Targeting the HIF2-VEGF axis in renal cell carcinoma

Anticancer therapies that target the HIF oxygen-sensing pathways are moving into the clinic, in particular in kidney cancer. Insights into the role of the tumor suppressor pVHL in oxygen sensing motivated the testing of drugs that target the transcription factor HIF or HIF-responsive growth factors, such as VEGF, for the treatment of cancers caused byVHLinactivation, such as clear-cell renal cell carcinoma (ccRCC). Multiple VEGF inhibitors are now approved for the treatment of ccRCC, and a HIF2 alpha inhibitor has advanced to phase 3 development for this disease. These inhibitors are now also increasingly combined with immune-checkpoint blockers. In this Perspective, we describe the understanding of the mechanisms of oxygen sensing and hypoxia signaling that resulted in the development of HIF2 alpha-targeted therapies for patients with VHL-associated tumors. We also present future directions for extending the use of these therapies to other cancers.