Development of novel modified aptamers to target Axl receptor in ovarian cancer

Background: Ovarian cancer is the fifth leading cause of cancer death in women and the most lethal gynecologic malignancy with a rate of survival of 40%. Aberrant GAS6-AXL signaling pathways are associated with many human diseases, including bone diseases, immune-suppression, fibrosis, cancer progression and metastasis. Experimental evidences demonstrated that patients expressing high levels of Axl shows shorter over-survival than patients expressing low levels of Axl in epithelial ovarian cancer. Therefore, there is the need to find novel strategies for silencing and blocking this signaling pathway and the dissemination of ovarian cancer. Methods: In this study we hypothesized that dithiophosphate modified AXL-aptamers lead long-lasting bio-disponibility and high stability, resulting in decreased migration, and proliferation. We synthetized and screened a library of 17 aptamers that differ in the position of the modification inside the sequence. Results: Among these 17 dithiophosphate aptamers, we selected the aptamers that showed better effect on the downregulation of p-Axl. The analysis of p-Axl in ovarian cancer cell lines a specific and strong binding when compared with scramble control. In vitro cell viability, growth, and migration, as well as in vivo therapeutic effectiveness in murine xenograft models, were also assessed following the inhibition of p-Axl in ovarian cancer. The experimental validation identifies significant inhibition of p-AXL, clonogenic ability, and migration. Furthermore, treatment with modified AXL-aptamers lead long-lasting bio-disponibility, high stability and inhibited growth of SKOV3ip1. Conclusions: These findings identify dithiophosphate modified AXL-aptamers as potential therapeutic tool to target GAS6-AXL signaling pathway in ovarian cancers expressing high levels of this oncogenic protein. Legal entity responsible for the study: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Funding: National Institute of Health Disclosure: All authors have declared no conflicts of interest.