Inhibitors of angiogenesis Authors
Educational Series Green Series
Cite this article as: Almendro, V. & Gascón, P. Clin Transl Oncol (2006) 8: 475. doi:10.1007/s12094-006-0047-3 Abstract
Angiogenesis and neovascularization are important mechanisms for tumor growth, progression and, subsequent metastasis. Cancer cells, as part of an inflammatory process, produce and induce multiple molecules (proangiogenic and antiangiogenic) from the surrounding stromal cells. Vascular Endothelial Growth Factor (VEGF) is the most relevant proangiogenic molecule among them. Many inhibitors of angiogenesis have been developed in the last years with the aim to block the tumor blood supply as a new anticancer strategy. Bevacizumab, an anti-VEGF, has been already approved for its use in colorectal cancer showing prolonged disease free survival as well as overall survival. It shows also important activity in breast, lung, ovarian and kidney cancer. Many others inhibitors are in advanced clinical development and show promising results as well. Current basic and clinical research in this field is generating great expectations for the future of cancer treatment.
Key words angiogenesis inhibitors antiangiogenesis
Supported by an unrestricted educational grant from Pfizer.
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971; 285:1182–6.
Gullino PM. Angiogenesis and oncogenesis. J Natl Cancer Inst. 1978;61:639–45.
Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascitis fluid. Science. 1983;219:983–5.
Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989;161:851–8.
Gerber HP, McMurtrey A, Kowalski J, et al. VEGF regulates endothelial cell survival by the P13-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem. 1998;273: 30336–43.
Benjamin LE, Golijanin D, Itin A, et al. Selective ablation of immature bloos vessels in established human tumors follows vascular endothelial growth factor with-drawl. J Clin Invest. 1999;105:159–65.
Jain RK. Normalizing tumor vasculature with antiangio genic therapy: a new paradigm for combination therapy. Nature Med. 2001;7:987–9.
Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Med. 2004;10:145–7.
Kabbinavar F, Hurwitz H, Fehrenbacher L, et al. 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;21:60–5.
Kabbinavar F, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23:3697–705.
Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005;23:3502–8.
Kabbinavar F, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol. 2005;23:3706–12.
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab with irinotecan, fluorouracil and leucovorin in the treatment of metastatic colorectal cancer. N Engl J Med. 2004;550:2335–42.
Giantonio BJ, Catalana PJ, Meropol NJ, et al. High dose bevacizumab in combination with FOLFOX4 improves survival in patients with previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol. 2005;25:16S, abstract #2.
Hochster H, et al. Gastointestinal Cancers Symposium, Hollywood, Florida, 2005.
Holash J, David S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99:11593–8.
Morgan JA, Garrett HJ, Schutte H, et al. Sunitinib for patients (pts) with advanced imatinib (IM)-refractory GIST: Early results from a «treatment-use» trial. Proceedings ASCO. 2006;24:529s, abstract #9540.
Rini BI, George DJ, Michaelson JE, et al. Efficacy and safety of sunitinib malate (SU11248) in bevacizumab-refractory metastatic renal cell carcinoma (mRCC). Proceedings ASCO. 2006;24:222s, abstract #4522.
Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the multikinase inhibitor sorafenib (BAY 43-9006) in patients with advanced RCC. European Cancer Conference, ECCO-15. 2005; Personal communication.
Gore ME, Scudier B. Emerging efficacy endpoints for targeted therapies in advanced renal cell carcinoma. Oncology. 2006;20 (6 Suppl 5):S19–24.
Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565–71.