PO-459 Systemic anti-inflammatory effect of a new anticancer cyclic peptide ALOS4

Abstract

IntroductionChronic inflammation is the primary pathological element of cancer development. Here we demonstrate a synthetic cyclic peptide ALOS4 capable of suppressing tumour growth following systemic administration and possessing anti-inflammatory properties. ALOS4 was initially isolated by phage display for its ability to bind αvβ3 integrin, possessing no functional activity of RGD peptides and characterised by tumour suppressor activity in preclinical xenograft and syngeneic models of melanoma. Importantly, ALOS4 displayed no signs of toxicity in treated animals even at the highest doses, which significantly exceeded optimal efficacious doses. In this study, we aimed to identify the mechanisms underlying the profound antitumor activity of this safe peptide.Material and methodsWe utilised a large panel of cell-based repeater assays designed to detect modulators of a variety of signalling pathways including p53-, NF-kB-, hypoxia, heat shock, irradiation and other types of stress responses. We also tested the effects of ALOS4 on tumour cell growth, adhesion, migration, clonogenicity, morphology and other in vitro properties.Results and discussionsALOS4 showed no detectable activity in most of these assays with some exceptions: first, ALOS4 treatment prevented weight lost in cancer bearing mice and second, ALOS4 suppressed the ability of treated cells to induce interferon type I signalling in response to double stranded RNA mimics (Poly I:C). Based on this observation, as well as negative in vitro cell-based assay results, we hypothesised that the antitumor effect of ALOS4 may be mediated by a systemic anti-inflammatory effect rather than by a direct effect on tumour cells. Consistent with this hypothesis, ALOS4 treatment dramatically modulated the abundance and content of the population of immunocytes infiltrating subcutaneously growing melanomas in mice.ConclusionThese results suggest that ALOS4 can represent an anticancer agent with a new mechanism of activity that targets the tumor-supporting interferon-driven mechanism of tumor-host interaction and improves the overall condition of the mouse as a whole.