Abstract 2142: Role of TRAIL signaling through the development of carcinogen-induced colorectal cancer

Abstract

Abstract TNF-related apoptosis-inducing ligand (TRAIL/APO-2L) is a death ligand that can induce apoptosis by its cognate death receptors (DRs). Due to its unique ability to selectively induce DR-mediated apoptosis in cancer cells while showing no apparent toxicity to normal cells, the rhTRAIL has been actively studied for cancer therapy. Clinical studies of TRAIL revealed a broad tolerability in humans but failed to demonstrate a robust therapeutic benefit in oncology. The main factors responsible for the disappointing results of TRAIL used in cancer patients are 1) its short half-life (less than 30 min in humans) and 2) heterogeneous primary cancers are generally TRAIL-resistant. To overcome the short half and low potency of TRAIL in vivo, we have developed an engineered PEGylated TRAIL (TRAILPEG). PEGylation is a gold standard to extend the half-life of protein drugs and a highly efficient commercial strategy. While investigating the improved therapeutic potential of TRAILPEG in colitis-associated cancer (CAC), we validated that TRAILPEG can ameliorate an inflammatory bowel disease (IBD), the high risk for CRC. Therapeutic efficacy of systemically administered long-acting TRAIL was validated in vivo in IBD and CAC animal models showing an anti-inflammatory and anti-cancer effects. Dimethylhydrazine metabolite azoxymethane (AOM) used to induce CAC in A/J mice, while a chronic inflammation model of colitis/IBD was induced with DSS without the AOM. Most of the mice administered with AOM/DSS developed adenocarcinoma on the distal part of the colon, but the number of adenocarcinomas per colon was significantly lower in the TRAILPEG treated mice than in the vehicle-treated groups. The shortening of the colon length, a measurable characteristic of colitis severity was more recovered in mice treated with TRAILPEG compared to disease control. The TRAILPEG treatment significantly decreased the number of large neoplasms in total tumor and led to an over 30~40% reduction in the total tumors. In addition, the symptoms of rectal bleeding in the AOM/DSS mice was rare to detect. The elevated MPO activity was significantly suppressed by TRAILPEG treatment. In parallel, we found that TRAILPEG treatment resulted in the activation of Caspase-8 and decrease of phosph-STAT3 suggesting the dual roles of TRAIL signaling for apoptosis and anti-inflammation by western blotting. The mRNA levels of inflammatory cytokines including of IL-6, IL-17, MCP-1, ICAM-1, and TNF-β were recovered by TRAILPEG in the AOM/DSS model. Our studies demonstrated that TRAILPEG could effectively treat IBD and CAC in AOM/DSS mice model. The mechanisms involved in this effect of TRAILPEG on IBD and CAC were associated with an increase of cell death, as well as, intervention inflammatory responses. Citation Format: Yumin Oh, Seulki Lee, Kang Choon Lee. Role of TRAIL signaling through the development of carcinogen-induced colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2142. doi:10.1158/1538-7445.AM2017-2142