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疾病的晚期阶段。在过去的20年中，卵巢癌的总生存率尚未显着升高。由于没有良好的标记来检测早期疾病，因此必须确定改善当前卵巢癌治疗的治疗靶标，以防止肿瘤的生长和进展，以及卵巢肿瘤向继发器官（转移）传播。我们最近的发现支持这样的想法：Wnt7a在Wnt/？ - Catenin途径介导的卵巢癌肿瘤进展中起着至关重要的作用。我们的进一步研究表明，FGF1是Wnt7a/？ - catenin信号传导靶基因，具有致癌活性，从而通过卵巢癌中的CDH1下调导致上皮 - 间质转变（EMT）。此外，烟酰胺被选为抑制Wnt7a依赖性TCF/LEF报告基因，FGF1水平和细胞活力以及体内肿瘤进展的最有效药物。因此，该提案的目的是检查WNT7A-FGF1信号传导的机制，特别是解决FGF1是否是Wnt7a/？ - catenin信号传导的下游目标，以及Wnt7A-FGF1信号传导是否具有促进毛刺进展，散发和/或转移的活性。此外，我们将通过抑制wnt7a/？ - catenin-fgf1信号传导来确定烟酰胺是否可以成为卵巢癌治疗的有用药物。 AIM1，我们将评估FGF1是否是wnt7a/？ - catenin信号传导的转录靶标。我们还将检查Wnt和FGF级联对卵巢癌的影响，确定FGF1是否激活PI3K/AKT信号传导导致蜗牛-EMT级联反应以促进转移性进展，并且其激活取决于WNT7A。 AIM2，我们将评估Wnt7a/？ - Catenin-FGF1信号传导上烟酰胺的靶机理。我们还将确定烟酰胺对卵巢癌前环境中细胞功能以及肿瘤进展和转移的影响。此外，我们将检查烟酰胺对化学耐药性卵巢癌的影响，以确定烟酰胺是否可以诱导化学抗性细胞中的死亡。由于迫切需要新药来治疗这种毁灭性疾病，如果确定在临床前的环境中有望有望，烟酰胺可能会对临床环境中卵巢癌患者的生活产生巨大影响。