The Case for Curiosity-Driven Research: New Treatments for Cancer and Anemia Emerging from Studies of an Obscure Hereditary Cancer Syndrome

ABSTRACTS: von Hippel-Lindau (VHL) Disease, which was described in the medical literature about a century ago, presents as a hereditary cancer syndrome and is caused by inactivating mutations of the VHL tumor suppressor gene. VHL patients are at high risk for kidney cancers, blood vessel tumors called hemangioblastomas, and neural crest tumors called paragangliomas. VHL mutations, now as acquired mutations rather than inherited mutations, also play important roles in the non-hereditary counterparts of these tumors. VHL-associated tumors often stimulate angiogenesis and red blood cell production due to overproduction of VEGF and erythropoietin, respectively, both of which are normally induced by low oxygen (hypoxia). This was a clue that the VHL protein likely played a role in oxygen sensing. Many hypoxia-inducible genes are regulated by a transcription factor called HIF (hypoxia-inducible factor), which contains an unstable alpha subunit and a stable beta subunit. We and others showed that the VHL protein binds to the HIF alpha subunits and targets them for destruction, but only if the latter have undergone oxygen-dependent hydroxylation of conserved prolyl residues by the EglN family of prolyl hydroxylases. Under low oxygen conditions, EglN activity falls and HIF levels rise. Drugs that inhibit HIF, and particularly HIF2, are now approved to treat sporadic kidney cancer and VHL disease. Conversely, multiple EglN inhibitors, which stabilize HIF, are approved for the treatment of anemia.