UOW researcher part of global team working to understand role of KDM4 in fatal brain cancer
While investigating a potential drug treatment to inhibit a protein linked to glioblastoma brain cancer, researchers unexpectedly discovered the drug was far more effective against another protein linked to the cancer.
The findings, published this week in Nature Chemical Biology, contradict previous research and open a promising new avenue in drug discovery and treatment for one of the most aggressive and fatal types of brain cancer.
Glioblastoma, a highly aggressive cancer that occurs in the brain and spinal cord, makes up about half of malignant brain tumours in adults. It is a fast-growing, complex disease with no known cure. Survival rates are grim, with around 5-7% of patients still alive after five years.
Five years ago, University of Wollongong (UOW) early career researcher Dr Jennifer Baker embarked on a research project, born out of her 2021 NHMRC Ideas Grant, to untangle the role of the protein KDM4 in glioblastoma.
Dr Baker joined a multi-disciplinary, multi-institutional team examining whether the molecule QC6352 could prevent the growth of glioblastoma cells by targeting the protein KDM4.
KDM4 is part of a family of mutated genes, known as oncogenes, that have the potential to cause cancer. In addition to glioblastoma, KDM4 has been linked to a number of other cancers, including renal, lung, breast, prostate, colorectal, and gynaecological.
Yet, as often happens in complex research of this nature, there was a surprise along the way. As the project progressed, a second protein emerged as a powerful player in obstructing cancer cells.
"When glioblastoma cells were treated with the molecule QC6352, it significantly inhibited the cancer cells," Dr Baker said. "But when another KDM4 inhibitor was used, it had little impact. This led us to believe that there was another protein that was causing the inhibition of the glioblastoma cells."
The other protein was dihydroorotate dehydrogenase (DHODH), which has a known role in glioblastoma. QC6352 was designed to block KDM4 but was actually a much more potent tool against DHODH.
In fact, the researchers found it was more than 1000 times better at blocking DHODH. They needed only a tiny fraction of the dose to inhibit DHODH, compared to what was needed to inhibit KDM4.
"This means that when researchers are using QC6352 in glioblastoma cell models, it is likely that the blocking effect they are seeing is due to DHODH inhibition, not KDM4 inhibition, which is what has previously been reported," Dr Baker said.
It was an accidental discovery built on the back of years of meticulous work to understand how glioblastoma forms and how it can be treated.
"In science, you often set out chasing one thread, and if you're paying attention, that thread leads you somewhere you never expected to look. Checking for off‑target effects is crucial in drug discovery," Dr Baker said.
"This is the culmination of five years of research. It involved experts in many areas of science, including chemical, cell and molecular biology, medicinal chemistry, oncology and structural biology. Collaboration, patience and persistence are crucial to making these big breakthroughs."
The paper also revealed a new set of compounds from Dr Baker's lab at UOW that successfully impede KDM4 without affecting DHODH. The team are developing the compounds further with the hope of establishing KDM4 as a promising drug target in cancer treatment.
Alongside Dr Baker, her PhD student Angus Saxton (University of Newcastle) and lead author Dr Lenka Munoz (University of Sydney), the publication also features contributors from Children's Cancer Institute Australia, University of Oxford and Harvard University.
About the research
'DHODH is the key target of the KDM4 inhibitor QC6352 in glioblastoma stem cells' was published in Nature Chemical Biology.
The paper is co-authored by Lenka Munoz, Paul Workman, Jayden Sterlin, Jacinda Holtsmark, George Joun, Karen Tran, Tian D'Araujo, Mani Kuchibhotla, Terrance Johns, Antoine deWeck, Lipin Loo, Gregory Neely, Chloe Shard, Guillermo Gomez, Ashwini Patil, Angus Saxton, Jennifer Baker, Yuchen Feng, Andreas Krämer, Susanne Muller, Mathias Francois, Matthew Graus, Paul Brennan, Matthew Holland, Zhihe Lei, Diana Shi, and Julie-Aurore Losman.
Dr Baker's research was funded in part by a 2021 NHMRC Ideas Grant.
