Antiangiogenic therapy in malignant glioma: promise and challenge.
Malignant glioma represents one of the most lethal and angiogenic cancers. Angiogenesis is a fundamental process of blood vessel growth that is a hallmark of cancer. Although several molecular mechanisms contribute to tumor angiogenesis in gliomas, the vascular endothelial growth factor (VEGF) pathway appears particularly important and has been a prominent therapeutic target in cancer treatment. Several preclinical studies have demonstrated efficacy of antiangiogenic agents in both subcutaneous and orthotopic malignant glioma xenograft models. Recently, a phase II clinical trial of bevacizumab, a neutralizing monoclonal antibody to VEGF, in combination with irinotecan has demonstrated promising radiographic response and survival benefit in patients with recurrent malignant glioma. Several other antiangiogenic agents such as inhibitors to platelet derived growth factors (PDGFs), fibroblast growth factors (FGFs), angiopoietins/Tie-2 system, protein kinase C and integrins are currently in preclinical and clinical development. Despite the encouraging results of antiangiogenic therapies in malignant glioma, there are several challenges to be overcome to achieve optimal clinical benefit. Identification of biomarkers to predict response or resistance and to monitor antiangiogenic effects is important to enrich for patients who are likely to respond to therapy and to define the optimal biological dose. At present, antiangiogenic therapies remain palliative suggesting that overcoming antiangiogenic resistance may require multi-targeted agents, combination of agents targeting different angiogenic pathways or multi-modality combination with radiation, chemotherapy, other targeted therapeutics or immunotherapy. In this review, we will discuss the current development, promise and challenge of antiangiogenic therapy in malignant glioma.
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The Preston Robert Tisch Brain Tumor Center, Division of Neurology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Rich
Jeremy N
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D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D042501:Angiogenic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042682:Angiopoietins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D033581:Stem Cell Transplantation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D042682:Angiopoietins; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D016023:Integrins; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors; D017228:Hepatocyte Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor; D011493:Protein Kinase C