Scientists identify unexpected target for cancer drug

A cancer drug currently being tested in patients may not work in the way scientists originally thought, a new study suggests. 

The drug, known as zavondemstat, was developed to target KDM4, a group of proteins that can help cancer cells grow and spread. 

But researchers from the University of Sydney found the drug works mainly by blocking DHODH, an enzyme cancer cells need to make DNA and multiply. 

The team made the discovery while investigating whether zavondemstat and a related compound, QC6352, could be used to treat glioblastoma – an aggressive form of brain cancer. 

Lead author of the study, Professor Lenka Munoz, said: ‘We can think of DHODH as a machine producing bricks needed to build new DNA. If you switch off the machine, the cell starts running out of bricks and can no longer efficiently copy its DNA and keep dividing.’ 

The results, published Tuesday in the journal Nature Chemical Biology, could affect how scientists interpret previous research on zavondemstat and QC6352, a drug that blocks proteins tumour cells need to grow.

‘We tested these compounds to investigate whether they could potentially be repurposed for glioblastoma treatment,’ Munoz said. ‘When we tested other KDM4 inhibitors, we found they did not reproduce the anticancer effects observed with QC6352.

‘If blocking KDM4 was driving those effects, we would have expected the other inhibitors to behave similarly. Instead, the results suggested QC6352 was acting through a different mechanism.’

The study, which also involved experts from Goethe University, Oxford University and the Institute of Cancer Research in London, doesn’t show that zavondemstat is ineffective against cancer. 

Munoz added: ‘Researchers around the world have used QC6352 as a leading tool to study KDM4 biology, while the related drug zavondemstat progressed into clinical trials based on the same understanding.

‘Our study found much of the anticancer activity of these compounds is driven by blocking DHODH rather than KDM4.’

Experts claim the finding could also point to a new approach to treating glioblastoma, although more research is needed.

The research can be read in full here. 

Image: CDC/UnSplash

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