Abstract 4410: Inhibition of cell surface polysialic acid biosynthesis modulates tumor cell migration.
Authors: Springett Bradley R. , Al-Saraireh Yousef M.J. , Viprey Virginie , Sutherland Mark , Begouin Melanie , Northrop Matthew , Saeed Rida , Loadman Paul M. , Patterson Laurence H. , Shnyder Steven D. , Falconer Robert A. 
Published: August 2014

Polysialic acid (polySia) is a linear alpha-2,8-linked carbohydrate homopolymer of up to 100 sialic acid residues. It is characteristically re-expressed on the surface of NCAM (neuronal cell adhesion molecule) in many cancer cells where it modulates tumour dissemination. PolySia-NCAM expression is strongly associated with poor clinical prognosis and correlates with aggressive/invasive disease in small cell lung cancer, pancreatic cancer, neuroblastoma and many other tumours principally of neural crest origin [1]. SiRNA knockdown of polysialyltransferases (polySTs) ST8SiaII and ST8SiaIV, the enzymes responsible for polysialylation of neural cell adhesion molecule (NCAM), has been shown to abolish cell migration in tumour cells [2]. Besides brain regions with persistent neuronal plasticity, polySia is essentially absent from the adult body. Its exclusive synthesis by two polySTs, ST8SiaIV and particularly ST8SiaII, present a novel, selective, highly attractive but largely unexplored therapeutic opportunity [1].

We have embarked on a programme of design and synthesis of novel polyST inhibitors, and have established a screening cascade to determine enzyme inhibition and effects on polySia-expressing cells in vitro. Using endoneuraminidase, an enzyme that specifically cleaves polySia chains from NCAM, we can assess the rate and extent to which polySia growth is inhibited in the presence of agent in cellular systems. In addition, an in vitro scratch assay was established to evaluate modulation of cell migration using a transfected isogenic cell line system (C6-STX: polySia +, ST8SiaII + / C6-WT: polySia -, ST8SiaII - [3]) and neuroblastoma cell lines known to express polySia-NCAM, ST8SiaIV and ST8SiaII (SHSY-5Y and IMR-32).

We have identified compounds, including ICT-3067, ICT-3128 and ICT-3147, which lead to a significant reduction in cell surface polySia-NCAM and that modulate tumour cell migration in in vitro. We have also identified a number of key modifications to CMP-sialic acid precursor molecules which dramatically decrease cell migration in ST8SiaII-expressing cells, through modulation of polySia assembly. It is also noteworthy that the potency of these compounds has been increased with simple chemical modifications, resulting in greater lipophilicity.

In summary, a number of efficient modulators of polySia assembly and their efficacy in reducing cell migration is described. This points to the potential of the polySia biosynthesis pathway, and in particular the polySTs, as attractive therapeutic targets in metastatic tumours.

[1] Falconer, R.A. et al., Curr. Cancer Drug Targets, 2012, 12, 925-939; [2] Schreiber et al., Gastroenterology, 2008, 134, 1555-1566; [3] Suzuki, M. et al., Glycobiology, 2005, 15, 887-894.

Citation Format: Bradley R. Springett, Yousef M.J. Al-Saraireh, Virginie Viprey, Mark Sutherland, Melanie Begouin, Matthew Northrop, Rida Saeed, Paul M. Loadman, Laurence H. Patterson, Steven D. Shnyder, Robert A. Falconer. Inhibition of cell surface polysialic acid biosynthesis modulates tumor cell migration. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4410. doi:10.1158/1538-7445.AM2013-4410