Abstract 5455: Antitumor activity of death receptor agonists for prostate cancer therapy

Abstract

Abstract Clinical trials on TRAIL and death receptor (TRAIL-R1 and TRAIL-R2) agonist antibodies are being carried out through out the world. Until today, there are no small organic molecules that bind to TRAIL-death receptors, and induce apoptosis mainly in cancer cells. Through molecular and biological approaches, we have identified novel death receptor agonists (small molecular weight organic compounds). Death receptor agonists termed as “DRAs” inhibited cell viability and colony formation, and induced apoptosis in androgen-dependent (LNCaP) and -independent (PC-3) human prostate cancer cell lines, but had no effect on human normal prostate epithelial cells and hepatocytes. The combinations of DRAs with TRAIL had additive effects on apoptosis in prostate cancer cells. Commonly used anticancer drugs further enhanced the apoptosis-inducing potential of DRAs. DRAs recruited FADD and activated caspase-8, and thus formed active TRAIL-DISC (death-inducing signaling complex) similar to that of TRAIL. DRAs inhibited the growth of PC-3 and LNCaP xenografts in nude mice, and prostate cancer growth in TRAMP mice. In vivo, DRAs inhibited tumor cells proliferation (Ki67 staining) and induced caspase-3 activity and apoptosis (TUNEL staining). Pharmacokinetics data demonstrate that DRA is stable, possesses a long terminal half-life, and meats the criteria of clinical trials. Our data suggest, for the first time, that DRAs are specific activators of death receptor pathway of apoptosis, and can be used to treat human prostate cancer. Further studies are underway to assess their clinical significance for the treatment of prostate cancer. (Funding Support: Department of Defense, US Army) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5455.