Thus, drugs that boost Smurf2 levels in cancer cells and its binding to HIF proteins will have anti-cancer efficacy since HIF promotes tumor blood vessel formation, cancer cell invasion and metastases, and its inhibition is associated with reduced tumor growth and metastasis. 

The classical understanding of how cells respond and adapt to hypoxia by inducing HIF proteins was awarded the Nobel Prize in Physiology or Medicine in 2019, including for work showing that the Von Hippel Lindau (VHL) tumor suppressor protein targets HIF for degradation and that this is blocked by oxygen modifications on HIF proteins. In kidney cancer the VHL tumor suppressor is frequently mutated leading to unregulated HIF proteins that drive cancer. In Von Hippel Lindau disease, VHL mutations that are inherited predispose affected individuals to develop kidney cancer and cerebellar hemangiomas (vascular tumors due to high levels of HIF proteins). 

HIF proteins induce VEGF and Erythropoietin to promote wound healing and red blood cell production. In the field of cancer, bevacizumab (Avastin), the first anti-angiogenic drug that targets VEGF, was developed by Genentech (now Roche) and has several billion dollars in sales annually. VEGF normally promotes wound healing so that in patients who do not have cancer, an increase in VEGF in a wound accelerates wound healing. In kidney disease, there is anemia due to reduced erythropoietin production. Thus, with the discovery of Smurf2 as a regulator of HIF proteins, our goal is to use small molecules to increase Smurf2 as a cancer therapeutic strategy and to lower Smurf2 (or block its activity), in patients without cancer, as a strategy to promote wound healing or treat anemia of chronic disease.