Abstract 2639: Development of immunocytotoxic RNA therapeutics for human melanoma

Abstract

Abstract Pattern recognition receptors (PRRs) are a pivotal component of anti-infectious immunity, and selective induction of PRR-mediated apoptosis in cancer cells represents a novel therapeutic strategy. Retinoic acid inducible gene-I (RIG-I) is a cytoplasmic PRR that recognizes virus-associated molecular patterns, such as uncapped 5′triphosphate (5′ppp) RNA. RIG-I activation triggers innate immune response and apoptosis in infected cells, resulting in the inhibition of viral spread. Interestingly, certain cancer cells are highly sensitive to RIG-I-mediated apoptosis, and treatment with RIG-I-stimulating RNAs can selectively kill cancer cells and facilitate the induction of anti-cancer immunity. Therefore, RIG-I-stimulating RNAs may prove valuable as immunostimulatory and anti-cancer agents. Because RNAs are extremely sensitive to serum nucleases, modified RNAs have been employed to increase the stability of RNA-based therapeutics. Such modifications, however, often abrogate the immunostimulatory activity of RNAs, which hinders their development as immunostimulatory agents. Herein, we demonstrate that short single-stranded RNAs (ssRNAs) (23-93 nucleotides) with 5′ppp and stem-loop structure(s) are a potent stimulus for type I interferon (IFN) production and apoptosis of human melanoma and prostate cancer cells. 2′fluoro (2′F) modification of these 5′ppp ssRNAs not only improves serum stability, but also enhances the ability of the RNAs to induce IFNβ production and apoptosis of human cancer cells, compared to their unmodified counterparts, while 2′ O-methyl modification abrogates the anti-cancer and IFN-inducing activities of 5′ppp ssRNAs. These 5′ppp 2′F ssRNAs elicit RIG-I- and mitochondrial antiviral-signaling protein-mediated IFN production and cytotoxic effects. This study suggests that such modified RNAs may represent a novel and effective anti-cancer therapeutic. Citation Format: Jaewoo Lee, Youngju Lee, Bruce A. Sullenger. Development of immunocytotoxic RNA therapeutics for human melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2639. doi:10.1158/1538-7445.AM2014-2639