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

描述(申请人提供)：卵巢癌占女性癌症死亡的6%。这种异质疾病绕过了我们最好的治疗方法，迫使我们开发新的药物靶点，以诱导卵巢癌细胞死亡。天然免疫受体如dsRNA受体、黑色素瘤分化相关基因5、dsRNA依赖的蛋白激酶受体、维甲酸诱导基因I和Toll样受体3在肿瘤细胞上表达，并可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(有反应)或存活(无反应)的情况下死亡的卵巢癌细胞系，这些细胞可以作为模型系统，为基于dsRNA的治疗开发开发允许的和限制性的生物标志物。我们的所有细胞系(CAOV-3、OVCAR-3、D0V13和SKOV-3)都表达dsRNA受体的mRNA，但只有CAOV-3和0VCAR3在刺激时上调dsRNA受体的表达，随后发生凋亡。这个模型系统为我们提供了机会来定义dsRNA诱导的凋亡反应的机制细节，并研究我们的无反应细胞系中的生存途径，这些途径可能成为dsRNA/生存途径拮抗剂双重疗法的靶点。 公共卫生相关性：卵巢癌是所有妇科癌症中最致命的。新的化疗药物与识别有反应的患者的生物标记物相结合，将使医生能够为每个患者确定最有效的治疗方法。该项目旨在定义识别dsRNA反应性卵巢癌肿瘤的生物标记物。

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.