TIC10/ONC201: a bend in the road to clinical development

Tumor necrosis factor (TNF) –related apoptosis-inducing ligand (TRAIL) is an immuno-surveillance cytokine that is expressed in various tissues and cells [1, 2]. The expression of TRAIL on immune cells plays a role in immune surveillance in the prevention of tumors and metastasis [3]. TRAIL is attractive as an anti-tumor agent because of its capability to induce apoptosis in cancer cells by activating death receptors 4 and 5 (DR4 and DR5) with little toxicity against normal cells [2]. Despite its robust cell killing of tumor cells in vitro, efficacy of TRAIL receptor agonists has been limited in clinical trials, and this limited activity is thought to be due to lack of reliable predictive biomarkers of sensitivity and drug properties that limit efficacy such as short serum half-life, stability, and bio-distribution [3, 4].