Targeting In Vivo Delivery Of Sirnas To Study The Role Of Klf6 In Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC), the most lethal of all gynaecologic cancers, is the fifth most common cause of cancer death in women. As many ovarian cancers are asymptomatic in early stages, patients often present late in the course of their illness with widespread, disseminated disease. Despite concerted clinical and research efforts, survival rates of patients with late stage EOC have not substantially improved over the last two decades. Therefore, a better understanding of the underlying genetic factors responsible for the initiation, progression, and recurrence of EOC is essential to define novel therapeutic targets and pathways. Our recent studies have identified the tumor suppressor KLF6 and its alternatively spliced isoform, KLF6-SV1 as critical regulators of the development and progression of EOC. Most notably, KLF6-SV1 is overexpressed in virtually all late stage EOC while cell lines stably engineered to downregulate KLF6-SV1 exhibit decreased proliferation, invasion, and tumor formation in vivo. Therefore, and as a starting point for defining a future rational therapeutic strategy, these studies were primarily designed to explore the effect on in vivo tumor growth and behaviour of siRNA-mediated treatment targeting KLF6-SV1. State-of-the-art, chemically-modified siRNA molecules – which increase knockdown efficiency, specificity and serum stability - were designed and tested in vitro for their eventual use in vivo. SiRNA targeted to KLF6-SV1 decreased cellular proliferation and increased apoptosis in vitro, representing an exciting potential therapeutic and justifying future in vivo study.