Biological Evidence for Dual Antiangiogenic-Antiaromatase Activity of the VEGFR Inhibitor PTK787/ZK222584 In vivo

摘要

Aromatase inhibitors have improved the treatment of estrogen receptor (ER)-positive breast cancer; aromatase inhibitors show superior efficacy to tamoxifen in both early and advanced breast cancer (1-4). Despite these advances, the efficacy of aromatase inhibitors, at least in the metastatic setting, is limited by inevitable disease progression or relapse. The combination of aromatase inhibitors with agents targeting other key biochemical pathways required for tumor viability has been proposed as a potentially successful strategy to enhance tumor shrinkage and delay endocrine resistance (5). The majority of preclinical models and clinical trials have investigated the combination of aromatase inhibitors with epidermal growth factor receptor/human epidermal growth factor receptor 2 (HER2) inhibitors (6-8). There is extensive evidence supporting the role of angiogenesis in breast cancer, and vascular endothelial growth factor (VEGF) is a critical regulator of this process (9). VEGF and VEGF receptors (VEGFR) have been implicated in resistance to hormonal therapies (10). This has led to the hypothesis that concomitantly targeting the VEGF and ER signaling pathways may provide enhanced therapeutic benefit.