VEGF-targeted therapy: Mechanisms of anti-tumour activity

Nature Reviews Cancer

Volumn 8, Issue 8, 2008, Pages 579-591

  Ellis, Lee M ^a   Hicklin, Daniel J ^b  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA INTERFERON; ANTINEOPLASTIC AGENT; AXITINIB; BEVACIZUMAB; CAPECITABINE; CARBOPLATIN; CISPLATIN; DACARBAZINE; FLUOROURACIL; FOLINIC ACID; GEMCITABINE; INTERFERON; IRINOTECAN; OXALIPLATIN; PACLITAXEL; SEMAXANIB; SORAFENIB; SUNITINIB; VASCULOTROPIN; VATALANIB;

ANTINEOPLASTIC ACTIVITY; BREAST CANCER; CANCER CHEMOTHERAPY; CLINICAL TRIAL; COLORECTAL CANCER; DRUG HALF LIFE; HUMAN; IMMUNOMODULATION; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; MELANOMA; PRIORITY JOURNAL; REVIEW;

ANGIOGENESIS INHIBITORS; HUMANS; NEOPLASMS; PROTEIN KINASE INHIBITORS; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 47949089077     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc2403     Document Type: Review

References (110)

1. Keck, P. J. et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246, 1309-1312 (1989).
2. Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306-1309 (1989).
3. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335-2342 (2004). This seminal paper reports the results of the first randomized phase III clinical trial demonstrating the benefits of bevacizumab in combination with chemotherapy in patients with metastatic colorectal cancer.
4. Escudier, B. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125-134 (2007).
5. Llovet, J. et al. Sorafenib improves survival in advanced hepatocellular carcinoma (HCC): results of a phase III randomized placebo-controlled trial (SHARP trial). J. Clin. Oncol. Part I. 25, 2007 ASCO Annual Meeting Proceedings LBA1 (2007).
6. Miller, K. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 357, 2666-2676 (2007).
7. Motzer, R. J. et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115-124 (2007).
8. Sandler, A. et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542-2550 (2006).
9. Hanahan, D. and Bergers, G. Modes of resistance to anti-angiogenic therapy. Nature Rev. Cancer 8, 592-603 (2008).
10. Dvorak, H. F. 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, 4368-4380 (2002).
11. Hicklin, D. J. & Ellis, L. M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J. Clin. Oncol. 23, 1011-1027 (2005). A comprehensive review of VEGF biology.
12. Kowanetz, M. & Ferrara, N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin. Cancer Res. 12, 5018-5022 (2006).
13. Waltenberger, J., Claesson-Welsh, L., Siegbahn, A., Shibuya, M. & Heldin, C. H. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J. Biol. Chem. 269, 26988-26995 (1994).
14. Hiratsuka, S., Minowa, O., Kuno, J., Noda, T. & Shibuya, M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc. Natl Acad. Sci. 95, 9349-9354 (1998).
15. Laakkonen, P. et al. Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res. 67, 593-599 (2007).
16. Alitalo, K. & Carmeliet, P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1, 219-227 (2002).
17. Kukk, E. et al. VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development 122, 3829-3837 (1996).
18. Bielenberg, D. R. & Klagsbrun, M. Targeting endothelial and tumor cells with semaphorins. Cancer Metastasis Rev. 26, 421-431 (2007).
19. Camp, E. R. et al. Roles of nitric oxide synthase inhibition and vascular endothelial growth factor receptor-2 inhibition on vascular morphology and function in an in vivo model of pancreatic cancer. Clin. Cancer Res. 12, 2628-2633 (2006).
20. Klagsbrun, M., Takashima, S. & Mamluk, R. The role of neuropilin in vascular and tumor biology. Adv. Exp. Med. Biol. 515, 33-48 (2002).
21. Soker, S., Miao, H. Q., Nomi, M., Takashima, S. & Klagsbrun, M. VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding. J. Cell Biochem. 85, 357-368 (2002).
22. Soker, S., Takashima, S., Miao, H. Q., Neufeld, G. & Klagsbrun, M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92, 735-745 (1998).
23. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83-95 (2007).
24. Gimbrone, M. A. Jr, Leapman, S. B., Cotran, R. S. & Folkman, J. Tumor angiogenesis: iris neovascularization at a distance from experimental intraocular tumors. J. Natl Cancer Inst. 50, 219-228 (1973).
25. Rafii, S., Lyden, D., Benezra, R., Hattori, K. & Heissig, B. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nature Rev. Cancer 2, 826-835 (2002).
26. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820-827 (2005).
27. Sun, C., Jain, R. K. & Munn, L. L. Non-uniform plasma leakage affects local hematocrit and blood flow: implications for inflammation and tumor perfusion. Ann. Biomed. Eng. 35, 2121-2129 (2007).
28. Yang, A. D. et al. Improving delivery of antineoplastic agents with anti-vascular endothelial growth factor therapy. Cancer 103, 1561-1570 (2005).
29. Casanovas, O., Hicklin, D. J., Bergers, G. & Hanahan, D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 299-309 (2005).
30. Goodman, V. L. et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin. Cancer Res. 13, 1367-1373 (2007).
31. Kane, R. C. et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin. Cancer Res. 12, 7271-7278 (2006).
32. Karaman, M. W. et al. A quantitative analysis of kinase inhibitor selectivity. Nature Biotechnol. 26, 127-132 (2008).
33. Choueiri, T. et al. Use of Von-Hippel Lindau (VHL) mutation status to predict objective response to vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (RCC). J. Clin. Oncol. 25, 5012 (2007).
34. Rini, B. I. et al. Clinical response to therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: impact of patient characteristics and Von Hippel-Lindau gene status. BJU Int. 98, 756-762 (2006).
35. Lee, C. G. et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 60, 5565-5570 (2000).
36. Inai, T. 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. 165,35-52 (2004).
37. Yao, J. C. & Hoff, P. M. Molecular targeted therapy for neuroendocrine tumors. Hematol. Oncol. Clin. North Am. 21, 575-581; x (2007).
38. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58-62 (2005). This manuscript provides the theory and available supporting data for the normalization hypothesis associated with anti-VEGF therapy.
39. Rafii, S. & Lyden, D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nature Med. 9, 702-712 (2003).
40. + cells in the endothelium of tumor vessels in the mouse brain. Neurosurgery 59, 374-382; discussion 374-382 (2006).
41. Yoong, K. F., Afford, S. C., Randhawa, S., Hubscher, S. G. & Adams, D. H. Fas/Fas ligand interaction in human colorectal hepatic metastases: a mechanism of hepatocyte destruction to facilitate local tumor invasion. Am. J. Pathol. 154, 693-703 (1999).
42. Stessels, F. et al. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br. J. Cancer 90, 1429-1436 (2004).
43. Sardari Nia, P., Hendriks, J., Friedel, G., Van Schil, P. & Van Marck, E. Distinct angiogenic and non-angiogenic growth patterns of lung metastases from renal cell carcinoma. Histopathology 51, 354-361 (2007).
44. Kulke, M. H. et al. Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J. Clin. Oncol. 24, 3555-3561 (2006).
45. Stadler, W. M. et al. Multi-institutional study of the angiogenesis inhibitor TNP-470 in metastatic renal carcinoma. J. Clin. Oncol. 17, 2541-2545 (1999).
46. Hlatky, L., Hahnfeldt, P. & Folkman, J. Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn't tell us. J. Natl. Cancer Inst. 94, 883-893 (2002).
47. Hicklin, D. J. Promoting angiogenesis to a fault. Nature Biotech. 25, 300-302 (2007).
48. Li, J. L. et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res. 67, 11244-11253 (2007).
49. Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444, 1032-1037 (2006).
50. Ridgway, J. et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083-1087 (2006).
51. Cohen, M. H., Gootenberg, J., Keegan, P. & Pazdur, R. FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist 12, 713-718 (2007).
52. Wedam, S. B. et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J. Clin. Oncol. 24, 769-777 (2006).
53. Willett, C. G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Med. 10, 145-147 (2004).
54. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182-1186 (1971). This is a historic manuscript hypothesizing that inhibition of angiogenesis may be a therapeutic strategy for patients with cancer.
55. Fujio, Y. & Walsh, K. Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J. Biol. Chem. 274, 16349-16354 (1999).
56. Gerber, H. P. et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J. Biol. Chem. 273, 30336-30343 (1998).
57. Benjamin, L. E. & Keshet, E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc. Natl Acad. Sci. USA 94, 8761-8766 (1997). This manuscript describes studies demonstrating the role of VEGF as endothelial cell survival factor.
58. Bruns, C. J. et al. Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases. Cancer 89, 488-499 (2000).
59. Laird, A. D. et al. SU6668 inhibits Flk-1/KDR and PDGFRβ in vivo, resulting in rapid apoptosis of tumor vasculature and tumor regression in mice. FASEB J. 16, 681-690 (2002).
60. Mendel, D. B. et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9, 327-337 (2003).
61. Ratain, M. J. & Eckhardt, S. G. Phase II studies of modern drugs directed against new targets: if you are fazed, too, then resist RECIST. J. Clin. Oncol. 22, 4442-4445 (2004).
62. Browder, T. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 60, 1878-1886 (2000).
63. Kerbel, R. S. & Kamen, B. A. The anti-angiogenic basis of metronomic chemotherapy. Nature Rev. Cancer 4, 423-436 (2004).
64. Klement, G. et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 105, R15-R24 (2000). This manuscript describes the effect of dual targeting of the tumour vasculature with anti-VEGF therapy and low-dose 'metronomic' chemotherapy.
65. Shaked, Y. et al. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 106, 3058-3061 (2005).
66. Garcia, A. A. et al. 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, 76-82 (2008).
67. Bertolini, F., Shaked, Y., Mancuso, P. & Kerbel, R. S. The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nature Rev. Cancer 6, 835-845 (2006). This paper describes the role and importance of endothelial progenitor cells in tumour angiogenesis.
68. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194-1201 (2001).
69. Grunewald, M. et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124, 175-189 (2006).
70. De Falco, E. et al. SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood 104, 3472-3482 (2004).
71. Peters, B. A. et al. Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nature Med. 11, 261-262 (2005).
72. Gao, D. et al. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319, 195-198 (2008).
73. Purhonen, S. et al. Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc. Natl Acad. Sci. USA 105, 6620-6625 (2008).
74. Curiel, T. J. et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res. 64, 5535-5538 (2004).
75. Horowitz, J. R. et al. Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium. Arterioscler. Thromb. Vasc Biol. 17, 2793-2800 (1997).
76. Yasuda, H. et al. Nitroglycerin treatment may enhance chemosensitivity to docetaxel and carboplatin in patients with lung adenocarcinoma. Clin. Cancer Res. 12, 6748-6757 (2006).
77. Beaudry, P. et al. Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: implications for use as a surrogate marker of antiangiogenic activity. Clin. Cancer Res. 11, 3514-3522 (2005).
78. Clamp, A. & Jayson, G. in Antiangiogenic Agents in Cancer Therapy (eds Teicher, B. & Ellis, L.) 525-536 (Humana Press, Totowa, 2008).
79. Morgan, B. et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J. Clin. Oncol. 21, 3955-3964 (2003).
80. Yao, J. C. et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alfa-2b. J. Clin. Oncol. 26, 1316-1323 (2008).
81. Baluk, P., Morikawa, S., Haskell, A., Mancuso, M. & McDonald, D. M. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am. J. Pathol. 163, 1801-1815 (2003).
82. Morikawa, S. et al. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am. J. Pathol. 160, 985-1000 (2002).
83. Dickson, P. V. et al. Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin. Cancer Res. 13, 3942-3950 (2007).
84. Wildiers, H. et al. Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br. J. Cancer 88, 1979-1986 (2003).
85. Franco, M. et al. Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia. Cancer Res. 66, 3639-3648 (2006).
86. Claes, A. et al. Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol. Cancer Ther. 7, 71-78 (2008).
87. Kasman, I. et al. Mechanistic evaluation of the combination effect of anti-VEGF and chemotherapy [abstract]. Proc. Am. Assoc. Cancer Res. Annu. Meeting 2008 Abstract 2494.
88. Dallas, N. A. et al. Functional significance of vascular endothelial growth factor receptors on gastrointestinal cancer cells. Cancer Metastasis Rev. 26, 433-441 (2007).
89. Bachelder, R. E. et al. Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res. 61, 5736-5740 (2001).
90. Fan, F. et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 24, 2647-2653 (2005).
91. Wu, Y. et al. Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer. Clin. Cancer Res. 12, 6573-6584 (2006).
92. Gray, M. et al. Therapeutic targeting of neuropilin-2 on colorectal carcinoma cells implanted in the murine liver. J. Natl Cancer Inst. 100, 109-120 (2008).
93. Gabrilovich, D. I. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nature Med. 2, 1096-1103 (1996).
94. Ohm, J. E. et al. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 101, 4878-4886 (2003).
95. Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767-811 (2000).
96. Banchereau, J. & Palucka, A. K. Dendritic cells as therapeutic vaccines against cancer. Nature Rev. Immunol. 5, 296-306 (2005).
97. Colonna, M., Pulendran, B. & Iwasaki, A. Dendritic cells at the host-pathogen interface. Nature Immunol. 7, 117-120 (2006).
98. Steinman, R. M. et al. Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann. N. Y. Acad. Sci. 987, 15-25 (2003).
99. + progenitor cells by tumor-derived vascular endothelial cell growth factor. Clin. Exp. Metastasis 17, 881-888 (1999).
100. Zou, W. et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nature Med. 7, 1339-1346 (2001).
101. Gabrilovich, D. et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92, 4150-4166 (1998).
102. Gabrilovich, D. I., Ishida, T., Nadaf, S., Ohm, J. E. & Carbone, D. P. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin. Cancer Res. 5, 2963-2970 (1999).
103. Fricke, I. et al. Vascular endothelial growth factor-trap overcomes defects in dendritic cell differentiation but does not improve antigen-specific immune responses. Clin. Cancer Res. 13, 4840-4848 (2007).
104. Dikov, M. M. et al. Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J. Immunol. 174, 215-222 (2005).
105. Laxmanan, S. et al. Vascular endothelial growth factor impairs the functional ability of dendritic cells through Id pathways. Biochem. Biophys. Res. Commun. 334, 193-198 (2005).
106. Mimura, K., Kono, K., Takahashi, A., Kawaguchi, Y. & Fujii, H. Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2. Cancer Immunol. Immunother. 56, 761-770 (2007).
107. Fukasawa, M., Matsushita, A. & Korc, M. Neuropilin-1 interacts with integrin β1 and modulates pancreatic cancer cell growth, survival and invasion. Cancer Biol. Ther. 6, 1173-1180 (2007).
108. Geretti, E., Shimizu, A. & Klagsbrun, M. Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis. Angiogenesis 1, 31-39 (2008).
109. Sulpice, E. et al. Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity. Blood 111, 2036-2045 (2008).
110. Wu, Y. et al. The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma. Int. J. Cancer 119, 1519-1529 (2006).