Abstract 1375: Development of synthetic heparan sulfate oligosaccharides as anti-angiogenic agents

Abstract

Abstract Angiogenesis has been validated as a target in multiple randomised trials in ovarian cancer, in which addition of VEGF pathway inhibitors to conventional cytotoxic treatment resulted in increased progression-free and in some trials overall survival. However, the benefit from VEGF pathway inhibitors is still modest and the redundancy of angiogenic cytokines might be one of the underlying mechanisms. The majority of angiogenic cytokines, such as FGFs, HGF, VEGF165, IL-8, SDF-1α, HB-EGF that are also linked to ovarian cancer, critically depend on the linear glycosaminoglycan, heparan sulfate (HS), for their biological activity. HS is composed of repeating disaccharides that consist of N-substituted glucosamine and a hexuronic acid residue and is bound to core proteins which support signaling complex formation. The critical importance of glucosamine-6-O-sulfate (6S) moieties in assembling the growth factor/receptor signaling complex implies that reduced 6S content in HS will impact angiogenesis and thereby tumor growth. We used chemical synthesis to produce three differentially sulfated dodecasaccharides (12-mers). All three 12-mers were homogeneously sulfated at the 2-O position of iduronate (IS) and the N-position of glucosamine (NS). The first 12-mer lacked 6S moieties ([NSIS]6), the second 12-mer had a single 6S introduced at the non-reducing end of the molecule ([NS6SIS]1-[NSIS]5) and the third 12-mer was uniformly 6-O-sulfated ([NS6SIS]6). Comparison of anti-angiogenic properties of these 12-mers revealed differential inhibitory activities against angiogenic cytokines. While a single 6S at the non-reducing end slightly improved inhibition of FGF2- and VEGF165-induced angiogenic responses when compared to non-6S-sulfated 12-mer, it produced striking changes in the biological effects on IL-8/SDF-1α. Addition of one 6S abolished inhibitory activity of [NSIS]6 against IL-8, but conferred superior activity in inhibition of SDF-1α, in vitro and in vivo. These dramatic differential effects were absent if all glucosamine residues were 6-O-sulfated. NSIS 12-mer with a single 6S inhibited FGF-2-dependent microvessel formation in tumor xenografts, FGFR signaling in tumor blood vessels, but was insufficient in inhibiting tumor growth, most likely due to the dominant role of VEGF. We demonstrate unique structure-activity relationships for inhibition of SDF-1α and IL-8 which opens new opportunities in the development of glycotherapeutics. We show that oligosaccharides can be designed to target multiple or specific angiogenic cytokines, thus demonstrating the feasibility in generating agents that overcome resistance to VEGF inhibitors. Citation Format: Gordon C. Jayson, Steen U. Hansen, Gavin J. Miller, Claire Cole, Graham Rushton, John M. Gardiner, Egle Avizienyte. Development of synthetic heparan sulfate oligosaccharides as anti-angiogenic agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1375. doi:10.1158/1538-7445.AM2015-1375