Anti-Vascular Endothelial Growth Factor Monoclonal Antibodies

  • Ernest S. Han
  • Bradley J. Monk
Part of the Macromolecular Anticancer Therapeutics book series (CDD&D)


As tumors grow and metastasize, they require the formation of new blood vessels or angiogenesis. This process is regulated by a complex balance of pro- and antiangiogenic factors. One of these factors, vascular endothelial growth factor (VEGF), has been extensively studied and found to be an important stimulatory signal that drives angiogenesis. VEGF belongs to a family that consists of six glycoproteins and binds to one or more of the three VEGF receptors. The various VEGF ligands and receptors mediate angiogenesis, vasculogenesis, and lymphangiogenesis. Recently, neuropilins have been shown to be important co-receptors and help to modulate VEGF and VEGF receptor interactions. VEGF and its receptor have become targets for monoclonal antibody therapies in the treatment of various cancers. Bevacizumab, which is directed against VEGF, has been the most extensively studied drug with several phase III trials already completed. Based on improvement in patient survival, bevacizumab has been FDA approved for use in combination with chemotherapy for the treatment of metastatic colorectal cancer, non-small cell lung cancer, and breast cancer. Although most of the trials investigating bevacizumab involved treating patients with advanced disease, there are two ongoing phase III trials of bevacizumab in combination with cytotoxic chemotherapy in the adjuvant setting in patients with advanced stage epithelial ovarian cancer. Newer antibody therapy directed at VEGF (VEGF-Trap and HuMV833) and VEGF receptor (IMCL-1121b and IMC-18F1) is still in development and early clinical trials. Despite the improvements in patient survival, several challenges still lie ahead and include potential serious side effects such as gastrointestinal perforation, determining appropriate dosing, dealing with resistance to antiangiogenesis drugs, and identifying biologic markers for predicting and monitoring response to therapy. Targeting VEGF has been an important novel strategy in treating cancers and will continue to improve with our understanding of angiogenesis in malignancy.


Vascular Endothelial Growth Factor Ovarian Cancer Epithelial Ovarian Cancer Vascular Endothelial Growth Factor Receptor Metastatic Colorectal Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



thymoma viral proto-oncogene


Alanine aminotransferase


American society of clinical oncology


Dynamic contrast enhanced magnetic resonance imaging


Dose-limiting toxicities


European organisation for research and treatment of cancer


Food and drug administration




Gynecologic oncology group


Human epidermal growth factor


Hypoxia inducible factor


Hazard ratio for death


Humanized mouse monoclonal anti-VEGF antibody MV833






Maximal tolerable dose


murine monoclonal antibody


Non-small-cell lung cancer


Optimal biological dose


Overall survival


Platelet-derived growth factor


Poly(ethylene) glycol


Positron emission tomography


Progression-free survival


Placental growth factor


Response evaluation criteria in solid tumors


Response rate




Single nucleotide polymorphisms


Vascular endothelial growth factor


VEGF receptors


  1. 1.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70CrossRefPubMedGoogle Scholar
  2. 2.
    Li C-Y, Shan S, Huang Q, et al. (2000) Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst 92: 143–147CrossRefPubMedGoogle Scholar
  3. 3.
    Huang LE, Gu J, Schau M, et al. (1998) Regulation of hypoxia-inducible factor 1 is mediated by an O2-dependent degradation domain via the ubiquitinproteasome pathway. Proc Natl Acad Sci USA 95:7987–7992CrossRefPubMedGoogle Scholar
  4. 4.
    Kallio PJ, Wilson WJ, O’Brien S, et al. (1990) Regulation of the hypoxia inducible transcription factor 1 by the ubiquitin-proteasome pathway. J Biol Chem 274:6519–6525CrossRefGoogle Scholar
  5. 5.
    Salceda S, Caro J (1997) Hypoxia-inducible factor 1 (HIF-1) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272:22642–22647CrossRefPubMedGoogle Scholar
  6. 6.
    Maxwell PH, Wiesener MS, Chang GW, et al. (1999) The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275CrossRefPubMedGoogle Scholar
  7. 7.
    Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721-732Google Scholar
  8. 8.
    Hicklin DJ, Ellis LM (2005) Role of vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027CrossRefPubMedGoogle Scholar
  9. 9.
    Dvorak HF, Orenstein NS, Carvalho AC, et al. (1979) Induction of a fibrin-gel investment: an early event in line 10 hepatocarcinoma growth mediated by tumor-secreted products. J Immunol 122:166–174PubMedGoogle Scholar
  10. 10.
    Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20:4368–4380CrossRefPubMedGoogle Scholar
  11. 11.
    Houck KA, Ferrara N, Winer J, et al. (1991) The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 5:1806–1814CrossRefPubMedGoogle Scholar
  12. 12.
    Tischer E, Mitchell R, Hartman T, et al. (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266:11947–11954PubMedGoogle Scholar
  13. 13.
    Poltorak Z, Cohen T, Sivan R, et al. (1997) VEGF145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J Biol Chem 272:7151–7158CrossRefPubMedGoogle Scholar
  14. 14.
    Lei J, Jiang A, Pei D (1998) Identification and characterization of a new splicing variant of vascular endothelial growth factor: VEGF183. Biochim Biophys Acta 1443:400–406PubMedGoogle Scholar
  15. 15.
    Ferrara N, Gerber HP, LeCouter J (2003) Biology of VEGF and its receptors. Nat Med 9(6): 669–676CrossRefPubMedGoogle Scholar
  16. 16.
    Fan F, Wey JS, McCarty MF, et al. (2005) Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 24:2647–2653CrossRefPubMedGoogle Scholar
  17. 17.
    Wei JS, Fan F, Gray MJ, et al. (2005) Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer 104:427–438CrossRefGoogle Scholar
  18. 18.
    Taylor AP, Goldenberg DM (2007) Role of placenta growth factor in malignancy and evidence that an antagonistic PlGF/Flt-1 peptide inhibits the growth and metastasis of human breast cancer xenografts. Mol Cancer Ther 6(2):524–531CrossRefPubMedGoogle Scholar
  19. 19.
    Millauer B, Wizigmann-Voos S, Schnűrch H, et al. (1993) High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72:835–846CrossRefPubMedGoogle Scholar
  20. 20.
    Zeng H, Dvorak HF, Mukhopadhyay D (2001) Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) receptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways. J Biol Chem 276:26969–26979CrossRefPubMedGoogle Scholar
  21. 21.
    Su JL, Yen CJ, Chen PS, et al. (2007) The role of VEGF-C/VEGFR-3 axis in cancer progression. Br J Cancer 96:541–545CrossRefPubMedGoogle Scholar
  22. 22.
    He Y, Kozaki K-I, Karpanen T, et al. (2002) Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 94(11):819–825PubMedGoogle Scholar
  23. 23.
    Hoshida T, Isaka N, Hagendoorn J, et al. (2006). Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res 66(16):8065–8074CrossRefPubMedGoogle Scholar
  24. 24.
    Roberts N, Kloos B, Cassella M, et al. (2006) Inhibition of VEGFR-3 activation with the antagonistic antibody potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res 66(5):2650–2657CrossRefPubMedGoogle Scholar
  25. 25.
    Laakkonen P, Waltari M, Holopainen T, et al. (2007) Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res 67(2):593–599CrossRefPubMedGoogle Scholar
  26. 26.
    Tammela T, Zarkada G, Wallgard E, et al. (2008) Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454:656–663CrossRefPubMedGoogle Scholar
  27. 27.
    He Z and Tessier-Lavigne M (1997) Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell 90(4): 739-751Google Scholar
  28. 28.
    Kolodkin AL, Levengood DV, Rowe EG, et al. (1997) Neuropilin is a semaphorin III receptor. Cell 90(4):753-762Google Scholar
  29. 29.
    Neufeld G, Kessler O (2008) The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer 8:632–645CrossRefPubMedGoogle Scholar
  30. 30.
    Pan Q, Chanthery Y, Liang WC, et al. (2007) Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11:53–67CrossRefPubMedGoogle Scholar
  31. 31.
    Caunt M, Mak J, Liang WC, et al. (2008) Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 13:331–342CrossRefPubMedGoogle Scholar
  32. 32.
    Folkman J, Watson K, Ingber D (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58–61CrossRefPubMedGoogle Scholar
  33. 33.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182-1186.Google Scholar
  34. 34.
    Gerber HP, Ferrera N (2005) Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 65(3): 671–680PubMedGoogle Scholar
  35. 35.
    Presta LG, Chen H, O’Connor SJ, et al. (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593–4599PubMedGoogle Scholar
  36. 36.
    Lu J-F, Bruno R, Eppler S, et al. (2008) Clinical pharmacokinetics of bevacizumab in patients with solid tumors. Cancer Chemother Pharmacol 62:779–786CrossRefPubMedGoogle Scholar
  37. 37.
    Hurwitz H, Fehrenbacher L, Novotny W, et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342CrossRefPubMedGoogle Scholar
  38. 38.
    Giantonio BJ, Catalano PJ, Meropol NJ, et al. (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group study E3200. J Clin Oncol 25(12):1539–1544CrossRefPubMedGoogle Scholar
  39. 39.
    Saltz LB, Clarke S, Diaz-Rubio E, et al. (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019CrossRefPubMedGoogle Scholar
  40. 40.
    Sandler A, Gray R, Perry MC, et al. (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550CrossRefPubMedGoogle Scholar
  41. 41.
    Miller KD, Wang M, Gralow J, et al. (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676CrossRefPubMedGoogle Scholar
  42. 42.
    Fuchs CS, Marshall J, Mitchell E, et al. (2007) Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C study. J Clin Oncol 25(30):4779–4786CrossRefPubMedGoogle Scholar
  43. 43.
    Fuchs CS, Mitchell J, Barrueco J (2008) Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol 26(4):689–690CrossRefPubMedGoogle Scholar
  44. 44.
    Johnson DH, Fehrenbacher L, Novony WF, et al. (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:2184–2191CrossRefPubMedGoogle Scholar
  45. 45.
    Manegold C, von Pawel J, Zatloukal P, et al. (2007) Randomized, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer: BO17704. J Clin Oncol 25(18S): LBA7514Google Scholar
  46. 46.
    Miller KD, Chap LI, Holmes FA, et al. (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23(4):792–799CrossRefPubMedGoogle Scholar
  47. 47.
    Miles D, Chan A, Romieu G, et al. (2008) Randomized, double blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer: AVADO. J Clin Oncol 26:LBA1011Google Scholar
  48. 48.
    Ko A, Dito E, Schillinger B, et al. (2008) A phase II study evaluating bevacizumab in combination with fixed-dose rate gemcitabine and low-dose cisplating for metastatic pancreatic cancer: is an anti-VEGF strategy still applicable? Invest New Drugs 26: 463–471CrossRefPubMedGoogle Scholar
  49. 49.
    Kindler HL, Niedzwiecki D, Hollis D, et al. (2007) A double-blind, placebo-controlled, randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo in patients with advanced pancreatic cancer: a preliminary analysis of Cancer and Leukemia Group B. J Clin Oncol ASCO Annu Meet Proc Part I 25:4508Google Scholar
  50. 50.
    Rini BI, Rathmell WK (2007) Biological aspects and binding strategies of vascular endothelial growth factor in renal cell carcinoma. Clin Cancer Res 13(2 Suppl): 741s–746sCrossRefPubMedGoogle Scholar
  51. 51.
    Escudier B, Pluzanska A, Koralewski P, et al. (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomized, double-blind phase III trial. Lancet 370:2103–2111CrossRefPubMedGoogle Scholar
  52. 52.
    Monk BJ, Choi DC, Pugmire G, et al. (2005) Activity of bevacizumab (rhuMAB VEGF) in advanced refractory epithelial ovarian cancer. Gynecol Oncol 96:902–905CrossRefPubMedGoogle Scholar
  53. 53.
    Cohn DE, Valmadre S, Resnick KE, et al. (2006) Bevacizumab and weekly taxane chemotherapy demonstrates activity in refractory ovarian cancer. Gynecol Oncol 102:134–139CrossRefPubMedGoogle Scholar
  54. 54.
    Monk BJ, Han E, Josephs-Cowan CA, et al. (2006) Salvage bevacizumab (rhuMAB VEGF)-based therapy after multiple prior cytotoxic regimens in advanced refractory epithelial ovarian cancer. Gynecol Oncol 102:140–144CrossRefPubMedGoogle Scholar
  55. 55.
    Wright JD, Hagemann A, Rader JS, et al. (2006) Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma. Cancer 107:83–89CrossRefPubMedGoogle Scholar
  56. 56.
    Burger RA, Sill MW, Monk BJ, et al. (2007) Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a gynecologic oncology group study. J Clin Oncol 25(33): 5165–5171.CrossRefPubMedGoogle Scholar
  57. 57.
    Garcia AA, Hirte H, Fleming G, et al. (2008) Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 26(1):76–82.CrossRefPubMedGoogle Scholar
  58. 58.
    Cannistra SA, Matulonis UA, Penson RT, et al. (2007) Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25(33):5180–5186.CrossRefPubMedGoogle Scholar
  59. 59.
    Aghajanian C (2006) The role of bevacizumab in ovarian cancer – an evolving story. Gynecol Oncol 102:131–133CrossRefPubMedGoogle Scholar
  60. 60.
    Zhu X, Wu S, Dahut WL, et al. (2007) Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis 49:186–193CrossRefPubMedGoogle Scholar
  61. 61.
    Eremina V, Jefferson JA, Kowalewska J, et al. (2008) VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 358:1129–1136.CrossRefPubMedGoogle Scholar
  62. 62.
    Kamba T, McDonald DM (2007) Mechanisms of adverse effects of anti-VEGF therapy in cancer. Br J Cancer 96:1788–1795CrossRefPubMedGoogle Scholar
  63. 63.
    Nalluri SR, Chu D, Keresztes R, et al. (2008) Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients. JAMA 300:2277–2285CrossRefPubMedGoogle Scholar
  64. 64.
    Han ES, Monk BJ (2007) Bevacizumab in the treatment of ovarian cancer. Expert Rev Anticancer Ther 7(10):1339–1345CrossRefPubMedGoogle Scholar
  65. 65.
    Saif MW, Elfiky A, Salem RR (2007) Gastrointestinal perforation due to bevacizumab in colorectal cancer. Ann Surg Oncol 14:1860–1869CrossRefPubMedGoogle Scholar
  66. 66.
    Han ES, Monk BJ (2007) What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer? Gynecol Oncol 105(1):3–6CrossRefPubMedGoogle Scholar
  67. 67.
    Holash J, Davis S, Papadopoulos N, et al. (2002) VEGF-Trap: a VEGF blocker with potent antitumor effects. PNAS 99(17):11393–11398CrossRefPubMedGoogle Scholar
  68. 68.
    Dupont J, Schwartz L, Koutcher J, et al. (2004) Phase 1 and pharmacokinetic study of VEGF Trap administered subcutaneously to patients with advanced solid malignancies. J Clin Oncol 22:3009Google Scholar
  69. 69.
    Dupont J, Rothenberg ML, Spriggs DR, et al. (2005) Safety and pharmacokinetics of intravenous VEGF Trap in a phase I clinical trial of patients with advanced solid tumors. J Clin Oncol 23(16S):3029Google Scholar
  70. 70.
    Byrne AT, Ross L, Holash J, et al. (2003) Vascular endothelial growth factor-Trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res 9:5721–5728PubMedGoogle Scholar
  71. 71.
    Hu L, Hofmann J, Holash J, et al. (2005) Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in an human ovarian cancer model. Clin Cancer Res 11(19):6966–6971CrossRefPubMedGoogle Scholar
  72. 72.
    Tew WP, Colombo N, Ray-Coquard I, et al. (2007) VEGF-Trap for patients with recurrent platinum-resistant epithelial ovarian cancer: preliminary results of a randomized, multicenter phase II trial. J Clin Oncol 25(18S):5508Google Scholar
  73. 73.
    Massarelli E, Miller VA, Leighl NB, et al. (2007) Phase II study of the efficacy and safety of intravenous AVE0005 (VEGF Trap) given every 2 weeks in patients with platinum- abd erlotinib-resistant adenocarcinoma of the lung. J Clin Oncol 25(18S):7627Google Scholar
  74. 74.
    De Groot JF, Wen PY, Lamborn K, et al. (2008) Phase II single arm trial of aflibercept in patients with recurrent temozolomide-resistant glioblastoma: NABTC 0601. J Clin Oncol 26:2020CrossRefGoogle Scholar
  75. 75.
    Jayson GC, Zweit J, Jackson A, et al. (2002) Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies. J Natl Cancer Inst 94:1484–1493PubMedGoogle Scholar
  76. 76.
    Asano M, Yukita A, Suzuki H (1999) Wide spectrum of antitumor activity of a neutralizing monoclonal antibody to human vascular endothelial growth factor. Jpn J Cancer Res 90:93–100PubMedGoogle Scholar
  77. 77.
    Jayson GC, Mulatero C, Ranson M, et al. (2005) Phase I investigation of recombinant anti-human vascular endothelial growth factor antibody in patients with advanced cancer. Eur J Cancer 41:555–563CrossRefPubMedGoogle Scholar
  78. 78.
    Zhu Z, Hattori K, Zhang H, et al. (2003) Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity. Leukemia 17:604–611CrossRefPubMedGoogle Scholar
  79. 79.
    Spannuth WA, Nick AM, Jennings NB, et al. (2009) Functional significance of VEGFR-2 on ovarian cancer cells. Int J Cancer 124(5):1045-1053Google Scholar
  80. 80.
    Camidge DR, Eckhardt SG, Diab S, et al. (2006) A phase I dose-escalation study of weekly IMC-1121B, a fully human anti-vascular endothelial growth factor receptor 2 IgG1 monoclonal antibody in patients with advanced cancer. J Clin Oncol ASCO Ann Meet Proc Part I 24(18S):3032Google Scholar
  81. 81.
    Wu Y, Zhong Z, Huber J, et al. (2006) Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer. Clin Cancer Res 12(21):6573–6584CrossRefPubMedGoogle Scholar
  82. 82.
    Krishnamurthi SS, LoRusso PM, Goncalves PH, et al. (2008) Phase 1 study of weekly anti-vascular endothelial growth factor receptor-1 monoclonal antibody IMC-18F1 in patients with advanced solid malignancies. J Clin Oncol 26:14630Google Scholar
  83. 83.
    Ton NC, Parker GL, Jackson A, et al. (2007) Phase I evaluation of CDP791, a PEGylated di-Fab’ conjugate that binds vascular endothelial growth factor receptor 2. Clin Cancer Res 13(23):7113-7118Google Scholar
  84. 84.
    Jain RK, Xu L (2007) αPlGF: a new kid on the antiangiogenesis block. Cell 131:443–445CrossRefPubMedGoogle Scholar
  85. 85.
    Fischer C, Jonckx B, Mazzone M, et al. (2007) Anti-PLGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131(3):463-475Google Scholar
  86. 86.
    Bhatt RS, Seth P, Sukhatme VP (2007) Biomarkers for monitoring antiangiogenic therapy. Clin Cancer Res 13(2 Suppl):777s–780sCrossRefPubMedGoogle Scholar
  87. 87.
    Duda DG, Batchelor TT, Willett CG, et al. (2007) VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects. Trends Mol Med 13(6):223–230CrossRefPubMedGoogle Scholar
  88. 88.
    Jain RK, Duda DG, Clark JW, et al. (2006) Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 3(1):24–40CrossRefPubMedGoogle Scholar
  89. 89.
    Jubb AM, Hurwitz HI, Bai W, et al. (2006) Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol 24(2):217–227CrossRefPubMedGoogle Scholar
  90. 90.
    Longo R, Gasparini G (2007) Challenges for patient selection with VEGF inhibitors. Cancer Chemother Pharmacol 60:151–170CrossRefPubMedGoogle Scholar
  91. 91.
    Longo R, Gasparini G (2008) Anti-VEGF therapy: the search for clinical biomarkers. Expert Rev Mol Diagn 8(3):301–314CrossRefPubMedGoogle Scholar
  92. 92.
    Sessa C, Guibal A, Del Conte G, et al. (2008) Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations? Nat Clin Pract Oncol 5(7):378–391CrossRefPubMedGoogle Scholar
  93. 93.
    Emmenegger U, Kerbel RS (2005) A dynamic de-escalating dosing strategy to determine the optimal biological dose for antiangiogenic drugs. Clin Cancer Res 11(21):7589–7944CrossRefPubMedGoogle Scholar
  94. 94.
    DePrimo SE, Bello CL, Smeraglia J, et al. (2007) Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med 5:32CrossRefPubMedGoogle Scholar
  95. 95.
    Rini BI, Michaelson MD, Rosenberg JE, et al. (2008) Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol 26(22):3743–3748CrossRefPubMedGoogle Scholar
  96. 96.
    Burstein HJ, Chen Y-H, Parker LM, et al. (2008) VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res 14(23):7871–7877CrossRefPubMedGoogle Scholar
  97. 97.
    Rudge JS, Holash J, Hylton D, et al. (2007) VEGF Trap complex formation measures production rates if VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci USA 104(47):18363–18370CrossRefPubMedGoogle Scholar
  98. 98.
    Ince WL, Jubb AM, Holder SN, et al. (2005) Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst 97:981–989CrossRefPubMedGoogle Scholar
  99. 99.
    Schneider BP, Wang M, Radovich M, et al. (2008) Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 26(28):4672–4678CrossRefPubMedGoogle Scholar
  100. 100.
    Azad NS, Annunziata CM, Steinberg SM, et al. (2008) Lack of reliability of CA125 response criteria with anti-vegf molecularly targeted therapy. Cancer 112:1726–1732CrossRefPubMedGoogle Scholar
  101. 101.
    Markman M (2008) Lack of Reliability of CA125 response criteria with anti-VEGF molecularly targeted therapy. Cancer 113(10):2833–2834CrossRefGoogle Scholar
  102. 102.
    Fernando NT, Koch M, Rothrock C, et al. (2008) Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res 14(5):1529–1539CrossRefPubMedGoogle Scholar
  103. 103.
    Kadenhe-Chiweshe A, Papa J, McCrudden KW, et al. (2008) Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation. Mol Cancer Res 6(1):1–9CrossRefPubMedGoogle Scholar
  104. 104.
    Jubb AM, Oates AJ, Holden S, et al. (2006) Predicting benefit from anti-angiogenesis agents in malignancy. Nat Rev Cancer 6:626–635CrossRefPubMedGoogle Scholar
  105. 105.
    Lu C, Thaker PH, Lin YG, et al. (2008) Impact of vessel maturation on antiangiogenic therapy in ovarian cancer. Am J Obstet Gynecol 198:477.e1–477.e10CrossRefGoogle Scholar
  106. 106.
    Tang P, Cohen SJ, Bjarnason GA, et al. (2008) Phase II trial of aflibercept (VEGF Trap) in previously treated patients with metastatic colorectal cancer: a PMH phase II consortium trial. J Clin Oncol 26:4027CrossRefGoogle Scholar
  107. 107.
    Verheul HMW, Hammers H, van Erp K, et al. (2007) Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model. Clin Cancer Res 13(14):4201–4208CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Ernest S. Han
    • 1
  • Bradley J. Monk
    • 2
  1. 1.Division of Gynecologic OncologyCity of HopeDuarteUSA
  2. 2.Division of Gynecologic OncologyUniversity of California IrvineOrangeUSA

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