Current approaches to overcome the limit of TRAIL-based treatment in colorectal cancer: From fusion protein to nano-delivery platform.

Colorectal cancer (CRC), one of common malignancies, ranks second in cancer-related mortality worldwide. Despite advances in targeted therapy and immune therapy, patients with metastatic CRC have poor 5-year survival, which is approximately 14%. Multiple investigations are underway with the aim to improve outcome of this cohort. The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been considered as an ideal candidate in the field of cancer treatment because it is able to selectively induce apoptosis of cancer or transformed cells while sparing normal cells or tissues. TRAIL or TRAIL-based therapies have shown significant tumoricidal effects in multiple cancer xenograft models, and phase I clinical trials have demonstrated its safety. However, most phase II or III trials fail to show robust efficacy, which may be related to their poor pharmacokinetic characteristics, such as short half-life and inadequate accumulation in tumor sites, and TRAIL resistance. Recently, several studies have developed novel methods to improve efficacy of TRAIL, by fusing molecules with diverse functions to TRAIL, by utilizing nanoparticles or cellular vehicles to deliver TRAIL, and by combining TRAIL with other agents. In this review, we emphasize the existing approaches to overcome the aforementioned issues with the aim to enhance efficacy of TRAIL for the treatment of CRC.