VHL / HIF oxygen sensing
The VHL/HIF pathway is how cells sense oxygen (the 2019 Nobel Prize). VHL destroys HIF when oxygen is present. Kidney cancers lose VHL, so HIF-2α is permanently on and drives blood vessel growth and proliferation.
In normoxia, prolyl hydroxylases (PHD) hydroxylate HIF-α, allowing the VHL E3 ligase to ubiquitinate it for proteasomal degradation. In hypoxia (or with VHL loss in ~90% of clear-cell RCC), HIF-α accumulates, dimerises with HIF-1β (ARNT), and transcribes VEGF, PDGF, GLUT1, CAIX, cyclin D1, and EPO. HIF-2α is the oncogenic paralogue in RCC; belzutifan blocks its dimerisation. CAIX is a PET and radioligand target (89Zr-girentuximab).
In one picture
VHL is the shredder that destroys the 'we are suffocating' memo whenever there is oxygen around. Kidney cancer breaks the shredder, so the memo piles up and the cell keeps ordering new blood vessels and sugar.
Diagram
top- Belzutifan (HIF-2α) in VHL disease and RCC, adjuvant with pembrolizumab (2026)
- VEGF-directed therapy downstream
- CAIX-targeted imaging (89Zr-girentuximab) and radioligands in development
Pages like this
not linked directly; found by shared links- PathwayVEGF angiogenesis
Shares Hallmark: inducing or accessing vasculature, Angiogenesis, Belzutifan, HIF-2α.
- PathwayGlutamine addiction
Shares Hallmark: reprogramming cellular metabolism, Warburg effect, Nutrient competition & metabolic immunosuppression, Cancer metabolism.
- IdeaCAIX theranostics: 89Zr-girentuximab PET and 177Lu/225Ac-girentuximab therapy
Shares CAIX PET (89Zr-girentuximab), HIF-2α, Renal cell carcinoma.
- IdeaBiomarker-selected adjuvant therapy in RCC (ctDNA, CAIX PET, gene signatures)
Shares CAIX PET (89Zr-girentuximab), Belzutifan, Renal cell carcinoma.
- TrialLITESPARK-022
Shares Belzutifan, HIF-2α, Renal cell carcinoma.
- TrialLITESPARK-005
Shares Belzutifan, HIF-2α, Renal cell carcinoma.
- TechnologyHypoxia-activated prodrugs
Shares Nutrient competition & metabolic immunosuppression, HIF-2α, The angiogenic switch & tumour vessels.
- TermMyeloid-derived suppressor cells (MDSCs)
Shares The pre-metastatic niche, Nutrient competition & metabolic immunosuppression, VEGF / VEGFR.