Abstract 4395: Strategy to overcome inherent TRAIL-based therapeutic limitations

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent because of its selective ability to induce apoptosis in activated immune cells or cancer cells with minimal toxicity in normal cells. However, a short biological half-life and the development of inherent TRAIL resistance in a variety of cancer cells, including colorectal cancer cells (CRC), results in the poor performance of TRAIL as a chemotherapeutic agent. To overcome these limitation, we developed PEGylated TRAIL (PEG-TRAIL) to compensate the short half-life of TRAIL offering improved pharmacokinetics in non-human primates. In parallel, we found that pre-sensitization with doxorubicin resulted in the upregulated expression of the functional TRAIL receptor, DR5, in highly TRAIL-resistant HT-29 cells by Western blotting and qRT-PCR. Although neither individual treatment of doxorubicin nor TRAILPEG induced apoptosis, pre-sensitization with doxorubicin followed by PEG-TRAIL induced significant apoptosis through the activation of both extrinsic and intrinsic apoptotic pathways promoted by the cleavage of caspases 8, 9, and 3. DR5, but not DR4, was recruited to the TRAIL-induced Death-Inducing Signaling Complex (DISC) within HT-29 cells pre-sensitized with doxorubicin, suggesting a TRAIL/DR5 specific pathway in CRC. To maximize the therapeutic efficacy of the sensitizer in vivo, doxorubicin was encapsulated in tumor-homing hyaluronic acid nanoparticles (HAC/DOX). Confocal microscopy and HPLC analysis enabled us to observe the efficient uptake and biodistribution of HAC/DOX in tumor tissues from xenografted HT-29 cells. HAC/DOX effectively sensitized the xenograft tumor, bearing the highly TRAIL-resistant HT-29 cells to TRAIL-induced apoptosis through the upregulated expression of DR5 and activation of caspases. Our study suggests an innovative approach to overcome the inherent TRAIL-based therapeutic limitations by introducing long-acting TRAIL and a tumor-homing TRAIL sensitizer to induce cancer cell-specific apoptosis in TRAIL-resistant CRC, particularly in physiological conditions. Citation Format: Yumin Oh, Maggie Swierczewska, Seulki Lee. Strategy to overcome inherent TRAIL-based therapeutic limitations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4395. doi:10.1158/1538-7445.AM2015-4395