Hypoxia and HIF
When oxygen runs low, HIF proteins switch on a survival programme: new vessels, more glucose uptake, escape. VHL normally destroys HIF; kidney cancer loses VHL and runs the programme permanently. Belzutifan blocks HIF-2α directly.
Diagram
Pick a product above a diagram to see the nodes it hits and the escape routes below the block. Hover or tap any node or arrow for what it is; every node opens its target, glossary entry or the pathway page. Violet boxes are druggable targets.
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.
What happens
In plain words, then the glossary entries the stage rests on. Chapter 5, Feeding the tumour: A tumour is a construction site that never stops.
When oxygen runs low, HIF proteins switch on a survival programme: new vessels, more glucose uptake, escape. VHL normally destroys HIF; kidney cancer loses VHL and runs the programme permanently. Belzutifan blocks HIF-2α directly.
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.
The molecular players
The proteins and genes at this stage, with their role and how many products act on each. Listed players come from the atlas; drawn players sit as nodes in the diagrams above.
A master switch that kidney cancer cells leave permanently on when they lose the VHL gene; belzutifan blocks it.
The signal tumours use to grow their own blood supply. Blocking it starves tumours and, surprisingly, helps immunotherapy work.
Where medicines act
Products grouped by the node they hit, most advanced first, with the cancers an approved product is linked to. Pick one above the diagram to see it light up.
- AnlotinibApprovedNon-small-cell lung cancerSmall-cell lung cancerSarcomas (soft tissue, bone, GIST)
- AxitinibApprovedRenal cell carcinomaClear cell renal cell carcinomaAdenoid cystic carcinoma
- BevacizumabApprovedColorectal cancerOvarian cancerNon-small-cell lung cancer
- Bevacizumab (glioblastoma use)ApprovedGlioma & glioblastoma
- CabozantinibApprovedHepatocellular carcinomaAdvanced hepatocellular carcinoma (BCLC C)Renal cell carcinoma
- Camrelizumab + rivoceranibApprovedHepatocellular carcinoma
- DonafenibApprovedHepatocellular carcinomaThyroid cancer
- FruquintinibApprovedColorectal cancer
- +21 more at VEGF / VEGFR →
Measured by
Biomarkers, tests and assays in the corpus that read this stage in a patient.
Open questions
What is not known at this stage: the atlas's own questions, the bottlenecks it bears on, and the ideas in the corpus that try to answer them.
- Why does HIF-2α inhibition work in RCC and not in other hypoxic tumours?
- Can hypoxia imaging select patients for hypoxia-activated prodrugs or dose-painted radiotherapy?
- early clinicalCAIX theranostics: 89Zr-girentuximab PET and 177Lu/225Ac-girentuximab therapy
Almost every clear-cell kidney cancer carries the CAIX protein. Image it with one radioactive antibody, then treat with the same antibody carrying a therapeutic isotope.
- early clinicalindustryUse a hypoxia scan to pick patients for adenosine-pathway drugs
Tumours starved of oxygen produce a chemical that switches immune cells off. A scan can show which tumours are starved, and those are the ones to treat with blockers.
- preclinical evidenceresearchSoften the tissue that new metastases need in order to grow
Cancer cells need stiff, cross-linked tissue scaffolding to settle and grow in a new organ. Blocking the enzymes that build it may stop new colonies taking hold.
src/data/mechanics-atlas.ts). Players, medicines, escape routes, tests, ideas and papers are resolved from the knowledge graph at build time through the stage's pathways, targets and terms, so every item here has its own page and sources. Where a section is missing, the corpus has no record tied to the stage yet. Nothing here is medical advice; see about and methodology. Stage 5.4 of 56.