Defining double-stranded RNA receptor induced apoptosis in ovarian cancer.

描述（由申请人提供）：卵巢癌占妇女癌症死亡人数的6%。这种异质性疾病阻碍了我们最好的治疗方法，迫使我们开发新的药物靶点，诱导卵巢癌细胞死亡。先天性免疫受体，如dsRNA受体黑色素瘤分化相关基因5、dsRNA依赖性蛋白激酶受体、视黄酸诱导基因I和toll样受体3，在肿瘤细胞上表达，可以作为启动凋亡信号的强大开关。我们的初步数据已经确定了在dsRNA模拟中死亡（反应性）或存活（无反应性）的卵巢癌细胞系，这些细胞系可以作为模型系统，为基于dsRNA的治疗开发开发允许或限制性生物标志物。我们所有的细胞系（CAOV-3、OVCAR-3、D0V13和SKOV-3）均表达dsRNA受体mRNA，但只有CAOV-3和0VCAR3在受到刺激后上调dsRNA受体的表达并随后发生凋亡。该模型系统使我们有机会定义dsRNA诱导的凋亡反应的机制细节，并研究非反应细胞系的生存途径，这些细胞系可以作为dsRNA/生存途径拮抗剂双重治疗的目标。

DESCRIPTION (provided by applicant): Ovarian cancer accounts for 6% of cancer deaths in women. This heterogeneous disease circumvents our best treatments forcing us to develop novel drug targets that will induce ovarian cancer cell death. Innate immune receptors, like the dsRNA receptors melanoma differentiation-associated gene 5, dsRNA- dependent protein kinase receptor, retinoic acid inducible gene I and Toll-like receptor 3, are expressed on tumor cells and can act as powerful switches to initiate an apoptotic signal. Our preliminary data has identified ovarian cancer cell lines that die upon dsRNA simulation (responsive) or survive (non-responsive) that can serve as model systems to develop permissive versus restrictive biomarkers for dsRNA-based therapy development. All our cell lines (CAOV-3, OVCAR-3, D0V13 and SKOV-3) express mRNA for the dsRNA receptors but only CAOV-3 and 0VCAR3 upregulate dsRNA receptor expression when stimulated and subsequently undergo apoptosis. This model system offers us the opportunity to define the mechanistic details of the dsRNA-induced apoptotic response and investigate survival pathways in our non-responsive cell lines that could be targeted for dsRNA/survival pathway antagonist dual therapies. PUBLIC HEALTH RELEVANCE: Ovarian cancer is the most lethal of all gynecological cancers. Novel chemotherapeutics coupled to biomarkers that will identify responsive patients would allow physicians to determine the most efficacious method of treatment for each patient. This project seeks to define biomarkers that would identify dsRNA-responsive ovarian cancer tumors.