Experimental cancer drug works differently than researchers originally thought

A cancer drug currently being tested in patients may have entered clinical trials based on an incorrect understanding of how it works, according to a new study led by the University of Sydney in collaboration with Goethe University, Oxford University and the Institute of Cancer Research, London. 

Published in Nature Chemical Biology, the study found the experimental drug zavondemstat and a closely related research compound, QC6352 – developed to treat cancers such as colorectal, pancreatic and prostate cancer – do not primarily target KDM4, a family of proteins which can help cancer cells grow and spread when it becomes overactive. Instead, both compounds largely work by blocking DHODH, an enzyme cancer cells rely on to produce the molecules needed for rapid growth.

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."

Lenka Munoz, Lead Author, Professor, University of Sydney School of Medical Sciences and Charles Perkins Center

These findings could affect the interpretation of previous studies around the world that used the research compound (QC6352) to investigate the biology of the cancer protein and may have implications for the ongoing clinical development of the zavondemstat drug. 

The discovery emerged from research investigating whether zavondemstat and QC6352 could be repurposed for glioblastoma, the most common and aggressive form of brain cancer. 

"We tested these compounds to investigate whether they could potentially be repurposed for glioblastoma treatment," Professor Munoz said.

"When we tested other KDM4 inhibitors, we found they did not reproduce the anti-cancer 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."

Using patient-derived glioblastoma stem cells, tumour models and a series of genetic, mechanistic and molecular experiments, the researchers traced the compounds' response to DHODH rather than KDM4.

"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," Professor Munoz said.

"Our study found much of the anti-cancer activity of these compounds is driven by blocking DHODH rather than KDM4."

Study highlights broader issue facing cancer drug development

Professor Munoz said the findings highlight a broader challenge in cancer drug development.

"Getting a drug's mechanism wrong can lead to poorly designed clinical trials, inappropriate patient selection and years of research focused on the wrong biological target," she said.

"There are well-known examples of cancer drugs advancing through large clinical trials before researchers realised they were not working through the mechanism originally proposed. 

"Our study shows this is not just a historical problem but one still happening today. Greater rigour is needed to ensure we understand exactly how potential treatments work before they move into clinical testing.

"Establishing a drug's true mechanism early can protect patients, prevent wasted research effort and help ensure what limited funding we have is directed towards genuinely promising treatments."

The findings also point to DHODH inhibition as a potential new avenue for glioblastoma treatment. Several drugs targeting DHODH are already being investigated for other cancers, raising the possibility they could eventually be tested in patients with brain cancer. 

Beyond identifying the drug's true target, the researchers developed new compounds that inhibit KDM4 without affecting DHODH, which could help scientists study the role of KDM4 more accurately in future cancer research.