Abstract C12: Preclinical characterization of a novel FLIP-targeted antisense phosphorothioate oligonucleotide

Abstract

Abstract FLIP (FLICE-inhibitory protein) is a major inhibitor of death receptor-mediated activation of caspase 8 (FLICE, Fas-associated death domain-like interleukin-1 -converting enzyme). We have previously found that FLIP is not only a key regulator of death receptor-mediated apoptosis, but also inhibits chemotherapy-induced apoptosis in several cancers. Furthermore, we found that silencing FLIP expression using siRNA approaches was in itself sufficient to induce apoptosis in several different cancer models. These results suggest that FLIP is a promising therapeutic target in several cancers. In this study, we describe the pre-clinical characterisation of a novel FLIP-targeted antisense phosphorothioate oligonucleotide (AS PTO). Of 5 potential sequences identified, one AS PTO potently down-regulated FLIP. Down-regulation of FLIP by this AS PTO resulted in caspase 8 activation and apoptosis induction in non-small cell lung (NSCLC), colorectal and prostate cancer cell lines. Furthermore, the FLIP AS PTO sensitized cancer cells to apoptosis induced by the clinically relevant death ligand TRAIL (TNF-related apoptosis-inducing ligand). Moreover, the FLIP AS PTO also sensitized NSCLC cells to apoptosis induced by the chemotherapeutic agents cisplatin and taxol. Importantly, compared to a control non-targeted PTO, the FLIP-targeted AS PTO demonstrated in vivo antitumor activity against NSCLC xenografts and enhanced the antitumor effects of cisplatin. In summary, we have identified a novel FLIP-targeted AS PTO that has in vitro and in vivo activity and which may therefore have potential for clinical development. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C12.