Cancer drug enters clinical trials based on a false mechanism

A cancer drug currently being tested in patients appears to have entered clinical trials based on an incorrect understanding of how it works, according to an international study led by The University of Sydney.

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

“When we tested other KDM4 inhibitors, we found they did not reproduce the anticancer effects observed with QC6352,” explained Professor Lenka Munoz, lead author on the study.

“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 found that both compounds largely work by blocking DHODH — an enzyme cancer cells rely on to produce the molecules needed for rapid growth — rather than KDM4.

“We can think of DHODH as a machine producing bricks needed to build new DNA,” Munoz said. “If you switch off the machine, the cell starts running out of bricks and can no longer efficiently copy its DNA and keep dividing.”

These findings could affect the interpretation of previous studies around the world that used QC6352 to investigate the biology of the cancer protein and may have implications for the ongoing clinical development of zavondemstat. As noted by Munoz, “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.”

Munoz said the findings highlight the issue of getting a drug’s mechanism wrong, noting that it can lead to “poorly designed clinical trials, inappropriate patient selection and years of research focused on the wrong biological target”.

“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,” she continued.

“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.”

The good news is, the findings 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 have developed new compounds that inhibit KDM4 without affecting DHODH, which could help scientists study the role of KDM4 more accurately in future cancer research.

“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,” Munoz concluded.

Image credit: iStock.com/Jiratcha Piamnoppacun