# Hypoxia-activated prodrugs

Source: https://onco.cc/technologies/hypoxia-activated-therapy/  
OnCo record `hypoxia-activated-therapy` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A harmless molecule that turns into a poison only where there is no oxygen, which in the body means inside a tumour.

## Summary

Tumour cores are hypoxic in a way normal tissue is not, so a prodrug reduced only under low oxygen should be tumour-selective. Evofosfamide failed two phase 3 trials in 2015; the field has since focused on better patient selection using hypoxia imaging or gene signatures, and on newer scaffolds. It remains a clean idea with a poor clinical record.

## Fields

- Kind: Technology
- Status: phase-2
- Last checked: 2026-09-08
- Tags: frontier
- Principle: One-electron reduction of a nitroaromatic or quinone trigger is reversed by oxygen; where oxygen is absent, fragmentation releases an active cytotoxin.
- Strengths: Exploits a difference no normal tissue shares; Kills the hypoxic cells radiotherapy misses; Combines with radiation and antiangiogenics
- Limitations: Two phase 3 failures without hypoxia selection; Needs a validated hypoxia biomarker; The prodrug must diffuse into a poorly perfused region

## Sources

- ClinicalTrials.gov: hypoxia-activated prodrug: https://clinicaltrials.gov/search?term=hypoxia-activated%20prodrug

## Connected records

- cancers: [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Sarcomas (soft tissue, bone, GIST)](https://onco.cc/cancers/sarcoma/)
- fronts: [Chemotherapy](https://onco.cc/fronts/chemotherapy/), [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [Anti-angiogenic therapy](https://onco.cc/technologies/antiangiogenic/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [FDG PET](https://onco.cc/technologies/fdg-pet/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/)
- targets: [HIF-2α](https://onco.cc/targets/hif2a/)
- roadmaps: [Radical oncology: what could change the war by 2035](https://onco.cc/roadmaps/frontier-2035/)
- pathways: [Nutrient competition & metabolic immunosuppression](https://onco.cc/pathways/nutrient-competition-tme/), [The angiogenic switch & tumour vessels](https://onco.cc/pathways/angiogenic-switch/)
- companies: [Threshold Pharmaceuticals](https://onco.cc/companies/threshold-pharmaceuticals/)

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