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PMID: 17462954 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects.

Trends in molecular medicine ·Vol. 13 ·No. 6 ·2007-06-00 ·Pages 223-30

Duda DG, Batchelor TT, Willett CG, Jain RK

Abstract

Despite setbacks, the clinical development of antiangiogenic agents has accelerated remarkably over the past 3-4 years. Consequently, there are currently three direct inhibitors of the VEGF pathway approved for use in cancer therapy. Other agents that block the VEGF pathway are in advanced stages of clinical development and have shown promising results. With these exciting developments come crucial questions regarding the use of these new molecular-targeted agents, alone or in combination with standard cytotoxic or targeted agents. Importantly, the mechanisms of action of anti-VEGF therapy remain unknown. Here, we discuss several potential mechanisms of action such as tumor vascular normalization, bone marrow-derived cell recruitment blockade and cytostatic effects of anti-VEGF therapy. We review the current progress, the major stumbling blocks and the future directions for anti-cancer therapy using anti-VEGF agents, emphasizing clarification of the underlying molecular mechanisms of action and biomarker identification and validation.

MeSH Terms
Animals Antineoplastic Agents/pharmacology,therapeutic use Biomarkers, Tumor/metabolism Humans Neoplasms/blood supply,drug therapy,metabolism Neovascularization, Pathologic/drug therapy Vascular Endothelial Growth Factor A/antagonists & inhibitors,metabolism
Chemicals
Antineoplastic Agents Biomarkers, Tumor Vascular Endothelial Growth Factor A
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Duda Dan G
Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street, Cox-734, Boston, MA 02114, USA.
Batchelor Tracy T
Willett Christopher G
Jain Rakesh K
References (66)
66 references, click to expand
  1. Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours.
    Eur J Cancer. 2005 Jun;41(9):1291-9 PMID: 15939265
  2. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines.
    Cancer. 2005 Jul 15;104(2):427-38 PMID: 15952180
  3. A protocol for phenotypic detection and enumeration of circulating endothelial cells and circulating progenitor cells in human blood.
    Nat Protoc. 2007;2(4):805-10 PMID: 17446880
  4. Complete pathological response to bevacizumab and chemoradiation in advanced rectal cancer.
    Nat Clin Pract Oncol. 2007 May;4(5):316-21 PMID: 17464339
  5. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients.
    J Clin Oncol. 2005 Nov 1;23(31):8136-9 PMID: 16258121
  6. Angiogenesis in life, disease and medicine.
    Nature. 2005 Dec 15;438(7070):932-6 PMID: 16355210
  7. 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 Jan 1;24(1):16-24 PMID: 16330672
  8. 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. 2006 Jan 10;24(2):217-27 PMID: 16365183
  9. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature.
    Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H560-76 PMID: 16172168
  10. Lessons from phase III clinical trials on anti-VEGF therapy for cancer.
    Nat Clin Pract Oncol. 2006 Jan;3(1):24-40 PMID: 16407877
  11. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer.
    J Clin Oncol. 2006 Feb 10;24(5):769-77 PMID: 16391297
  12. MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy.
    Neurology. 2006 Apr 25;66(8):1258-60 PMID: 16636248
  13. Antiangiogenic therapy: a universal chemosensitization strategy for cancer?
    Science. 2006 May 26;312(5777):1171-5 PMID: 16728631
  14. Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy.
    Blood. 2006 Jul 15;108(2):452-9 PMID: 16543470
  15. Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes.
    Cancer Res. 2006 Sep 15;66(18):9054-64 PMID: 16982747
  16. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.
    Lancet. 2006 Oct 14;368(9544):1329-38 PMID: 17046465
  17. Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells.
    Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15491-6 PMID: 17030814
  18. The multifaceted circulating endothelial cell in cancer: towards marker and target identification.
    Nat Rev Cancer. 2006 Nov;6(11):835-45 PMID: 17036040
  19. Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer.
    Semin Oncol. 2006 Oct;33(5 Suppl 10):S1-7 PMID: 17145519
  20. Future directions in vascular endothelial growth factor-targeted therapy for metastatic colorectal cancer.
    Semin Oncol. 2006 Oct;33(5 Suppl 10):S41-9 PMID: 17145524
  21. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.
    N Engl J Med. 2006 Dec 14;355(24):2542-50 PMID: 17167137
  22. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.
    Nature. 2006 Dec 21;444(7122):1032-7 PMID: 17183313
  23. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.
    Nature. 2006 Dec 21;444(7122):1083-7 PMID: 17183323
  24. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
    N Engl J Med. 2007 Jan 11;356(2):115-24 PMID: 17215529
  25. Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression.
    Development. 2000 Sep;127(18):3941-6 PMID: 10952892
  26. Angiogenesis in cancer and other diseases.
    Nature. 2000 Sep 14;407(6801):249-57 PMID: 11001068
  27. Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells.
    Cancer Res. 2001 Aug 1;61(15):5736-40 PMID: 11479209
  28. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy.
    Nat Med. 2001 Sep;7(9):987-9 PMID: 11533692
  29. Clinical translation of angiogenesis inhibitors.
    Nat Rev Cancer. 2002 Oct;2(10):727-39 PMID: 12360276
  30. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy.
    J Clin Oncol. 2002 Nov 1;20(21):4368-80 PMID: 12409337
  31. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy?
    Nat Rev Cancer. 2002 Nov;2(11):826-35 PMID: 12415253
  32. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer.
    J Clin Oncol. 2003 Jan 1;21(1):60-5 PMID: 12506171
  33. The biology of VEGF and its receptors.
    Nat Med. 2003 Jun;9(6):669-76 PMID: 12778165
  34. Angiopoietin-1 activates both anti- and proapoptotic mitogen-activated protein kinases.
    FASEB J. 2003 Aug;17(11):1523-5 PMID: 12824293
  35. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.
    N Engl J Med. 2003 Jul 31;349(5):427-34 PMID: 12890841
  36. Blood vessels and nerves: common signals, pathways and diseases.
    Nat Rev Genet. 2003 Sep;4(9):710-20 PMID: 12951572
  37. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer.
    Nat Med. 2004 Feb;10(2):145-7 PMID: 14745444
  38. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer.
    Nat Rev Drug Discov. 2004 May;3(5):391-400 PMID: 15136787
  39. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab.
    J Natl Cancer Inst. 2005 Jul 6;97(13):981-9 PMID: 15998951
  40. Common mechanisms of nerve and blood vessel wiring.
    Nature. 2005 Jul 14;436(7048):193-200 PMID: 16015319
  41. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study.
    J Clin Oncol. 2005 Aug 20;23(24):5464-73 PMID: 16027440
  42. PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival.
    Nat Cell Biol. 2005 Sep;7(9):870-9 PMID: 16113679
  43. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors.
    Cancer Cell. 2005 Oct;8(4):299-309 PMID: 16226705
  44. Sorafenib in advanced clear-cell renal-cell carcinoma.
    N Engl J Med. 2007 Jan 11;356(2):125-34 PMID: 17215530
  45. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients.
    Cancer Cell. 2007 Jan;11(1):83-95 PMID: 17222792
  46. Detection of circulating endothelial cells: CD146-based magnetic separation enrichment or flow cytometric assay?
    J Clin Oncol. 2007 Feb 10;25(5):e1-2; author reply e3-5 PMID: 17290051
  47. Vascular biology: vessel guidance.
    Nature. 2007 Feb 15;445(7129):722-3 PMID: 17301780
  48. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model.
    Cancer Res. 2007 Mar 15;67(6):2729-35 PMID: 17363594
  49. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors.
    Cancer Res. 2004 Jun 1;64(11):3731-6 PMID: 15172975
  50. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
    N Engl J Med. 2004 Jun 3;350(23):2335-42 PMID: 15175435
  51. Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies.
    Cancer Res. 2004 Sep 15;64(18):6616-25 PMID: 15374976
  52. Tumor angiogenesis: therapeutic implications.
    N Engl J Med. 1971 Nov 18;285(21):1182-6 PMID: 4938153
  53. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.
    Science. 1983 Feb 25;219(4587):983-5 PMID: 6823562
  54. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells.
    Biochem Biophys Res Commun. 1989 Jun 15;161(2):851-8 PMID: 2735925
  55. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.
    Nature. 1996 Apr 4;380(6573):435-9 PMID: 8602241
  56. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene.
    Nature. 1996 Apr 4;380(6573):439-42 PMID: 8602242
  57. Vascular endothelial growth factor is essential for initial but not continued in vivo growth of human breast carcinoma cells.
    Cancer Res. 1997 Sep 15;57(18):3924-8 PMID: 9307273
  58. A 2-week pretreatment with 13-cis-retinoic acid + interferon-alpha-2a prior to definitive radiation improves tumor tissue oxygenation in cervical cancers.
    Strahlenther Onkol. 1998 Nov;174(11):571-4 PMID: 9830438
  59. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases.
    Cancer Cell. 2004 Dec;6(6):553-63 PMID: 15607960
  60. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.
    Science. 2005 Jan 7;307(5706):58-62 PMID: 15637262
  61. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer.
    J Clin Oncol. 2005 Feb 1;23(4):792-9 PMID: 15681523
  62. Imaging angiogenesis: applications and potential for drug development.
    J Natl Cancer Inst. 2005 Feb 2;97(3):172-87 PMID: 15687360
  63. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers.
    Cancer Res. 2005 Jan 15;65(2):465-72 PMID: 15695388
  64. Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials.
    Ann Oncol. 2005 Apr;16(4):558-65 PMID: 15705616
  65. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells.
    Oncogene. 2005 Apr 14;24(16):2647-53 PMID: 15735759
  66. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.
    Cell. 2005 May 6;121(3):335-48 PMID: 15882617
Article Info
Journal
Trends in molecular medicine
Abbr.
Trends Mol Med
ISSN
1471-4914
DOI
10.1016/j.molmed.2007.04.001
Published
2007-06-00
Epub
2007-00-25
Pages
223-30
Language
English
Region
England
NLM ID
100966035
PMCID
PMC2686126
Subset
IM
Grants
NCI NIH HHS · R21 CA117079-02 · United States
NCI NIH HHS · R21 CA099237-02 · United States
NCI NIH HHS · R21 CA099237 · United States
NCI NIH HHS · R21 CA117079 · United States
NCI NIH HHS · R01 CA115767-03 · United States
NCI NIH HHS · R01-CA115767 · United States
NCI NIH HHS · P01-CA80124 · United States
NCI NIH HHS · P01 CA080124 · United States
NCI NIH HHS · R21-CA099237 · United States
NCI NIH HHS · R01 CA115767 · United States
NCI NIH HHS · R21-CA117079 · United States
NCI NIH HHS · P01 CA080124-08 · United States
External Links
PubMed source DOI: 10.1016/j.molmed.2007.04.001 PMC Full Text View journal details
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