Safety and tolerability of TRAIL receptor agonists in cancer treatment.

Targeting the death receptor pathway of apoptosis represents a promising approach for the development of novel cancer therapeutics, since death receptors on the cell surface are directly linked to the apoptotic machinery. The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor/ligand system is of particular interest among the death receptor superfamily for therapeutic targeting in cancer, since TRAIL has been reported to preferentially induce apoptosis in cancer cells, while sparing non-malignant cells. Evaluation of TRAIL receptor agonists in clinical trials has revealed that they are, in principle, well-tolerated but exert limited efficacy in unselective patient populations. Currently, the challenge resides in the development of rational TRAIL-based combination therapies with potent TRAIL receptor agonists in order to exploit the potential of death receptor targeting for cancer therapy.