What if a cancer drug works, but not the way scientists thought it would? A recent study found evidence of just that in laboratory models of glioblastoma, involving the research compound QC6352 and a related experimental drug, zavondemstat.
Both were developed to block KDM4, a family of proteins that can become overactive, fueling cancer’s growth and spread. But when researchers investigated QC6352 as a potential treatment for glioblastoma, an aggressive brain cancer, they found that while QC6352 did indeed trigger anticancer effects in the laboratory, the drug didn’t fully behave like other known KDM4 inhibitors and didn’t produce the same effects. Additional experiments uncovered why.
In glioblastoma cells, QC6352’s anticancer effects were mainly driven by its ability to block a different enzyme, DHODH, which also supports cancer cell 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,” said Lenka Munoz, one of the study’s authors and a professor of Molecular Cancer Pharmacology at the University of Sydney in a press release.
Realizing that a drug doesn’t exactly work how researchers originally thought isn’t isolated to this one instance, Munoz said in an email. In fact, it’s well established that new medications don’t always hit the intended target, Munoz said.
“This problem is considerably more common than we realize,” she said. “It is well recognized within the drug discovery community, and scientists have been raising concerns about inadequate target validation for many years.”
“I would like our findings to serve as a wake-up call for the cancer drug discovery community."
Lenka Munoz
Professor, Molecular Cancer Pharmacology at the University of Sydney
The drug tivantinib, for example, entered advanced clinical trials as what researchers thought was a selective inhibitor of the MET kinase, Munoz said.
“Subsequent studies demonstrated that its anticancer activity was largely independent of MET inhibition and instead involved disruption of microtubules, which are essential for cell division,” she said.
Do these nuances matter? An incorrect understanding of how a treatment works can in fact create a cascade of problems, according to Munoz.
“In modern targeted cancer therapy, understanding the mechanism is particularly important because it determines which patients are most likely to benefit, how the drug should be combined with other treatments and how resistance might develop,” Munoz said.
Mislabeling a drug’s mechanism can then cause trial investigators to enroll inappropriate patients or study ineffective treatment combinations. It can also potentially increase safety risks. And these problems can contribute to clinical trial failures, even if the drug has real potential.
“There are also broader consequences. An incorrectly characterized compound may be used by hundreds of researchers to investigate the biology of a particular target, potentially generating misleading conclusions that influence entire research programs,” Munoz said. “This represents an enormous waste of time, funding and scientific effort.”
The questions around QC6352 illustrate these potential problems.
“The compound was widely used to investigate KDM4 biology, and its clinical analogue, zavondemstat, progressed into clinical trials as a first-in-class KDM4 inhibitor,” she said.
The findings may call into question previous studies around the world that used QC6352 to investigate the KDM4 cancer protein, according to Munoz.
Zavondemstat was licensed to Tachyon Therapeutics by Celgene Quanticel Research, which was later acquired by Bristol Myers Squibb. Tachyon began a phase 1 trial of the drug, TACH101, in patients with solid tumors. The trial’s authors said the results supported further evaluation of the drug, but the company discontinued the study for business reasons, according to the published trial report. Munoz said she hasn’t met with the company that developed zavondemstat and doesn’t know what the study means for the drug’s future.
But now that researchers have a better understanding of how QC6352 works, it could open the door to future applications, including brain cancer.
“Identifying DHODH as the primary driver of QC6352's anticancer activity provides a stronger biological rationale for investigating DHODH inhibition as a therapeutic strategy in glioblastoma,” Munoz said.
She also hopes researchers take a broader lesson from the study findings. While cancer dominates pharma R&D, there’s not enough emphasis on target validation, Munoz said.
“Our 2023 study … which systematically reviewed 662 publications, revealed that only 4% of eligible studies followed all recommended practices for target validation,” she said in an email.
That amounted to just 11 of the 267 publications eligible for the study’s full assessment of chemical-probe practices.
Ultimately, researchers should be doing more to establish a drug’s mechanism before making substantial investments in its development.
“I would like our findings to serve as a wake-up call for the cancer drug discovery community,” she said. “Scientists have been discussing reproducibility, unreliable chemical probes and incorrect interpretation of drug mechanisms for many years. Yet, as our study demonstrates, these problems continue to occur, sometimes even with compounds that have advanced into clinical trials.”
