Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L) is a type II trans membrane protein belonging to the Tumor Necrosis Factor (TNF) superfamily that are widely expressed on the surface of Natural Killer (NK) and T cells, macrophages and dendrite cells.
These proteins bind to the Death receptor 4 (DR4) and 5 (DR5), and trigger apoptosis in tumor cells. Discovery of TRAIL proteins and its receptors came as a promising therapeutic approach in anti-cancer target therapies because of its unique quality of binding to variety of tumor cells while sparing the normal vital cells of the body. Unfortunately, first generation of TRAIL agonist didn’t match the expected clinical efficacy as most tumors were resistant to the apoptosis induced by TRAIL proteins. Later, it was identified that poor clinical efficacy of these agents was due to their insufficient agonist activity.
Since then, vigorous research is going on for developing novel TRAIL-Receptor targeting agents with increased agonistic activity. Currently, many second generation therapies targeting TRAIL receptor are in development. For instance, hvTRA, a novel second generation TRAIL agonist has demonstrated an efficient and sustained reduction in melanoma cell growth in cell lines and xenograft models. Recently, a research demonstrated that TRAIL-coated lipid-nanoparticles improves TRAIL cytotoxic ability. Combination of TRAIL agonist along with other anti-cancer drugs has the potential to overcome resistance and can provide greater anti-tumor activity. For example, Choline kinase inhibitors in combination with TRAIL enhances the TRAIL-induced apoptosis and can overcome the resistance.
Although, the combination approach and second generation TRAIL agonist are mostly in early clinical developmental stage, but evidences based on various research work indicates the emergence of promising TRAIL agonist in near future. Companies like Apogenix, Genmab, MedImmune etc., are developing drug candidates which are likely to enter into clinical studies in next few years.