Is HIF activation Janus faced? The therapeutic effects of the HIF-2α inhibitor

von Hippel-Lindau (VHL) disease is a rare autosomal dominant hereditary syndrome that is caused by biallelic VHL inactivation following Knudson’s 2-hit hypothesis of tumorigenesis. Although VHL disease presents with variable phenotypes, inactivation of the VHL protein causes benign and malignant tumors, most commonly renal cell carcinoma (RCC), pheochromocytoma, pancreatic neuroendocrine tumor, retinal hemangioblastoma, and central nervous system (CNS) hemangioblastoma. 1 Maher E.R. Neumann H.P. Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011; 19: 617-623 Google Scholar RCC and CNS tumors are the main causes of death in people with VHL disease. 1 Maher E.R. Neumann H.P. Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011; 19: 617-623 Google Scholar The incidence of RCC varies depending on the subtype of VHL disease, with asymptomatic tumors detected as early as 16 years in some affected individuals. 1 Maher E.R. Neumann H.P. Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011; 19: 617-623 Google Scholar In patients with VHL disease and suspected RCC >3 cm in tumor size, partial nephrectomy is recommended. 2 National Comprehensive Cancer NetworkNCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer, Version 4.2022). https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440Date accessed: March 3, 2022 Google Scholar Because RCC is a recurring event over decades, the impact of repeated operations on the kidney and overall health remains a major concern. 1 Maher E.R. Neumann H.P. Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011; 19: 617-623 Google Scholar Alternative treatments that reduce the need for surgery would be a significant advance in the management of VHL disease.