancer Patient Carcinoma Cell Cycle Cell Survival Cell physiology Cells Cessation of life Clinical Cyclin D1 Diffuse Pattern Disease Down-Regulation Epithelial Epithelial ovarian cancer FGF1 gene Family Fibroblast Growth Factor Gene Targeting Genes Goals Human Invaded Lead Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Mediating Mesenchymal Metastatic to Molecular Neoplasm Metastasis Oncogenic Organ Ovarian Ovarian Carcinoma Pathway interactions Patients Pharmaceutical Preparations Play Relative (related person)Reporter Reporting Research Role Secondary to Serous Signal Pathway Signal Transduction Snails Staging Survival Rate Testing Therapeutic Tumor Tissue United States Food and Drug Administration Up-Regulation WNT7A gene cancer cell cancer therapy epithelial to mesenchymal transition improved in vivo member mortality novel ovarian neoplasm overexpression pre-clinical prevent programs public health relevance therapeutic target tumor growth tumor progression

项目摘要

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.

描述（由申请人提供）：卵巢癌是最致命的妇科恶性肿瘤。高死亡率主要是由于该病就诊时已处于晚期。过去20年来，卵巢癌的总体生存率并未显着提高。由于没有良好的标记物来检测早期疾病，因此确定改善当前卵巢癌治疗的治疗靶点非常重要，以防止肿瘤生长和进展，以及卵巢肿瘤扩散到次要器官（转移）。我们最近的研究结果支持这样的观点，即 WNT7A 在 WNT/β-catenin 通路介导的卵巢癌肿瘤进展中发挥着关键作用。我们的进一步研究表明，FGF1 是 WNT7A/β-catenin 信号转导靶基因，具有致癌活性，通过下调卵巢癌中的 CDH1 导致上皮间质转化 (EMT)。此外，氯硝柳胺被选为抑制 WNT7A 依赖性 TCF/LEF 报告基因活性、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，特别是解决FGF1是否是WNT7A/β-catenin信号传导的下游靶点，以及WNT7A-FGF1信号传导是否具有促进肿瘤进展、扩散和扩散的活性。 /或转移。此外，我们将确定氯硝柳胺是否可以通过抑制 WNT7A/β-catenin-FGF1 信号传导成为治疗卵巢癌的有用药物。 Aim1，我们将评估 FGF1 是否是 WNT7A/β-连环蛋白信号传导的转录靶标。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，并且其激活依赖于WNT7A。 Aim2，我们将评估氯硝柳胺对 WNT7A/β-连环蛋白-FGF1 信号传导的靶作用机制。我们还将确定氯硝柳胺对卵巢癌临床前环境中细胞功能以及肿瘤进展和转移的影响。此外，我们将检查氯硝柳胺对化疗耐药性卵巢癌的影响，以确定氯硝柳胺是否可以诱导化疗耐药细胞死亡。由于迫切需要新药来治疗这种毁灭性的疾病，如果在临床前环境中确定有希望，那么氯硝柳胺可能会对临床环境中卵巢癌患者的生活产生巨大影响。