Tumor Angiogenesis

English Version

The current era of research in antiangiogenic therapy for cancer began in earnest in 1971 with the publication of Folkman’s imaginative hypothesis, but 33 years would elapse before the first drug developed as an inhibitor of angiogenesis was approved by the Food and Drug Administration (FDA). This approval was based on the survival benefit observed in a randomized phase trial of first line treatment of metastatic colorectal cancer; in that trial, bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), was combined with conventional chemotherapy. Bevacizumab therapy also increased overall survival in the first line treatment of advanced non small cell lung cancer when used in combination with standard chemotherapy. Two other antiangiogenic drugs, sorafenib and sunitinib, have also been approved by the FDA; these are oral small molecule receptor tyrosine kinase inhibitors (RTKIs). They target multiple receptor tyrosine kinases, including VEGF receptors and platelet derived growth factor (PDGF) receptors. Sorafenib and sunitinib have been beneficial in the treatment of metastatic renal cell cancer when used alone. Sorafenib monotherapy is also active in the treatment of hepatocellular carcinoma and was recently approved by the FDA for this indication.

The survival benefits of these treatments are relatively modest (usually measured in months), with the possible exception of the benefits for patients with renal cell carcinoma. These treatments are also costly and have toxic side effects. These concerns raise the following questions with respect to improving antiangiogenic therapy: How do such drugs work, and how does bevacizumab increase the efficacy of chemotherapy? Several theories have been postulated, including the theory that antiangiogenic drugs improve chemotherapy by causing “vessel normalization” in tumors (see Appendix 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). How do tumors become resistant to antiangiogenic drugs? Are there clinically useful markers that can predict the efficacy of this class of drug? Are there promising surrogate pharmacodynamic biomarkers that will help to determine the best dose of a particular agent? Will antiangiogenic RTKIs such as sunitinib or sorafenib consistently enhance the efficacy of chemotherapy? What accounts for the side effects of these agents?

Many recent discoveries have the potential not only to answer some of these questions but also to indicate new therapeutic targets and treatment strategies. The purpose of this review is to summarize a number of these discoveries, made mainly over the past 5 years, and to point out their potential clinical impact.

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