Importantly, no significant side effects have been reported so far, thus corroborating the apparent safety of sTRAIL treatment in humans. In addition, a number of agonistic antibodies (HGS-ETR1, HGS-ETR2, HGS-TR2J, LBY135, CS-1008, AMG 655) that selectively target TRAIL-R1 or TRAIL-R2 have been developed. All of these antibodies have potent tumouricidal activity in vitro and in vivo and appear to have a low toxicity profile in early-phase clinical studies BAY 73-4506 price [33,36–39]. An obvious difference between these TRAIL receptor-selective mAbs and TRAIL is the fact that TRAIL interacts with both of its agonistic receptors. This might provide TRAIL either with a wider

therapeutic spectrum or a narrower and more unpredictable therapeutic window, especially in light of its additional interaction with decoy TRAIL receptors. It is interesting to note that several groups have pursued the design of sTRAIL variants Lumacaftor order that show selectivity for TRAIL-R1 or TRAIL-R2

[40–43]. Although the precise fine specificity of some of these variants remains a matter of debate, the use of TRAIL receptor-selective variants for the treatment of a specific tumour type may prove valuable. For instance, CLL appears to be preferentially sensitive to TRAIL-R1 apoptotic signalling, whereas certain solid tumours appear to preferentially signal via TRAIL-R2. Rational integration of TRAIL receptor-selective sTRAIL variants may in those cases help to optimize efficacy. Importantly, as will be described in more detail below, normal cells can be sensitized to sTRAIL by certain other anti-cancer drugs. These side effects are likely due to a sensitizing effect by the co-administered drug on normal cells for the ubiquitous priming of TRAIL-R1 by sTRAIL trimers, as sTRAIL trimers are fully capable of TRAIL-R1 activation. In contrast, TRAIL-R2 is not/minimally activated by homotrimeric sTRAIL. Therefore, it seems a reasonable assumption that TRAIL-R1 signalling Calpain is the main

culprit behind potential side effects of sTRAIL trimers. Thus, the rational design and use of TRAIL-R2-selective sTRAIL variants may help to optimize therapeutic efficacy, while minimizing the occurrence of toxic side effects. The available preliminary data indicate that activation of apoptotic TRAIL receptor signalling using sTRAIL or agonistic TRAIL-R antibodies may indeed prove beneficial to cancer patients and certainly warrant further evaluation of this reagent in clinical trials. However, intrinsic and/or acquired resistance to TRAIL receptor signalling is likely to pose a significant hurdle to clinical efficacy. Indeed, almost half of tumour cell lines analysed have intrinsic resistance to TRAIL receptor signalling, which also holds true for GBM cell lines.