Pharmacogenetics of antiangiogenic therapy

Abstract

The concept of targeting tumor angiogenesis has moved from a pioneering research field into clinical practice, and the novel drugs now available are defining a new and promising avenue of targeted cancer therapy. As with many other target-specific treatments, however, the need for a rational selection of patients to be administered anti-angiogenic treatments is emerging, since the clinical activity of these agents appears to be limited to specific patients and is not predictable on the basis of standard approaches. Candidate targets for treatment optimization are vascular endothelial growth factors (VEGF) and their receptors (VEGFR), and while the activity of drugs inhibiting VEGF and VEGFR signal transduction pathways are likely to also be influenced by their intrinsic biological activities and the regulation of the gene expression of VEGF and VEGFR as well. The pharmacogenetic approach to anti-angiogenic therapy should be considered a possible strategy for delivering the optimal treatment to specific groups of patients affected by tumors, as well as by other pathological conditions dominated by pathological angiogenesis, including age-related macular degeneration or endometriosis. While pharmacogenetic studies are building stronger foundations for the systematic investigations of phenotype-genotype relationships in many fields of medicine, pharmacogenetic data regarding anti-angiogenic drugs are still lacking. Here, we review preclinical and clinical genetic studies mainly focusing on VEGF-A and VEGFR-2. Many genetic variants are being discovered, and single nucleotide polymorphisms of VEGF and VEGFR genes appear to be able to affect VEGF transcription, affinity to its receptor, and biological activity of signal transduction pathway. We suggest that pharmacogenetic profiling of patients who are candidates for the currently available anti-angiogenic agents may help in the selection of subjects to be treated on the basis of their likelihood of responding to the drugs, while avoiding major toxicities, including hypertension and bleeding. © 2008 Springer US.