oa Editorial [Hot Topic: Targeted Therapy for Glioblastoma Multiforme (Guest Editor: Marc-Eric Halatsch)]

Despite advances in neurosurgical techniques, radio- and chemotherapy, the prognosis of patients with glioblastoma multiforme remains poor. Against this background, more efficacious adjuvant therapies with less toxicity are urgently needed. While molecularly targeted therapy has evolved as a highly rational and specific approach to meet this requirement, preliminary clinical results have fallen short of expectations. Among the reasons for this disappointment is the fact that glioblastoma multiforme is driven by a multitude of differentially activated or silenced signaling pathways with both parallel and converging complex interactions. As a result, the existence of a single molecular key target conferring unconditional and irreplaceable cellular “oncogene addiction” not only for the majority of tumor cells, but also in the majority of glioblastoma patients has not been confirmed in clinical settings and must be considered unlikely. To add to this complexity, lack of sometimes even moderate efficacy of targeted therapy strategies in clinical trials may not necessarily reflect an inappropriate choice of the molecular target itself, but may simply be a consequence of incomplete target inhibition. Therefore, clinical trial designs incorporating molecular in addition to “classical” endpoints will become increasingly important. At the same time, advancement of our currently deficient understanding of what “intrinsic resistance” to targeted therapy really means critically depends on exactly this type of information. It may be expected that bioinformatics research network initiatives will continue to rapidly expand our knowledge of the molecular basis of cancer by defining mutational landscapes and mapping dynamic cross-interactions of multiple signaling pathways. While this undoubtedly represents unprecedented opportunity and challenge in glioblastoma research, the cellular and molecular heterogeneity of glioblastoma is likely to remain a major obstacle to successful implementation of a truly “personalized” therapeutic approach for years and decades ahead. Engaging in this demanding subfield of glioblastoma research may be especially rewarding as some of the future lessons on the basis of “acquired resistance” to targeted therapy will have to be learned by better understanding “heterogeneity”. By merging outstanding contributions of well-recognized experts in their fields, this Special Issue aims at highlighting hopes and disappointments, changes in paradigms and future perspectives of targeted therapy for glioblastoma multiforme. While the dilemma and limitations of monotargeting are comprehensively analyzed by Karpel et al., Sathornsumetee provides valuable insights into the potential of multitargeting. These intracellular approaches are thematically complemented by extracellular strategies involving targeted toxins as described in a state-of-the-art review by Candolfi et al. An impressively broad overview regarding nucleic acidbased therapeutics afforded by Shir and coauthors is extended and specifically elaborated by Rainov and Heidecke in their insightful work on the clinical development of experimental virus-mediated gene therapy. Angiogenesis is of eminent importance to the development, maintenance and progression of glioblastoma, and targeted interference with this complex process has produced sometimes puzzling results. In the maze of targeting angiogenesis, indispensable navigation and guidance is provided by Linkous and Yazlovitskaya.....