Aflibercept a new target therapy in cancer treatment: A review

Critical Reviews in Oncology/Hematology

Volumn 96, Issue 3, 2015, Pages 569-576

  Ricci, Vincenzo ^a   Ronzoni, Monica ^a   Fabozzi, Teresa ^a  

^a San Raf faele Institute   (Italy)

Author keywords

Aflibercept; Angiogenesis; Antiangiogenic agent; Placental growth factor; VEGF A; VEGF B

Indexed keywords

5 CHLOROURACIL DERIVATIVE; 6(2 AMINOETHYL) AMINO 5 CHLOROURACIL; ABIRATERONE; AFLIBERCEPT; BEVACIZUMAB; CAPECITABINE; CISPLATIN; DOCETAXEL; ENZALUTAMIDE; FLUOROURACIL; FOLINIC ACID; IRINOTECAN; OXALIPLATIN; PACLITAXEL; PEMETREXED; PREDNISONE; UNCLASSIFIED DRUG; HYBRID PROTEIN; VASCULOTROPIN RECEPTOR;

ABDOMINAL PAIN; ANGIOGENESIS; APOPTOSIS; BLEEDING; CANCER RECURRENCE; CANCER THERAPY; CASTRATION RESISTANT PROSTATE CANCER; CELL PROLIFERATION; COHORT ANALYSIS; DIARRHEA; DRUG EFFICACY; DRUG SAFETY; ENDOMETRIUM CARCINOMA; ENDOMETRIUM SARCOMA; ENDOTHELIUM CELL; ENZYME INHIBITION; FATIGUE; GLIOBLASTOMA; HEADACHE; HUMAN; HYPERTENSION; IMMUNOHISTOCHEMISTRY; MELANOMA; METASTATIC COLORECTAL CANCER; NEUROBLASTOMA; NEUTROPENIA; NON SMALL CELL LUNG CANCER; NONHODGKIN LYMPHOMA; NONHUMAN; OVARY CANCER; OVARY CARCINOMA; OVERALL SURVIVAL; PANCREAS CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME; PROGRESSION FREE SURVIVAL; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; PROTEIN SECRETION; PROTEINURIA; RANDOMIZED CONTROLLED TRIAL (TOPIC); RECTUM ULCER; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; STOMATITIS; TREATMENT RESPONSE; TUMOR MICROENVIRONMENT; TUMOR REGRESSION; TUMOR VASCULARIZATION; UTERINE TUBE CARCINOMA; UTERUS SARCOMA; METABOLISM; MOLECULARLY TARGETED THERAPY; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; PROGNOSIS;

HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; PROGNOSIS; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR; RECOMBINANT FUSION PROTEINS;

EID: 84983128441     PISSN: 10408428     EISSN: 18790461     Source Type: Journal    
DOI: 10.1016/j.critrevonc.2015.07.001     Document Type: Review

References (83)

1. Allen J.W., Moon J., Redman M., Gadgeel S.M., et al. Southwest Oncology Group S0802: a randomized, phase II trial of weekly topotecan with and without ziv-aflibercept in patients with platinum-treated small-cell lung cancer. J. Clin. Oncol. 2014, 32(23 (August 10)):2463-2470. Epub 2014 Jul 7. 10.1200/JCO. 2013.51.4109.
2. Andre T., Dumont S.N. Regorafenib approved in metastatic colorectal cancer. Bull. Cancer 2013, 100:1027-1029.
3. Baffert F., Le T., Sennino B., Thurston G., Kuo C.J., Hu-Lowe D., et al. Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am. J. Physiol. Heart Circ. Physiol. 2006, 290:H547-H559.
4. Bennouna J., Sastre J., Arnold et al D. ML18147 study investigators continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013, 1(14 (January)):29-37.
5. Byrne A.T., Ross L., Holash J., Nakanishi M., Hu L., Hofmann J.I., et al. Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin. Cancer. Res. 2003, 9:5721-5728.
6. Chen H., Modiano M.R., Neal J.W., Brahmer J.R., Rigas J.R., Jotte R.M., et al. A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer. Br. J. Cancer 2014, 110(3 (February)):602-608.
7. Chu Q.S. Aflibercept (AVE0005): an alternative strategy for inhibiting tumour angiogenesis by vascular endothelial growth factors. Expert Opin. Biol. Ther. 2009, 9(2 (Feburary)):263-271.
8. Clarke J.M., Hurwitz H.I. Targeted inhibition of VEGF receptor 2: an update on ramucirumab. Expert Opin Biol. Ther. 2013, 13:1187-1196.
9. Colombo N., Mangili G., Mammoliti S., Kalling M., Tholander B., Sternas L., et al. Aflibercept (VEGF Trap) for advanced epithelial ovarian cancer (EOC) patients (pts) with symptomatic malignant ascites: preliminary results of a pilot study. Gynecol. Oncol. 2012, 125(1 (April)):42-47.
10. Dalal S., Berry A.M., Cullinane C.J., Mangham D.C., Grimer R., Lewis I.J., et al. Vascular endothelial growth factor: a therapeutic target for tumors of the Ewing's sarcoma family. Clinical cancer research: an official journal of the 2005, 11:2364-2378.
11. De Groot J.F., Lamborn K.R., Chang S.M., Gilbert M.R., Cloughesy T.F., Aldape K., et al. Phase II. study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium, study. J Clin Oncol. 2011, 29(19 (July 1)):2689-2695.
12. Ebos J.M., Lee C.R., Kerbel R.S. Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin. Res. Cancer 2009, 15:5020-5025.
13. Elisei R., Schlumberger M.J., Muller S.P., et al. Cabozantinib in progressive medullary thyroid cancer. J. Clin. Oncol. 2013, 31:3639-3646.
14. Ellis L.M., Hicklin D.J. VEGF targeted therapy: mechanisms of anti-tumour therapy. Natl. Rev. 2008, 8:579-591.
15. Escudero-Esparza A., Martin T.A., Davies M.L., et al. PGF isoforms, PLGF-1 and PGF-2, in colorectal cancer and the prognostic significance. Cancer Genomics Proteomics 2009, 6:239-246.
16. Farace F., Massard C., Borghi E., Bidart J.M., Soria J.C. Vascular disrupting therapy-induced mobilization of circulating endothelial progenitor cells. Ann. Oncol. 2007, 18:1421-1422.
17. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr. Rev. 2004, 25:581-611.
18. Fischer C., Mazzone M., Jonckx B., et al. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy. Nat. Rev. Cancer 2008, 8:942-956.
19. Folkman J., DeVita V.T., Hellman S.M.D., et al. Cancer: Principles and Practice of Oncology 2005, 2865-2882. Lippincott Williams & Wilkins, Philadelphia. 7th edition.
20. Folkman J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 1971, 285(21):1182-1186.
21. Freyer G., Isambert N., You B., Zanetta S., Falandry C., Favier L., et al. Phase I. dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumours. Br. J. Cancer 2012, 107(4 (August 7)):598-603.
22. Frischer J.S., Huang J., Serur A., Kadenhe- Chiweshe A., McCrudden K.W., O'Toole K., et al. Effects of potent VEGF blockade on experimental Wilms tumor and its persisting vasculature. Int. J. Oncol. 2004, 25:549-553.
23. Fukasawa M., Korc M. Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines. Clinical cancer research: an official journal of the 2004, 10:3327-3332.
24. Gomez-Manzano C., Holash J., Fueyo J., Xu J., Conrad C.A., Aldape K.D., et al. VEGF Trap induces antiglioma effect at different stages of disease. Neuro. Oncol. 2008, 10:940-945.
25. Grothey A., Galanis E. Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat. Rev. Clin. Oncol. 2009, 6:507-518.
26. Hicklin D.J., Ellis L.M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J. Clin. Oncol. 2005, 23:1011.
27. Hillan K.J., Koeppen K.W., Tobin P., Pham T. The role of VEGF expression in response to bevacizumab plus capecitabine in metastatic breast cancer (MBC). Proc. Am. Soc. Clin. Oncol. 2003, 22:766.
28. Ho T.H., Jonasch E. Axitinib in the treatment of metastatic renal cell carcinoma. Future Oncol. 2011, 7:1247-1253.
29. Holash J., Davis S., Papadopoulos N., Croll S.D., Ho L., Russell M., Boland P., et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc. Natl. Acad. Sci. U. S. A 2002, 99:11393-11398.
30. Hu L., Hofmann J., Holash J., Yancopoulos G.D., Sood A.K., Jaffe R.B. Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model. Clin. Cancer Res. 2005, 11:6966-6971.
31. Huang J., Frischer J.S., Serur A., Kadenhe A., Yokoi A., McCrudden K.W., et al. Regression of established tumors and metastases by potent vascular endothelial growth factor blockade. Proc. Natl. Acad. Sci. U. S. A 2003, 100:7785-7790.
32. Inai T., Mancuso M., Hashizume H., Baffert F., Haskell A., Baluk P., et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am. J. Pathol. 2004, 165:35-52.
33. Isambert N., Freyer G., Zanetta S., You B., Fumoleau P., Falandry C., et al. Phase I. dose-escalation study of intravenous aflibercept in combination with docetaxel in patients with advanced solid tumors. Clin. Cancer Res. 2012, 18(6 (March 15)):1743-1750.
34. Jahangiri A., Aghi M.K., Carbonell W.S. Beta1 integrin: critical path to antiangiogenic therapy resistance and beyond. Cancer Res. 2014, 74:3-7.
35. Kadenhe-Chiweshe A., Papa J., McCrudden K.W., Frischer J., Bae J.O., Huang J., et al. Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation. Mol. Cancer Res. 2008, 6:1-9.
36. Kerbel R.S. Antiangiogenic therapy: a universal chemosensitization strategy for cancer. Science 2006, 312:1171-1175.
37. Kerbel R.S. Tumor angiogenesis. New Eng. J. Med. 2008, 358:2039-2049.
38. Kim E.S., Serur A., Huang J., Manley C.A., McCrudden K.W., Frischer J.S., et al.Potent V.E.G.F. blockade causes regression of coopted vessels in a model of neuroblastoma. Proc. Natl. Acad. Sci. U. S. A 2002, 99:11399-11404.
39. Kim E.S., Serur A., Huang J., Manley C.A., McCrudden K.W., Frischer J.S., et al. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc. Natl. Acad. Sci. U. S. A 2002, 99:11399-11404.
40. Le X.F., Mao W., Lu C., Thornton A., Heymach J.V., Sood A.K., et al. Specific blockade of VEGF and HER2 pathways results in greater growth inhibition of breast cancer xenografts that overexpress HER2. Cell Cycle 2008, 7:3747-3758.
41. Le X.F., Mao W., Lu C., Thornton A., Heymach J.V., Sood A.K., et al. Specific blockade of VEGF and HER2 pathways results in greater growth inhibition of breast cancer xenografts that overexpress HER2. Cell Cycle 2008, 7:3747-3758.
42. Leighl N.B., Raez L.E., Besse B., Rosen P.J., Barlesi F., Massarelli E., et al. A multicenter, phase 2 study of vascular endothelial growth factor trap (Aflibercept) in platinum- and erlotinib-resistant adenocarcinoma of the lung. J. Thorac. Oncol. 2010, 5(7 (July)):1054-1059.
43. Limentani S., Just R., Purdham A., Mulay M., Bair A., Tamby J.F., et al. A phase I dose escalation and pharmacokinetic (PK) study of intravenous (iv) aflibercept (VEGF Trap) plus FOLFOX4 in patients (pts) with advanced solid tumors: preliminary results. ASCO Meeting Abstracts 2008, 26:3556.
44. Lockhart A.C., Rothenberg M.L., Dupont J., Cooper W., Chevalier P., Sternas L., Phase I., et al. study of intravenous vascular endothelial growth factor Trap, aflibercept, in patients with advanced solid tumors. 2010. J. Clin. Oncol. 2009, 28:207-214.
45. Loupakis F., Ruzzo A., Salvatore L., Cremolini C., et al. Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer. BMC Cancer 2011, 11:247.
46. Lu H., Klein R.S., Schwartz E.L. Antiangiogenic and antitumor activity of 6-(2-aminoethyl) amino-5-chlorouracil, a novel small molecule inhibitor of thymidine phosphorylase, in combination with the vascular endothelial growth factor-trap. Clin. Cancer Res. 2009, 15:5136-5144.
47. Mackay H.J., Buckanovich R.J., Hirte H., Correa R., Hoskins P., Biagi J., et al. A phase II study single agent of aflibercept (VEGF Trap) in patients with recurrent or metastatic gynecologic carcinosarcomas and uterine leiomyosarcoma. A trial of the Princess Margaret Hospital, Chicago and California Phase II Consortia. Gynecol. Oncol. 2012, 125(1 (April)):136-140.
48. Mackay R.J., Buckanovich H., Hirte R., Correa P., et al. Princess Margaret Hospital, Ontario Canada A.;1; phase II study single agent of aflibercept (VEGF Trap) in patients with recurrent or metastatic gynaecologic carcinosarcomas and uterine leiomyosarcoma. A trial of the Princess Margaret Hospital, Chicago and California CancerPhase II Consortia. Gynecol Oncol. 2012, 125(1 (April 1)):136-140.
49. Mitchell E., van Hazel G., Cunningham D., et al. Evaluation of the effect of aflibercept (Z) on OS by timing of 1st line disease progression: a post-hoc analysis of the VELOUR trial. Ann Oncol. 2014, 25(Suppl. (2)). Abstract P-0226.
50. Motzer R.J., Michaelson M.D., Redman B.G., et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 2006, 24:16-24.
51. Motzer R.J., Hutson T.E., Tomczak P., et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 2007, 356:115-124.
52. Mukhopadhyay D., Datta K. Multiple regulatory pathways of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in tumors. Semin. Cancer Biol. 2004, 14:123-130.
53. Mulay M., Limentani S.A., Carroll M., Furfine E.S., Cohen D.P., Rosen L.S. Safety and pharmacokinetics of intravenous VEGF Trap plus FOLFOX4 in a combination phase I clinical trial of patients with advanced solid tumors. ASCO Meeting Abstracts 2006, 24:13061.
54. Neufeld G., Cohen T., Gengrinovitch S., et al. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999, 13(1):9-22.
55. Novello S., Ramlay R., Borbunova V.A., et al. Aflibercept in combination with docetaxel for second-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC): Final results of a multinational placebo-controlled phase III trial (EFC10261-VITAL). Proc. Int. Assoc. Study Lung Cancer 2015, 0.43.06.
56. Olofsson B., Korpelainen E., Pepper M.S., et al. Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc. Natl. Acad. Sci. U. S. A 1998, 95:11709-11714.
57. Patnaik A., Pipas M., Rosen L.S., Wood L., Phipps K., Mulay M., et al. A phase I dose escalation and pharmacokinetic (PK) study of intravenous (iv) aflibercept (VEGF Trap) plus weekly gemcitabine (Gem) in patients (pts) with advanced solid tumors: preliminary results. ASCO Meeting Abstracts 2008, 26:3558.
58. Pericay C., Folprecht G., Saunders M., et al. Phase 2 randomized, non comparative, open-label study of aflibercept and modified Folfox6 in the first-line treatment of metastatic colorectal cancer (AFFIRM). Ann Oncol. 2012, 23(Suppl. 4). iv16 abstract 0024.
59. Qiao L., Wong B.C. Role of Notch signaling in colorectal cancer. Carcinogenesis 2009, 30(12):1979-1986.
60. Rixe O., Verslype C., Méric J.B., Tejpar S., Bloch J., Crabbe M., et al. Safety and pharmacokinetics of intravenous VEGF Trap plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in a combination phase I clinical trial of patients with advanced solid tumors. ASCO Meeting Abstracts 2006, 24:13161.
61. Rougier P., Riess H., Manges R., Karasek P., Humblet Y., Barone C., et al. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur. J. Cancer 2013, 49(12 (August)):2633-2642.
62. Sawano A., Takahashi T., Yamaguchi S., et al. Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor. Cell Growth Differ. 1996, 7.
63. Schneider B.P., Wang M., Radovich M., et al. 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. 2008, 26:4672-4678.
64. Scott A.M., Wolchok J.D., Old L.J. Antibody therapy of cancer. Nat. Rev. Cancer 2012, 12:278-287.
65. Shalaby F., Rossant J., Yamaguchi T.P., et al. Failure of blood- island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995, 376.
66. Shibuya M. Tyrosine kinase receptor Flt/VEGFR family: its characterization related to angiogenesis and cancer. Genes Cancer 2010, 1:1119-1123.
67. Shweiki D., Neeman M., Itin A., et al. Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. Proc. Natl. Acad. Sci. U. S. A 1995, 92:768-772.
68. Tang P.A., Cohen S.J., Kollmannsberger C., et al. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin. Cancer Res. 2012, 18:6023-6031.
69. Tannock I.F., Fizazi K., Ivanov S., Karlsson C.T., Fléchon A., Skoneczna I., et al. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol. 2013, 14(8 (July)):760-768.
70. Tarhini A.A., Frankel P., Margolin K.A., Christensen S., Ruel C., Shipe- Spotloe J., et al. Aflibercept (VEGF Trap) in inoperable stage III or stage iv melanoma of cutaneous or uveal origin. Clin. Cancer Res. 2011, 17(20 (October 15)):6574-6581.
71. Tew W.P., Colombo N., Ray-Coquard I., Oza A., et al. VEGF-Trap for patients (pts) with recurrent platinum-resistant epithelial ovarian cancer (EOC): preliminary results of a randomized, multicenter phase II study. Cancer 2014, 120(3 (February)):335-343.
72. Twardowski P., Stadler W.M., Frankel P., Lara P.N., Ruel C., Chatta G., Phase I.I., et al. Study of Aflibercept (VEGF-Trap) in patients with recurrent or metastatic urothelial cancer, a California cancer consortium trial. Urology 2010, 76(4 (October)):923-926.
73. Van Cutsem E., Tabernero J., Lakomy R., et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J. Clin. Oncol. 2012, 30:3499-3506.
74. Van Cutsem E., Khayat D., Verslype C., Billemont B., Tejpar S., Meric J.B., Phase I., et al. dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours. Eur. J. Cancer 2013, 49(1 (January)):17-24.
75. Veikkola T., Alitalo K. VEGFs, receptors and angiogenesis. Semin. Cancer Biol. 1999, 9:211-220.
76. Verheul H.M., Hammers H., van Erp K., Wei Y., Sanni T., Salumbides B., et al. Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model. Clin. Cancer Res. 2007, 13:4201-4208.
77. Verslype C., Spano J., Van Cutsem E., Grapin J.P., Vandecaveye V., Bloch J., et al. Validation of the selected dose of aflibercept (VEGF Trap) plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in a phase I clinical trial of patients (pts) with advanced solid tumors (STs): preliminary results. ASCO Meeting Abstracts 2008, 26:14540.
78. Wachsberger P.R., Burd R., Cardi C., Thakur M., Daskalakis C., Holash J., et al. VEGF trap in combination with radiotherapy improves tumor control in U87 glioblastoma. Int. J. Radiat. Oncol. Biol. Phys. 2007, 67:1526-1537.
79. Ward J.E., Stadler W.M. Pazopanib in renal cell carcinoma. Clin. Cancer Res. 2010, 16:5923-5927.
80. Wells S.A., Robinson B.G., Gagel R.F., et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J. Clin. Oncol. 2012, 30:134-141.
81. Wulff C., Wilson H., Wiegand S.J., Rudge J.S., Fraser H.M. Prevention of thecal angiogenesis, antral follicular growth, and ovulation in the primate by treatment with vascular endothelial growth factor Trap R1R2. Endocrinology 2002, 143:2797-2807.
82. Yang W., Ahn H., Hinrichs M., et al. Evidence of a novel isoform of placenta growth factor (PlGF-4) expressed in human trophoblast and endothelial cells. J. Reprod. Immunol. 2003, 60:53-60.
83. Zhang F., Tang Z., Hou X., et al. VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. Proc. Natl. Acad. Sci. U. S. A 2009, 106:6152-6157.