Abstract 1774: Polysialyltransferase ST8SiaII: a new target for the treatment of metastatic tumors
Authors: Viprey Virginie , Springett Bradley R. , Al-Saraireh Yousef , Northrop Matthew , Sutherland Mark , Saeed Rida , Loadman Paul M. , Patterson Laurence H. , Shnyder Steven D. , Falconer Robert A. 
Published: May 2015

Polysialic acid (polySia) is a carbohydrate polymer expressed on the surface of NCAM (neuronal cell adhesion molecule) in many cancer cells where it modulates cell-cell and cell-matrix adhesion, migration, invasion and metastasis. 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 tumors principally of neuroendocrine origin [1]. SiRNA knockdown of polysialyltransferase ST8SiaII (STX), the enzyme primarily responsible for polySia synthesis in tumors, has been shown to abolish tumor cell migration [2]. Besides brain regions with persistent neuronal plasticity, polySia is essentially absent from the adult body. STX inhibition thus presents a novel, selective, highly attractive and largely unexplored therapeutic opportunity to reduce dissemination of polySia-expressing tumors [1]. Using cytidine monophosphate (CMP) as a tool compound, we have validated a highly sensitive HPLC-based inhibition assay, and demonstrated competitive inhibition of STX, leading to a reduction in polySia expression [3]. Having demonstrated for the first time that inhibition of STX by a small molecule leads to a reduction in tumor cell migration and invasion, we have designed and synthesised inhibitors of STX and the polysialylation process. The potency of these compounds has been increased by chemical modification, resulting in greater lipophilicity. Using an isogenic cell line system (rat glioma cells C6-STX: polySia+/STX+ and C6-WT: polySia-/STX- [4]) and naturally polySia expressing human neuroblastoma cells (SH-SY5Y, IMR-32) these compounds were evaluated for their ability to reduce polySia expression and to modulate cell migration in vitro. We have identified CMP-sialic acid precursors, including compounds ICT-3172 and ICT-3176, which reduced polySia expression and tumor cell migration by up to 70%. These effects were only found in cell lines expressing STX and polySia. In summary, we have identified a number of key modifications to polySia biosynthetic precursors which dramatically decrease cell migration in cells over-expressing STX through modulation of polySia assembly. The potential of the polySia biosynthesis pathway, and in particular STX, as attractive therapeutic targets in metastatic tumors is discussed.

[1] Falconer, R.A. et al., Curr. Cancer Drug Targets, 2012, 12, 925-939

[2] Schreiber et al.,Gastroenterology, 2008, 134, 1555-1566

[3] Al-Saraireh YMJ et al., PLoS ONE, 2013, 8:e7336

[4] Suzuki, M. et al., Glycobiology, 2005, 15, 887-894.

Citation Format: Virginie Viprey, Bradley R. Springett, Yousef Al-Saraireh, Matthew Northrop, Mark Sutherland, Rida Saeed, Paul M. Loadman, Laurence H. Patterson, Steven D. Shnyder, Robert A. Falconer. Polysialyltransferase ST8SiaII: a new target for the treatment of metastatic tumors. [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 1774. doi:10.1158/1538-7445.AM2014-1774