PO-213 Sigma receptors: development of novel therapeutic approaches in pancreatic cancer

Abstract

IntroductionPancreatic cancer is a highly malignant tumour, poorly responsive to conventional therapies that result in a progressive resistance to treatment. Sigma receptors (sigma-1 and sigma-2) are widespread in central nervous system and multiple peripheral tissues. Selective sigma ligands (agonists and antagonists) label tumour sites, induce apoptosis and inhibit tumour growth. However, the underlying mechanisms of action are highly dependent both on the type of the ligand and the type of the tumour they target. Sigma-2 receptor is overexpressed in pancreatic cancer and sigma-2 ligands cause apoptosis and enhance the action of known chemotherapeutic drugs. The aim of this study is to investigate the expression levels of sigma receptors, their relation to pancreatic cancer development and the potential use of sigma receptor ligands as drugs against this cancer using patient derived animal cancer models.Material and methodsThe expression of sigma receptors was examined in clinical samples of patients with pancreatic cancer, in patient derived ex vivo pancreatic cancer cell populations and in established pancreatic cell lines using Western Blot. The antiproliferative effect of sigma ligands was studied in vitro with Sulforhodamine B assay. The mechanism of action whereby siramesine, a lead sigma-2 agonist, induces cell death as well as the impact of siramesine on the cell cycle has been investigated using Flow Cytometry and Western Blot. The in vivo potency of siramesine, either as single agent or in combination with established drugs, has been studied in patient derived xenograft models of cancer.Results and discussionsExpression of sigma receptors was observed in all examined pancreatic cancer cell lines and tumour tissues. Sigma-2 receptor is highly expressed in cancer compared to normal tissues and overexpressed compared to sigma-1 receptor. Amongst the sigma ligands that have been tested, siramesine exhibits the best anticancer activity, induces caspase dependent cell death in a dose and time dependent manner and arrests cells at the G0/G1 phase. In vivo, siramesine exhibits good anticancer activity and enhances significantly the action of the known chemotherapeutic drug gemcitabine resulting in tumour growth inhibition.ConclusionSigma receptors seems to be a key component for targeting pancreatic cancer and developing novel therapeutic approaches. Sigma-2 receptor agonist, siramesine, shows promising anticancer activity against ex vivo pancreatic human cellular populations and in vivo human-to-mouse cancer models.