title: Current status and future directions of anti-angiogenic therapy for gliomas.
abstract: Molecular targets for the pathological vasculature are the vascular endothelial growth factor (VEGF)/VEGF receptor axis, integrins, angiopoietins, and platelet-derived growth factor receptor (PDGFR), as well as several intracellular or downstream effectors like protein kinase C beta and mammalian target of rapamycin (mTOR). Besides hypoxic damage or tumor cell starvation, preclinical models imply vessel independent tumor regression and suggest differential effects of anti-angiogenic treatments on tumorous and nontumorous precursor cells or the immune system. Despite compelling preclinical data and positive data in other cancers, the outcomes of clinical trials with anti-angiogenic agents in gliomas by and large have been disappointing and include VEGF blockage with bevacizumab, integrin inhibition with cilengitide, VEGF receptor inhibition with sunitinib or cediranib, PDGFR inhibition with imatinib or dasatinib, protein kinase C inhibition with enzastaurin, and mTOR inhibition with sirolimus, everolimus, or temsirolimus. Importantly, there is a lack of real understanding for this negative data. Anti-angiogenic therapies have stimulated the development of standardized imaging assessment and the integration of functional MRI sequences into daily practice. Here, we delineate directions in the identification of molecularly or image-based defined subgroups, anti-angiogenic cotreatment for immunotherapy, and the potential of ongoing trials or modified targets to change the game.
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg and German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany (W.W., M.P., A.W., A.H., F.W.); Department of Neuroradiology, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany (A.R., M.B.).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg and German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany (W.W., M.P., A.W., A.H., F.W.); Department of Neuroradiology, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany (A.R., M.B.).
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg and German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany (W.W., M.P., A.W., A.H., F.W.); Department of Neuroradiology, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany (A.R., M.B.).
authors.forename: Antje
authors.initials: A
authors.lastname: Wick
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg and German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany (W.W., M.P., A.W., A.H., F.W.); Department of Neuroradiology, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany (A.R., M.B.).
authors.forename: Anne
authors.initials: A
authors.lastname: Hertenstein
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg and German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany (W.W., M.P., A.W., A.H., F.W.); Department of Neuroradiology, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany (A.R., M.B.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Radbruch
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg and German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany (W.W., M.P., A.W., A.H., F.W.); Department of Neuroradiology, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany (A.R., M.B.).
authors.forename: Martin
authors.initials: M
authors.lastname: Bendszus
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University of Heidelberg and German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany (W.W., M.P., A.W., A.H., F.W.); Department of Neuroradiology, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany (A.R., M.B.).
authors.forename: Frank
authors.initials: F
authors.lastname: Winkler
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003131:Combined Modality Therapy / Q000379:methods; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A
keywords: angiogenesis; bevacizumab; cilengitide; evasive resistance; vascular normalization