We read with great interest the article by Van Steenkiste et al.1 that reported the benefits of placenta growth factor (PlGF) inhibition on portal hypertension in mice. The authors suggest that PlGF inhibitors could be useful for the treatment with chronic liver diseases. They emphasize the good safety profile of PlGF inhibitors, compared to the risk of bleeding associated with the use of anti–vascular endothelial growth factor (VEGF) agents such as sorafenib.
Sorafenib is a potent multikinase inhibitor that targets VEGF receptor 1 (VEGFR1), VEGFR2, and VEGFR3. PlGF, a member of the VEGF family, binds to VEGFR12 and thereby develops a proangiogenic effect. Thus, one could expect that the antiangiogenic potency of sorafenib could overlap that of the PlGF inhibitors, but also surpasses antiangiogenic effects through the inhibition of a broader spectrum of proangiogenic targets. As an illustration, Thabut et al.3 have recently shown that sorafenib down-regulates angiopoietin-1 and fibronectin at a molecular level, and inhibits both matrix restructuring and vascular remodeling in chronic liver diseases.
We recently reported a significant reduction in portal venous flow (54% of mean portal venous flow) in patients with advanced hepatocellular carcinoma who are receiving sorafenib.4 Our data show a consistent decrease in portal pressure within 30 days of therapy, suggesting that sorafenib may also represent a treatment option for patients with portal hypertension.
Portal hypertension is characterized by the formation of portoystemic collateral vessels, including gastroesophageal varices that cause life-threatening bleeding. However, no excess in bleeding events was reported in patients with hepatocellular carcinoma who were receiving sorafenib. Hence, sorafenib not only exerts antitumor effects but also protective effects on portal circulation and liver tissues that might counterbalance the theoretical risk of bleeding associated with anti-VEGF agents.
Whether anti-PlGF agents could be safer than sorafenib in patients with chronic liver disease is unknown, because no direct comparison was ever conducted. We suggest that further clinical studies of anti-PlGF agents should include ancillary studies assessing their effects on portal pressure in humans. On the other hand, studies assessing the effects of antiangiogenic agents on portal hypertension should probably include a comparison of anti-PlGF agents and sorafenib, with a specific focus on treatment safety.