Animal biodistribution studies with Tyrosine Kinase Inhibitor Library manufacturer radioiodinated rhTRAIL (125I-rhTRAIL) have demonstrated that intravenous injection of TRAIL does not yield detectable levels of TRAIL in the brain. Therefore, local

delivery strategies, such as convection-enhanced delivery (CED), seem more appropriate. CED uses positive pressure infusion to achieve locoregional delivery of therapeutic agents through an intracerebral catheter [90,91]. In animal models, CED can achieve locally high and effective concentrations. By now CED has progressed into phase III clinical studies for immunotoxin delivery [92,93], results of which are likely to yield insight into the feasibility of using CED on a routine basis in GBM patients and its potential applicability for TRAIL-based therapy. The ample preclinical data on GBM cell lines and primary GBM tissue, as well as the notable absence of TRAIL-related toxicity in phase I clinical trials,

clearly highlight that TRAIL receptor-targeted strategies hold great appeal for future cancer and more specifically GBM therapy. However, it is also evident from the available literature that GBM is unlikely to be sufficiently responsive to single-agent therapy with TRAIL receptor-targeted strategies. Indeed, when taking into account the inherent heterogeneity of GBM it seems most prudent to examine the feasibility of combinatorial strategies that on the one hand sensitize GBM cells to apoptosis, and Smoothened Agonist in vivo on the other hand induce apoptosis using TRAIL or agonistic TRAIL receptor antibodies. As highlighted in this

review, TRAIL can be combined with a variety of different conventional and novel therapeutic strategies to yield synergistic Methane monooxygenase pro-apoptotic activity. Of particular appeal in our opinion is the use of dual purpose TRAIL-based molecules, such as the EGFR-targeted TRAIL fusion protein scFv425:sTRAIL. This fusion protein simultaneously blocks EGFR mitogenic signalling; thereby sensitizing tumour cells to apoptosis, and induces apoptosis via TRAIL receptor signalling. This fusion protein efficiently activates apoptosis and shows promising in vivo activity. Obviously, further rational combination with other therapeutic strategies may help to optimize anti-GBM activity. An important aspect in considering GBM therapy is the observation that, as in many other types of tumour, a so-called ‘stem cell’ population can be identified in GBM. These glioblastoma stem cells (GSCs) can regrow into original glioblastoma in xenograft nude mouse models and express neural stem cell markers, such as CD133. Importantly, GSCs are particularly refractory to radiotherapy and chemotherapy due to, e.g. overexpression of multidrug resistance pumps and overexpression of aldehyde dehydrogenase. A recent report identified, in two primary patient-derived GSC cultures, that these cells were also refractory to sTRAIL treatment, partly due to selective down-regulation of caspase-8.