Abstract 2866: Anticancer effect of a new cyclic peptide ALOS4 is associated with its systemic anti-inflammatory activity

Abstract

Abstract The association of chronic inflammation with cancer development and progression has been well recognized. Here, we report a synthetic cyclic peptide, ALOS4, capable of suppressing tumor growth following systemic administration and possessing anti-inflammatory properties. Although ALOS4 was initially isolated by phage display for its ability to bind avb3 integrin and demonstrated tumor-suppressor activity in preclinical xenograft and syngeneic models of melanoma, it surprisingly showed no functional activity resembling RGD peptides in functional in vitro assays. Remarkably, ALOS4 displayed no signs of toxicity in treated animals, even at doses exceeding >100-fold beyond the efficacious dose. To identify the mechanisms underlying profound antitumor activity of this safe peptide, we used a large panel of cell-based repeater assays designed to detect modulators of a variety of signaling pathways including p53, NF-kB, and different types of stress responses including heat shock and hypoxia. We also tested the effects of ALOS4 on tumor cell growth, adhesion, clonogenicity, morphology and other in vitro properties. ALOS4 showed no detectable activity in any of these numerous assays with one exception: it suppressed the ability of treated cells to induce interferon type I signaling in response to mimics of double-stranded RNA (Poly I:C). Based on this observation, we hypothesized that the antitumor effect of ALOS4 is driven by a systemic anti-inflammatory effect rather than by a direct effect on tumor cells. Consistently, ALOS4 treatment dramatically altered both the abundance and content of the immunocyte population infiltrating subcutaneous melanomas in mice. These results suggest that ALOS4 may be an anticancer agent with a new mechanism of action that targets the tumor-supporting interferon-driven mechanism of tumor-host interaction. Citation Format: Elimelech Nesher, Albert Pinhasov, Maria Becker, Michael Kirby, Raichel Cohen Harazi, Shiri Yakobovich, Oryan Agranyoni, Bar Shoval, Shany I. Elbaz, Olga Udartseva, Ilya Gitlin, Katerina Leonova, Katerina Gurova, Andrei Gudkov, Igor Koman. Anticancer effect of a new cyclic peptide ALOS4 is associated with its systemic anti-inflammatory activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2866.