Clinical Efficacy and Safety of Angiogenesis Inhibitors: Sex Differences and Current Challenges

Vasoactive molecules, such as vascular endothelial growth factor (VEGF) and endothelins, share cytokine-like activities and regulate endothelial cell (EC) growth, migration and inflammation. Some endothelial mediators and their receptors are targets for currently approved angiogenesis inhibitors, drugs that are either monoclonal antibodies raised towards VEGF, or inhibitors of vascular receptor protein kinases and signaling pathways. Pharmacological interference with the protective functions of ECs results in a similar spectrum of adverse effects. Clinically, the most common side effects of VEGF signaling pathway inhibition include an increase in arterial pressure, left ventricular (LV) dysfunction ultimately causing heart failure, and thromboembolic events, including pulmonary embolism, stroke, and myocardial infarction. Sex steroids such as androgens, progestins, and estrogen and their receptors (ERα, ERβ, GPER; PR-A, PR-B; AR) have been identified as important modifiers of angiogenesis, and sex differences have been reported for anti-angiogenic drugs. This review article discusses the current challenges clinicians are facing with regard to angiogenesis inhibitor treatments, including the need to consider sex differences affecting clinical efficacy and safety. We also propose areas for future research taking into account the role of sex hormone receptors and sex chromosomes. Development of new sex-specific drugs with improved target and cell-type selectivity likely will open the way personalized medicine in men and women requiring antiangiogenic therapy and result in reduced adverse effects and improved therapeutic efficacy.