von-Hippel Lindau and Hypoxia-Inducible Factor at the Center of Renal Cell Carcinoma Biology

Hematol Oncol Clin North Am. 2023 Oct;37(5):809-825. doi: 10.1016/j.hoc.2023.04.011. Epub 2023 Jun 1.

Abstract

The most common form of kidney cancer is clear cell renal cell carcinoma (ccRCC). Biallelic VHL tumor suppressor gene inactivation is the usual initiating event in both hereditary (VHL Disease) and sporadic ccRCCs. The VHL protein, pVHL, earmarks the alpha subunits of the HIF transcription factor for destruction in an oxygen-dependent manner. Deregulation of HIF2 drives ccRCC pathogenesis. Drugs inhibiting the HIF2-responsive growth factor VEGF are now mainstays of ccRCC treatment. A first-in-class allosteric HIF2 inhibitor was recently approved for treating VHL Disease-associated neoplasms and appears active against sporadic ccRCC in early clinical trials.

Keywords: Belzutifan; Hypoxia-inducible factor; Kidney cancer; Renal cell carcinoma; von Hippel-Lindau disease.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Biology
  • Carcinoma, Renal Cell* / drug therapy
  • Carcinoma, Renal Cell* / genetics
  • Carcinoma, Renal Cell* / metabolism
  • Humans
  • Hypoxia
  • Kidney Neoplasms* / etiology
  • Kidney Neoplasms* / genetics
  • Transcription Factors
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

  • Von Hippel-Lindau Tumor Suppressor Protein
  • Transcription Factors