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VEGF-Targeting Therapy for Breast Cancer

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Vascular Endothelial Growth Factor (VEGF) plays an important role in multiple physiologic and pathologic processes involving endothelial cells. Several preclinical and clinical sources of evidence suggest its importance in human breast cancer. Based on the presumed biologic relevance of VEGF in human breast cancer, clinical trials using agents targeting VEGF were launched beginning in the late 1990s. This clinical trial effort came to fruition in 2005 with the success of the first large, prospective randomized trial of anti-VEGF therapy in patients with front-line metastatic breast cancer, which demonstrated the benefit of adding the monoclonal anti-ligand antibody bevacizumab to the chemotherapeutic agent paclitaxel. Based upon this success, numerous anti-VEGF agents are now being tested in patients with breast cancer, and adjuvant therapy trials are in development. Nevertheless, important questions remain regarding the biology and clinical development of these agents in breast cancer.

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References

  1. Schedin P, Elias A. Multistep tumorigenesis and the microenvironment. Breast Cancer Res 2004;6:93–101.

    Article  PubMed  CAS  Google Scholar 

  2. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–6.

    Article  PubMed  CAS  Google Scholar 

  3. Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 2001;280:C1358–66.

    PubMed  CAS  Google Scholar 

  4. Ferrara N. The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat 1995;36:127–37.

    Article  PubMed  CAS  Google Scholar 

  5. Hicklin D, Ellis L. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23:1011–27.

    Article  PubMed  CAS  Google Scholar 

  6. Tran J, Rak J, Sheehan C, et al. Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochem Biophys Res Commun 1999;264:781–8.

    Article  PubMed  CAS  Google Scholar 

  7. Pidgeon G, Harmey J, Foley D, et al. Vascular endothelial growth factor (VEGF) upregulates Bcl-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells. Br J Cancer 2001;85:273–8.

    Article  PubMed  CAS  Google Scholar 

  8. Zachary I. Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor. Am J Physiol Cell Physiol 2001;280:C1375–86.

    PubMed  CAS  Google Scholar 

  9. Gupta K, Kshirsagar S, Li W, et al. VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp Cell Res 1999;247:495–504.

    Article  PubMed  CAS  Google Scholar 

  10. Weis S, Cheresh D. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 2005;437:497–504.

    Article  PubMed  CAS  Google Scholar 

  11. McLeskey SW, Tobias CA, Vezza PR, et al. Tumor growth of FGF or VEGF transfected MCF-7 breast carcinoma cells correlates with density of specific microvessels independent of the transfected angiogenic factor. Am J Pathol 1998;153:1993–2006.

    PubMed  CAS  Google Scholar 

  12. Linderholm B, Lindh B, Beckman L, et al. The prognostic value of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and associations to first metastasis site in 1307 patients with primary breast cancer. Proc Am Soc Clin Oncol 2001;20:4a (abstract # 13).

    Google Scholar 

  13. Gown A, Rivkin S, Hunt H, et al. Prognostic factor of vascular endothelial growth factor (VEGF) expression in node-positive breast cancer. Proc Am Soc Clin Oncol 2001;20:427a (abstract # 1703).

    Google Scholar 

  14. Gasparini G. Prognostic value of vascular endothelial growth factor in breast cancer. Oncologist 2000;5(Suppl. 1):37–44.

    Article  PubMed  CAS  Google Scholar 

  15. Foekens J, Peters H, Grebenchtchikov N, et al. High tumor levels of vascular endothelial growth factor predict poor esponse to systemic therapy in advanced breast cancer. Cancer Res 2001;61:5407–14.

    PubMed  CAS  Google Scholar 

  16. Finkenzeller G, Weindel K, Zimmermann W, et al. Activated Neu/ErbB-2 induces expression of the vascular endothelial growth factor gene by functional activation of the transcription factor Sp 1. Angiogenesis 2004;7:59–68.

    Article  PubMed  CAS  Google Scholar 

  17. Konecny G, Meng Y, Untch M, et al. Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res 2004;10:1706–16.

    Article  PubMed  CAS  Google Scholar 

  18. Linderholm B, Andersson J, Lindh B, et al. Overexpression of c-erbB-2 is related to a higher expression of vascular endothelial growth factor (VEGF) and constitutes an independent prognostic factor in primary node-positive breast cancer after adjuvant systemic treatment. Eur J Cancer 2004;40:33–42.

    Article  PubMed  CAS  Google Scholar 

  19. Huh J-H, Calvo A, Stafford J, et al. Inhibition of VEGF receptors significantly impairs mammary cancer growth in C3(1)/Tag transgenic mice through antiangiogenic and nonantiangiogenic mechanisms. Oncogene 2005;24:790–800.

    Article  PubMed  CAS  Google Scholar 

  20. Dales J, Garcia S, Bonnier P, et al. Prognostic significance of VEGF receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) in breast carcinoma. Ann Pathol 2003;23:297–305.

    PubMed  Google Scholar 

  21. Sledge G, Miller K, Novotny W, et al. A phase II trial of single-agent rhuMAb VEGF (recombinant humanized monoclonal antibody to vascular endothelial growth factor) in patients with relapsed metastatic breast cancer. Proc Am Soc Clin Oncol 2000;19:3a (abstract 5c).

    Google Scholar 

  22. Miller K, Chap L, Holmes F, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–9.

    Article  PubMed  CAS  Google Scholar 

  23. Miller K, Wang M, Gralow J, et al. A randomized Phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res Treat 2005;94:S6 (Abstract #3).

    Google Scholar 

  24. Yen L, You X, Al Moustafa A, et al. Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene 2000;19:3460–9.

    Article  PubMed  CAS  Google Scholar 

  25. Pegram M, Reese D. Combined biological therapy of breast cancer using monoclonal antibodies directed against HER2/neu protein and vascular endothelial growth factor. Semin Oncol 2002;29:29–37.

    PubMed  CAS  Google Scholar 

  26. Pegram M, Yeon C, Ku N, et al. Phase I combined biological therapy of breast cancer using two humanized monoclonal antibodies directed against HER2 proto-oncogene and vascular endothelial growth factor (VEGF). Breast Cancer Res Treat 2004;88:S124.

    Google Scholar 

  27. Doshi A, Wedam S, Thomasson R, et al. Dynamic contrast MRI (DCE-MRI) as a potential predictor of clinical response in patients with inflammatory breast cancer (IBC). J Clin Oncol 2005;23:24s (Abstract #584).

    Google Scholar 

  28. Wedam S, Low J, Yang S, et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 2006;24:769–73.

    Article  PubMed  CAS  Google Scholar 

  29. Bianchi G, Loibi S, Zamagni C, et al. A Phase II multicentre uncontrolled trial of sorafenib (BAY 43-9006) in patients with metastatic breast cancer. Eur J Cancer Suppl 2005;3:78 (Abstract # 276).

    Google Scholar 

  30. Miller K, Burstein H, Elias A, et al. Phase II study of SU11248, a multitargeted receptor tyrosine kinase inhibitor (TKI), in patients (pts) with previously treated metastatic breast cancer. J Clin Oncol 2005;23:19s (Abstract # 563).

    Google Scholar 

  31. Miller K, Trigo J, Wheeler C, et al. A multicenter Phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin Cancer Res 2005;11:3369–76.

    Article  PubMed  CAS  Google Scholar 

  32. Miller K, Sweeney C, Sledge G. The Snark is a Boojum: the continuing problem of drug resistance in the antiangiogenic era. Ann Oncol 2003;14:20–8.

    Article  PubMed  CAS  Google Scholar 

  33. Kerbel R. Therapeutic implications of intrinsic or induced angiogenic growth factor redundancy in tumors revealed. Cancer Cell 2005;8:269–71.

    Article  PubMed  CAS  Google Scholar 

  34. Relf M, LeJeune S, Scott P, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor b-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 1997;57:963–69.

    PubMed  CAS  Google Scholar 

  35. Jain R. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001;7:987–9.

    Article  PubMed  CAS  Google Scholar 

  36. Taghian A, Abi-Raad R, Assaad S, et al. Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications. J Clin Oncol 2005;23:1951–61.

    Article  PubMed  CAS  Google Scholar 

  37. Sweeney C, Miller K, Sissons S, et al. The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res 2001;61:3369–72.

    PubMed  CAS  Google Scholar 

  38. Dias S, Hattori K, Heissig B, et al. Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci USA 2001;98:10857–62.

    Article  PubMed  CAS  Google Scholar 

  39. Bellamy W, Richter L, Sirjani D, et al. Vascular endothelial growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood 2001;97:1427–34.

    Article  PubMed  CAS  Google Scholar 

  40. Hayashibara T, Yamada Y, Miyanishi T, et al. Vascular endothelial growth factor and cellular chemotaxis: a possible autocrine pathway in adult T-cell leukemia cell invasion. Clinical Cancer Res 2001;7:2719–26.

    CAS  Google Scholar 

  41. Bachelder R, Crago A, Chung J, et al. Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res 2001;61:5736–40.

    PubMed  CAS  Google Scholar 

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Acknowledgment

Supported by a grant from the Breast Cancer Research Foundation and the Walther Medical Foundation.

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Authors and Affiliations

  1. Indiana University Cancer Center, Indianapolis, IN, 46202, USA

    George W. Sledge Jr.

  2. Indiana Cancer Pavilion, RT-473. 535 Barnhill Dr., Indianapolis, IN, 46202, USA

    George W. Sledge Jr.

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  1. George W. Sledge Jr.
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Correspondence to George W. Sledge Jr..

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Sledge, G.W. VEGF-Targeting Therapy for Breast Cancer. J Mammary Gland Biol Neoplasia 10, 319–323 (2005). https://doi.org/10.1007/s10911-006-9005-5

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  • DOI: https://doi.org/10.1007/s10911-006-9005-5

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