Strategies for Improving the Clinical Benefit of Antiangiogenic Drug Based Therapies for Breast Cancer

Article

Abstract

Viewed as a whole, the aggregate outcomes of a number of positive randomized phase III clinical trial results evaluating the VEGF-pathway targeting antiangiogenic drug bevacizumab, with or without concurrent chemotherapy, in metastatic breast cancer patients have been disappointingly modest. In the case of antiangiogenic tyrosine kinase inhibitors (TKIs) the results have been negative. Nevertheless, several findings indicate antiangiogenic drugs, especially bevacizumab, are active and can lead to demonstrable clinical benefit in some patients, thus stimulating research into developing strategies to significantly improve their efficacy and reduce toxicity. Some of these initiatives include: 1) discovery and validation of predictive markers that can prospectively identify patients more likely to benefit from antiangiogenic therapy; 2) recognition that the nature of the chemotherapy partner or backbone can strongly impact outcomes when combined with antiangiogenic drugs such as bevacizumab, and thus developing what may be improved combination chemotherapy partner regimens, e.g. metronomic chemotherapy; 3) evaluating prospectively in more depth whether subtypes of the disease—especially triple negative or inflammatory breast cancer—are more responsive to antiangiogenic therapy than other subtypes; 4) evaluating new agents that inhibit angiogenesis in a VEGF-independent manner and other types of drug that can be effectively combined with antiangiogenics, e.g. c-met inhibitors; 5) uncovering the basis of resistance or relapse/progression on the therapy with antiangiogenic drugs; 6) development of improved predictive preclinical breast cancer models for therapy testing, e.g. treatment of mice with established multi-organ breast cancer metastatic disease or genetically engineered mouse models of breast cancer, or mice bearing patient derived breast cancer tissue xenografts.

Keywords

Tumor angiogenesis Antiangiogenesis therapy VEGF Bevacizumab Tyrosine kinase Inhibitors Metastatic breast cancer Predictive biomarkers Resistance Metronomic chemotherapy 

Abbreviations

bFGF

basic fibroblast growth factor

BMDC

bone marrow derived cell

CRC

colorectal cancer

EGFR

epidermal growth factor receptor

FDA

Food and Drug Administration

GEMM

genetically engineered mouse model

HCC

hepatocellular carcinoma

HGF

hepatocyte growth factor

HIF-1

hypoxia inducible factor-1

NSCLC

non small cell lung cancer

OS

overall survival

PDGF

platelet-derived growth factor

PFS

progression free survival

TKI

tyrosine kinase inhibitor

RCC

renal cell carcinoma

SDF-1

stromal derived factor-1

SNP

single nucleotide polymorphism

UFT

tegafur-uracil

VEGF

vascular endothelial growth factor

VEGFR-2

vascular endothelial growth factor receptor-2

References

  1. 1.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.PubMedCrossRefGoogle Scholar
  3. 3.
    Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.PubMedCrossRefGoogle Scholar
  4. 4.
    Kerbel RS. Tumor Angiogenesis. New Engl J Med. 2008;358:2039–49.PubMedCrossRefGoogle Scholar
  5. 5.
    Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438:967–74.PubMedCrossRefGoogle Scholar
  6. 6.
    Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473–83.PubMedCrossRefGoogle Scholar
  7. 7.
    Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484–96.PubMedCrossRefGoogle Scholar
  8. 8.
    Korn EL, Freidlin B, Abrams JS. Bevacizumab in ovarian cancer. N Engl J Med. 2012;366:1256–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Mackey JR, Kerbel RS, Gelmon KA, et al. Controlling angiogenesis in breast cancer: a systematic review of anti-angiogenic trials. Cancer Treat Rev. 2012;38:673–88.PubMedCrossRefGoogle Scholar
  10. 10.
    Miller KD, Chap LI, Holmes FA, 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.PubMedCrossRefGoogle Scholar
  11. 11.
    Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–76.PubMedCrossRefGoogle Scholar
  12. 12.
    Pivot X, Schneeweiss A, Verma S, et al. Efficacy and safety of bevacizumab in combination with docetaxel for the first-line treatment of elderly patients with locally recurrent or metastatic breast cancer: results from AVADO. Eur J Cancer. 2011;47:2387–95.PubMedCrossRefGoogle Scholar
  13. 13.
    Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy With or Without Bevacizumab for First-Line Treatment of Human Epidermal Growth Factor Receptor 2-Negative, Locally Recurrent or Metastatic Breast Cancer. J Clin Oncol 2011; epub ahead of print.Google Scholar
  14. 14.
    Brufsky AM, Hurvitz S, Perez E, et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011;29:4286–93.PubMedCrossRefGoogle Scholar
  15. 15.
    Twombly R. Avastin's uncertain future in breast cancer treatment. J Natl Cancer Inst. 2011;103:458–60.PubMedCrossRefGoogle Scholar
  16. 16.
    Goozner M. Avastin hearing leads to more uncertainty over drug’s future. J Natl Cancer Inst. 2011;103:1148–50.PubMedCrossRefGoogle Scholar
  17. 17.
    Sharma SP. Avastin saga reveals debate over clinical trial endpoints. J Natl Cancer Inst. 2012;104:800–1.PubMedCrossRefGoogle Scholar
  18. 18.
    Montero AJ, Escobar M, Lopes G, Gluck S, Vogel C. Bevacizumab in the treatment of metastatic breast cancer: friend or foe? Curr Oncol Rep. 2012;14:1–11.PubMedCrossRefGoogle Scholar
  19. 19.
    Montero AJ, Avancha K, Gluck S, Lopes G. A cost-benefit analysis of bevacizumab in combination with paclitaxel in the first-line treatment of patients with metastatic breast cancer. Breast Cancer Res Treat. 2012;132:747–51.PubMedCrossRefGoogle Scholar
  20. 20.
    Carpenter D, Kesselheim AS, Joffe S. Reputation and precedent in the bevacizumab decision. N Engl J Med. 2011;365:e3.PubMedCrossRefGoogle Scholar
  21. 21.
    Hayes DF. Bevacizumab treatment for solid tumors: boon or bust? JAMA. 2011;305:506–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Stevenson CE, Nagahashi M, Ramachandran S, Yamada A, Bear HD, Takabe K. Bevacizumab and breast cancer: what does the future hold? Future Oncol. 2012;8:403–14.PubMedCrossRefGoogle Scholar
  23. 23.
    Miklos GL. Bevacizumab in neoadjuvant treatment for breast cancer. N Engl J Med. 2012;366:1638–40.PubMedGoogle Scholar
  24. 24.
    Montero AJ, Vogel C. Fighting fire with fire: rekindling the bevacizumab debate. N Engl J Med. 2012;366:374–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Dawood S, Shaikh AJ, Buchholz TA, et al. The use of bevacizumab among women with metastatic breast cancer: a survey on clinical practice and the ongoing controversy. Cancer. 2012;118:2780–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Aogi K, Masuda N, Ohno S, et al. First-line bevacizumab in combination with weekly paclitaxel for metastatic breast cancer: efficacy and safety results from a large, open-label, single-arm Japanese study. Breast Cancer Res Treat. 2011;129:829–38.PubMedCrossRefGoogle Scholar
  27. 27.
    Thomssen C, Pierga JY, Pritchard KI, et al. First-line bevacizumab-containing therapy for triple-negative breast cancer: analysis of 585 patients treated in the ATHENA study. Oncology. 2012;82:218–27.PubMedCrossRefGoogle Scholar
  28. 28.
    Smith IE, Pierga JY, Biganzoli L, et al. First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients. Ann Oncol. 2011;22:595–602.PubMedCrossRefGoogle Scholar
  29. 29.
    Barrios CH, Liu MC, Lee SC, et al. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res Treat. 2010;121:121–31.PubMedCrossRefGoogle Scholar
  30. 30.
    Bergh J, Greil R, Voytko N, et al. Sunitinib (SU) in combination with docetaxel (D) versus D alone for the first-line treatment of advanced breast cancer (ABC). J Clin Oncol 2011;28:LBA 1010.Google Scholar
  31. 31.
    Robert NJ, Saleh MN, Paul D, et al. Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: a phase III, randomized, open-label trial. Clin Breast Cancer. 2011;11:82–92.PubMedCrossRefGoogle Scholar
  32. 32.
    Crown J, Dieras V, Starosiawska E, et al. Phase III trial of sunitinib (SU) in combination with capecitabine (C) versus C in previously treated advanced breast cancer (ABC). J Clin Oncol 2010; abstract no. LBA 1011.Google Scholar
  33. 33.
    Martin M, Roche H, Pinter T, et al. Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol. 2011;12:369–76.PubMedCrossRefGoogle Scholar
  34. 34.
    Rugo HS, Stopeck AT, Joy AA, et al. Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer. J Clin Oncol. 2011;29:2459–65.PubMedCrossRefGoogle Scholar
  35. 35.
    Rugo HS. Inhibiting angiogenesis in breast cancer: the beginning of the end or the end of the beginning? J Clin Oncol. 2012;30:898–901.PubMedCrossRefGoogle Scholar
  36. 36.
    Baselga J, Segalla JG, Roche H, et al. Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol. 2012;30:1484–91.PubMedCrossRefGoogle Scholar
  37. 37.
    Furstenberger G, von Moos R, Lucas R, et al. Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy or primary breast cancer. Br J Cancer. 2006;94:524–31.PubMedCrossRefGoogle Scholar
  38. 38.
    Verma S, McLeod D, Batist G, Robidoux A, Martins IR, Mackey JR. In the end what matters most? A review of clinical endpoints in advanced breast cancer. Oncologist. 2011;16:25–35.PubMedCrossRefGoogle Scholar
  39. 39.
    Booth CM, Eisenhauer EA. Progression-free survival: meaningful or simply measurable? J Clin Oncol. 2012;30:1030–3.PubMedCrossRefGoogle Scholar
  40. 40.
    Buyse M, Sargent DJ, Saad ED. Survival is not a good outcome for randomized trials with effective subsequent therapies. J Clin Oncol. 2011;29:4719–20.PubMedCrossRefGoogle Scholar
  41. 41.
    Korn EL, Freidlin B, Abrams JS. Overall survival as the outcome for randomized clinical trials with effective subsequent therapies. J Clin Oncol. 2011;29:2439–42.PubMedCrossRefGoogle Scholar
  42. 42.
    Broglio KR, Berry DA. Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst. 2009;101:1642–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Burstein HJ, Chen YH, Parker LM, et al. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res. 2008;14:7871–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Jayson GC, Hicklin DJ, Ellis LM. Antiangiogenic therapy–evolving view based on clinical trial results. Nat Rev Clin Oncol. 2012;9:297–303.PubMedCrossRefGoogle Scholar
  45. 45.
    Mir O, Coriat R, Cabanes L, et al. An observational study of bevacizumab-induced hypertension as a clinical biomarker of antitumor activity. Oncologist. 2011;16:1325–32.PubMedCrossRefGoogle Scholar
  46. 46.
    Jubb AM, Harris AL. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol. 2010;11:1172–83.PubMedCrossRefGoogle Scholar
  47. 47.
    Schneider BP, 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;26:4672–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol. 2009;6:465–77.PubMedCrossRefGoogle Scholar
  49. 49.
    Bear HD, Tang G, Rastogi P, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012;366:310–20.PubMedCrossRefGoogle Scholar
  50. 50.
    von Minckwitz G, Eidtmann H, Rezai M, et al. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012;366:299–309.CrossRefGoogle Scholar
  51. 51.
    Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592–603.PubMedCrossRefGoogle Scholar
  52. 52.
    Rapisarda A, Melillo G. Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol. 2012;9:378–90.PubMedCrossRefGoogle Scholar
  53. 53.
    Ebos JML, Kerbel RS. Impact of antiangiogenic therapy on invasion, disease progression, and metastasis. Nat Rev Clin Oncol. 2011;8:210–21.PubMedCrossRefGoogle Scholar
  54. 54.
    Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8:579–91.PubMedCrossRefGoogle Scholar
  55. 55.
    Casanovas O, Hicklin D, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late stage pancreatic islet tumors. Cancer Cell. 2005;8:299–309.PubMedCrossRefGoogle Scholar
  56. 56.
    Shojaei F, Lee JH, Simmons BH, et al. HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010;70:10090–100.PubMedCrossRefGoogle Scholar
  57. 57.
    Huang D, Ding Y, Zhou M, et al. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 2010;70:1063–71.PubMedCrossRefGoogle Scholar
  58. 58.
    Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32.PubMedCrossRefGoogle Scholar
  59. 59.
    Gotink KJ, Broxterman HJ, Labots M, et al. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res. 2011;17:7337–46.PubMedCrossRefGoogle Scholar
  60. 60.
    Arrondeau J, Mir O, Boudou-Rouquette P, et al. Sorafenib exposure decreases over time in patients with hepatocellular carcinoma. Invest New Drugs 2011;epub ahead of print.Google Scholar
  61. 61.
    Helfrich I, Scheffrahn I, Bartling S, et al. Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma. J Exp Med. 2010;207:491–503.PubMedCrossRefGoogle Scholar
  62. 62.
    Sitohy B, Nagy JA, Jaminet SC, Dvorak HF. Tumor-surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy. Cancer Res. 2011;71:7021–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Kerbel RS. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science. 2006;312:1171–5.PubMedCrossRefGoogle Scholar
  64. 64.
    Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.PubMedCrossRefGoogle Scholar
  65. 65.
    Van der Veldt AA, Lubberink M, Bahce I, et al. Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell. 2012;21:82–91.PubMedCrossRefGoogle Scholar
  66. 66.
    Shaked Y, Ciarrocchi A, Franco M, et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science. 2006;313:1785–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Shaked Y, Henke E, Roodhart J, et al. Rapid chemotherapy-induced surge in endothelial progenitor cells: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell. 2008;14:263–73.PubMedCrossRefGoogle Scholar
  68. 68.
    Shaked Y, Kerbel RS. Antiangiogenic strategies on defense: blocking rebound by the tumor vasculature after chemotherapy. Cancer Res. 2007;67:7055–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Roodhart JM, Langenberg MH, Vermaat JS, et al. Late release of circulating endothelial cells and endothelial progenitor cells after chemotherapy predicts response and survival in cancer patients. Neoplasia. 2010;12:87–94.PubMedGoogle Scholar
  70. 70.
    Taylor M, Billiot F, Marty V, et al. Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells. Cancer Discov. 2012;2:434–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Munoz R, Man S, Shaked Y, et al. Highly efficacious non-toxic treatment for advanced metastatic breast cancer using combination UFT-cyclophosphamide metronomic chemotherapy. Cancer Res. 2006;66:3386–91.PubMedCrossRefGoogle Scholar
  72. 72.
    Kerbel RS, Kamen BA. Antiangiogenic basis of low-dose metronomic chemotherapy. Nature Rev Cancer. 2004;4:423–36.CrossRefGoogle Scholar
  73. 73.
    Pasquier E, Kavallaris M, Andre N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol. 2010;7:455–65.PubMedCrossRefGoogle Scholar
  74. 74.
    Browder T, Butterfield CE, Kraling BM, Marshall B, O'Reilly MS, Folkman J. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000;60:1878–86.PubMedGoogle Scholar
  75. 75.
    Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest. 2000;105:R15–24.PubMedCrossRefGoogle Scholar
  76. 76.
    Colleoni M, Rocca A, Sandri MT, et al. Low dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002;13:73–80.PubMedCrossRefGoogle Scholar
  77. 77.
    Orlando L, Cardillo A, Ghisini R, et al. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer. BMC Cancer. 2006;6:225.PubMedCrossRefGoogle Scholar
  78. 78.
    Aurilio G, Munzone E, Botteri E, et al. Oral Metronomic Cyclophosphamide and Methotrexate Plus Fulvestrant in Advanced Breast Cancer Patients: A Mono-Institutional Case-Cohort Report. Breast J 2012;epub ahead of print.Google Scholar
  79. 79.
    Montagna E, Cancello G, Bagnardi V, et al. Metronomic chemotherapy combined with bevacizumab and erlotinib in patients with metastatic HER2-negative breast cancer: clinical and biological activity. Clin Breast Cancer. 2012;12:207–14.PubMedCrossRefGoogle Scholar
  80. 80.
    Dellapasqua S, Bertolini F, Bagnardi V, et al. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer: clinical and biological activity. J Clin Oncol. 2008;26:4899–905.PubMedCrossRefGoogle Scholar
  81. 81.
    Dellapasqua S, Bagnardi V, Bertolini F, et al. Increased mean corpuscular volume of red blood cells predicts response to metronomic capecitabine and cyclophosphamide in combination with bevacizumab. Breast. 2012;21:309–13.PubMedCrossRefGoogle Scholar
  82. 82.
    Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol. 2005;23:939–52.PubMedCrossRefGoogle Scholar
  83. 83.
    Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3:347–61.PubMedCrossRefGoogle Scholar
  84. 84.
    Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298–308.PubMedCrossRefGoogle Scholar
  85. 85.
    Rapisarda A, Hollingshead M, Uranchimeg B, et al. Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol Cancer Ther. 2009;8:1867–77.PubMedCrossRefGoogle Scholar
  86. 86.
    Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012;2:270–87.PubMedCrossRefGoogle Scholar
  87. 87.
    Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH, Melillo G. Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res. 2004;64:1475–82.PubMedCrossRefGoogle Scholar
  88. 88.
    You WK, Sennino B, Williamson CW, et al. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res. 2011;71:4758–68.PubMedCrossRefGoogle Scholar
  89. 89.
    Ebos JML, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15:232–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Paez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220–31.PubMedCrossRefGoogle Scholar
  91. 91.
    Conley SJ, Gheordunescu E, Kakarala P, et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci USA. 2012;109:2784–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Martin M, Makhson A, Gligorov J, et al. Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer. Oncologist. 2012;17:469–75.PubMedCrossRefGoogle Scholar
  93. 93.
    Yardley DA, Burris III HA, Clark BL, et al. Hormonal therapy plus bevacizumab in postmenopausal patients who have hormone receptor-positive metastatic breast cancer: a phase II Trial of the Sarah Cannon Oncology Research Consortium. Clin Breast Cancer. 2011;11:146–52.PubMedCrossRefGoogle Scholar
  94. 94.
    Moreno Garcia V, Basu B, Molife LR, Kaye SB. Combining antiangiogenics to overcome resistance: rationale and clinical experience. Clin Cancer Res. 2012;18:3750–61.PubMedCrossRefGoogle Scholar
  95. 95.
    Rini B, Szczylik C, Tannir NM, et al. AMG 386 in combination with sorafenib in patients with metastatic clear cell carcinoma of the kidney : A randomized, double-blind, placebo-controlled, phase 2 study. Cancer 2012;epub ahead of print.Google Scholar
  96. 96.
    Francia G, Kerbel RS. Raising the bar for cancer therapy models. Nature Biotechnology. 2010;28:561–2.PubMedCrossRefGoogle Scholar
  97. 97.
    Singh M, Lima A, Molina R, et al. Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nature Biotechnology. 2010;28:585–93.PubMedCrossRefGoogle Scholar
  98. 98.
    Francia G, Cruz-Munoz W, Man S, Xu P, Kerbel RS. Perspective: mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat Rev Canc. 2011;11:135–41.CrossRefGoogle Scholar
  99. 99.
    Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2:471–8.PubMedGoogle Scholar
  100. 100.
    Tentler JJ, Tan AC, Weekes D, et al. Patient-derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol. 2012;9:338–50Google Scholar
  101. 101.
    Allegra CJ, Yothers G, O'Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011;29:11–6.PubMedCrossRefGoogle Scholar
  102. 102.
    Van Cutsem E, Lambrechts D, Prenen H, Jain RK, Carmeliet P. Lessons from the adjuvant bevacizumab trial on colon cancer: what next? J Clin Oncol. 2011;29:1–4.PubMedCrossRefGoogle Scholar
  103. 103.
    Shojaei F, Simmons BH, Lee JH, Lappin PB, Christensen JG. HGF/c-Met pathway is one of the mediators of sunitinib-induced tumor cell type-dependent metastasis. Cancer Lett. 2012;320:48–55.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Biological Sciences, Sunnybrook Research Institute, Department of Medical BiophysicsUniversity of TorontoTorontoCanada

Personalised recommendations