Targeting heparan sulfate proteoglycans in pancreatic cancer with Salmonella expressing bacterial heparinase III

Heparan sulfate proteoglycans (HSPG) regulate processes that drive tumor progression and promote treatment resistance in pancreatic ductal adenocarcinoma (PDAC), including increased fatty acid metabolism, sustained survival signaling, high fibrosis, and increased macropinocytosis. HSPG are regulated in a pro-tumor manner by site-specific cleavage of their heparan sulfate chains by mammalian heparanase; however, alternative cleavage by bacterial heparinase III (HepIII) has been shown to deactivate these proteins and prevent downstream pro-tumor signaling. To broadly target HSPG on tumor cells surfaces, we have expressed a highly active bacterial HepIII from Bacteroides on a clinically evaluated, attenuated strain of Salmonella typhimurium , YS1646 (YS-HepIII). This tumor-targeting YS both continuously expresses active HepIII enzyme and limits its expression to tumor tissue using an inducible system to circumvent toxicities that might arise from systemic HepIII treatment. Analysis of human PDAC cell lines treated with YS-HepIII i n vitro as well as of human PDAC xenograft tumors treated in vivo shows evidence of decreased macropinocytosis, reduced survival signaling, lipid storage depletion, and decreased expression of translation machinery. These vulnerabilities sensitize tumors to FDA approved cancer therapies. This translatable therapeutic has the potential to improve PDAC patient survival, an unmet medical need.