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A Review of VEGF/VEGFR-Targeted Therapeutics for Recurrent Glioblastoma

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A Review of VEGF/VEGFR-Targeted Therapeutics for Recurrent Glioblastoma 414 Original Article A Review of VEGF/VEGFR-Targeted Therapeutics for Recurrent Glioblastoma David A. Reardon, MDa,b; Scott Turner, MDc; Katherine B. Peters, MD, PhDc; Annick Desjardins, MDc; Sridharan Gururangan, MDa,b; John H. Sampson, MD, PhDa; Roger E. McLendon, MDd; James E. Herndon II, PhDe; Lee W. Jones, PhDf; John P. Kirkpatrick, MD, PhDf; Allan H. Friedman, MDa; James J. Vredenburgh, MDc; Darell D. Bigner, MD, PhDd; and Henry S. Friedman, MDa,b; Durham, North Carolina Key Words ability effect of VEGF inhibitors, the Radiologic Assessment in Neu- Glioblastoma, angiogenesis, vascular endothelial growth factor, ro-Oncology (RANO) criteria were recently implemented to bet- malignant glioma ter assess response among patients with glioblastoma. Although bevacizumab improves survival and quality of life, eventual tumor progression is the norm. Better understanding of resistance mech- Abstract anisms to VEGF inhibitors and identification of effective therapy Glioblastoma, the most common primary malignant brain tumor after bevacizumab progression are currently a critical need for pa- among adults, is a highly angiogenic and deadly tumor. Angiogen- tients with glioblastoma. (JNCCN 2011;9:414–427) esis in glioblastoma, driven by hypoxia-dependent and indepen- dent mechanisms, is primarily mediated by vascular endothelial growth factor (VEGF), and generates blood vessels with distinctive features. The outcome for patients with recurrent glioblastoma is poor because of ineffective therapies. However, recent encourag- ing rates of radiographic response and progression-free survival, Malignant gliomas, including the most common sub- and adequate safety, led the FDA to grant accelerated approval of type of glioblastoma, are rapidly growing destructive tu- bevacizumab, a humanized monoclonal antibody against VEGF, for mors that extensively invade locally but rarely metasta- the treatment of recurrent glioblastoma in May 2009. These results size. The current standard of care, including maximum have triggered significant interest in additional antiangiogenic safe resection followed by radiation therapy and temo- agents and therapeutic strategies for patients with both recurrent and newly diagnosed glioblastoma. Given the potent antiperme- zolomide chemotherapy, achieves median progression- free and overall survivals of only 6.9 and 14.7 months, respectively.1 After progression, salvage therapies have historically achieved radiographic response and From the Departments of aSurgery, bPediatrics, cMedicine, 6-month progression-free survival rates of 5% to 15%, d e f Pathology, Cancer Center Biostatistics, and Radiation Oncology, 2–4 The Preston Robert Tisch Brain Tumor Center, Duke University respectively. Several factors contribute to poor treat- Medical Center, Durham, North Carolina. ment response, including frequent de novo and acquired Submitted December 14, 2010; accepted for publication March 7, 2011. resistance, heterogeneity across and within tumors, Drs. Turner, Peters, Desjardins, Gururangan, Sampson, McLendon, complex and redundant intracellular pathways regulat- Herndon, Jones, Allan Friedman, and Bigner, have disclosed that they have no financial interests, arrangements, or affiliations with ing proliferation and survival, and restricted central ner- the manufacturers of any products discussed in their article or their competitors. Dr. Reardon has disclosed that he is a consultant vous system (CNS) delivery because of the blood–brain for and on the speakers’ bureau for Merck & Co., Inc./Schering- barrier and high interstitial peritumoral pressures.5,6 Plough Corporation and Roche/Genentech, Inc. Dr. Kirkpatrick has disclosed that he receives research support from Genentech, Inc. Given this background, recent clinical studies have Dr. Vredenburgh has disclosed that he is a consultant for Roche, shown substantive radiographic responses and improved and is on the advisory board and speakers’ bureau for Genentech, Inc. Dr. Henry Friedman has disclosed that he is on the advisory progression-free survival with bevacizumab, a human- board and speakers’ bureau for Genentech, Inc. Correspondence: David A. Reardon, MD, The Preston Robert Tisch ized monoclonal antibody targeting vascular endothelial Brain Tumor Center at Duke, Duke University Medical Center, Box growth factor (VEGF),7 among patients with recurrent 3624, Durham, NC 27710. E-mail: [email protected] malignant glioma.8–11 However, initial enthusiasm has © JNCCN–Journal of the National Comprehensive Cancer Network | Volume 9 Number 4 | April 2011 Original Article 415 VEGF Therapy for Glioblastoma been tempered by relatively modest improvements and placenta growth factor [PlGF]). VEGF-A, the in overall survival, difficulties in assessing response best characterized family member, typically localizes after anti-VEGF therapeutics, and an inability to adjacent to perinecrotic regions within glioma pseu- identify effective therapy after bevacizumab failure. dopalisades,29 increases with higher glioma grade,24,30 Nonetheless, initial results have sparked a flurry of and is associated with poor outcome among patients studies attempting to more effectively exploit this with glioblastoma.30,31 VEGF-A isoforms generated therapeutic strategy. This article reviews the de- by alternative splicing can also originate from host velopment, current status, and future challenges of sources, such as invading macrophages and platelets, VEGF-targeting therapeutics for patients with recur- whereas tumor stroma can sequester larger isoforms rent glioblastoma. that are enzymatically cleaved and released.32,33 The VEGF receptor (VEGFR) family includes VEGFR-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3, neuropilin-1 Angiogenesis in Malignant Glioma (NRP-1), and NRP-2, which exhibit different bind- Glioblastoma is among the most angiogenic of ma- ing affinities of the VEGF homologs. VEGFR-1 and lignancies.12 Angiogenic tumor vessels differ mark- VEGFR-2 regulate angiogenesis, whereas VEGFR-3 edly from normal vessels. The dense network of regulates lymphangiogenesis. The NRPs, originally angiogenic vessels in glioblastoma typically display defined as mediators of axonal guidance in the CNS, structural, functional, and biochemical abnormali- also function as VEGFR tyrosine kinase corecep- ties, including large endothelial cell fenestrae, defi- tors.34 VEGF binding to VEGFRs on tumor blood cient basement membrane, decreased pericytes and vessels markedly enhances permeability and acti- smooth muscle cells, haphazard interconnections vates endothelial cell proliferation, survival, and with saccular blind-ended extensions, complex tor- migration.35 Although primarily expressed by tumor tuosity, and dysregulated transport pathways.13–18 endothelium, several solid tumors, including glio- These changes culminate in leaky and unstable blastoma, express VEGFRs, which may function in blood flow, despite increased vessel density, which an autocrine manner to promote tumor growth.36 generates hypoxia, acidosis, and increased interstitial Tumor angiogenesis recruits several bone mar- pressure within the tumor microenvironment.19,20 row–derived proangiogenic cells, including endo- Angiogenesis in glioblastoma is driven by both thelial progenitor cells (EPCs) and pericyte pro- hypoxia-dependent and -independent mechanisms. genitor cells, which support tumor vessels, and Hypoxia, a prevalent feature in malignant glioma, CD45+ “vascular modulatory” myeloid cells. The inactivates prolyl hydroxylases, leading to hypoxia- latter include tumor-associated macrophages and inducible factor-1α (HIF-1α) accumulation. HIF- monocyte precursors expressing CD11b+, Tie-2, 1α dimerizes with constitutively expressed HIF-1β, or VEGFR-1.37–40 Several cytokines chemoattract translocates to the nucleus, and activates several these cells from the bone marrow to the tumor, hypoxia-associated genes, including VEGF.21 Inde- including VEGF, granulocyte-macrophage colony- pendent of hypoxia, glioblastomas commonly exhib- stimulating factor, and stromal-derived factor-1α it dysregulated activation of mitogenic and survival (SDF-1α).41–44 Bone marrow–derived progenitors pathways, including the Ras/mitogen-activated pro- significantly increase with hypoxia45 or after either tein kinase (MAPK) and phosphatidylinositol 3-ki- radiation therapy or cytotoxic chemotherapy.46,47 nase (PI3K)/akt cascades that upregulate VEGF and Furthermore, these cells can “home” to intracranial other proangiogenic factors.22,23 gliomas,48 and their levels are increased in patients Although VEGF is the prominent angiogenic with malignant glioma.42,49 Antiangiogenic therapy factor, glioblastoma tumors frequently express other can decrease circulating EPC levels in C6 murine proangiogenic factors, such as platelet-derived growth glioma subcutaneous xenografts,50 whereas SDF-1α factor (PDGF), fibroblast growth factor (FGF),24 in- inhibition can diminish recruitment and infiltra- tegrins, hepatocyte growth factor/scatter factor,25 tion of monocyte precursors.45,51 angiopoietins,26 ephrins,27 and interleukin-8.28 The Growing evidence links tumor angiogenesis with VEGF gene family includes 6 secreted glycoproteins cancer stem cell biology. Tumors derived from glioma (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, stem cells are more angiogenic and have higher ves- © JNCCN–Journal of the National Comprehensive Cancer Network | Volume 9 Number 4 | April 2011 416 Original Article Reardon et al. sel densities than those derived from nonglioma stem subsequent studies confirm that anti-VEGF
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