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

描述（由申请人提供）：卵巢癌占女性癌症死亡的6%。这种异质性疾病规避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。先天免疫受体，如dsRNA受体黑素瘤分化相关基因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，并且可以充当启动凋亡信号的强大开关。我们的初步数据已经鉴定了在dsRNA模拟后死亡（响应性）或存活（非响应性）的卵巢癌细胞系，其可以作为模型系统来开发用于基于dsRNA的疗法开发的允许性与限制性生物标志物。我们的所有细胞系（CAOV-3、OVCAR-3、D 0 V13和SKOV-3）表达dsRNA受体的mRNA，但只有CAOV-3和OVCAR 3在受到刺激时上调dsRNA受体表达并随后经历细胞凋亡。该模型系统为我们提供了定义dsRNA诱导的凋亡反应的机制细节并研究我们的非反应性细胞系中的存活途径的机会，所述非反应性细胞系可以靶向dsRNA/存活途径拮抗剂双重疗法。 公众健康相关性：卵巢癌是所有妇科癌症中最致命的。新的化疗药物与生物标志物结合，将识别反应患者，使医生能够确定最有效的治疗方法，为每一个病人。该项目旨在定义可识别dsRNA反应性卵巢癌肿瘤的生物标志物。

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.