University of Sydney researchers have discovered how a fertility gene helps deadly brain tumors survive chemotherapy. The finding could pave the way for new treatments that target the last cancer cells left behind.
Glioblastoma, the most aggressive form of brain cancer, almost always comes back after treatment. Now, University of Sydney scientists say they have uncovered a hidden survival trick that may explain why — and how doctors might finally stop these tumors from returning.
In a study published in the journal Nature Communications, researchers identified a small group of drug-tolerant cancer cells, known as persister cells, that can ride out chemotherapy and later regrow the tumor. Their work reveals that these cells hijack a fertility gene called PRDM9 to shield themselves from treatment, pointing to a new and highly targeted way to attack the disease.
The finding marks a major shift in how scientists understand this cancer, according to lead author Lenka Munoz, a professor in the Charles Perkins Centre at the University of Sydney.
“This is a world-first discovery that changes what we know about glioblastoma,” Munoz said in a news release. “By uncovering how these cancer cells recruit a fertility gene to survive treatment, we’ve opened the door to new approaches that we hope could lead to safer, more effective therapies.”
Glioblastoma accounts for about half of all brain tumors and kills up to 200,000 people worldwide each year. Even with surgery, radiation and chemotherapy, the median survival time is about 15 months, and recurrence is almost universal.
Clinicians refer to the tiny number of cells that survive treatment and later spark relapse as minimal residual disease. These cells are difficult to detect and even harder to eliminate, which is why relapse remains one of the biggest challenges in brain cancer care.
The new study zeroes in on how those persister cells stay alive. Under the stress of chemotherapy, the team found, glioblastoma cells switch on PRDM9 — a gene previously known only for its role in the earliest stages of egg and sperm formation.
Once activated in the tumor, PRDM9 helps rewire the cancer cells’ metabolism. Instead of dying off, the persister cells ramp up cholesterol production, which appears to help them withstand damage from chemotherapy and lie low until treatment ends.
Understanding this survival mechanism could be key to changing outcomes for patients.
“Chemotherapy kills most cancer cells, but in glioblastoma a few survive and are able to regrow the tumour. We think we’ve found their survival trick and potential ways to block it,” Munoz added.
To test that idea, the researchers blocked PRDM9 or cut off the cholesterol supply in laboratory and animal models. In both cases, they were able to wipe out persister cells. When these strategies were combined with chemotherapy, survival in mice improved dramatically.
The team also designed a new chemotherapy drug, called WJA88, that can penetrate the brain more effectively than many existing drugs. They paired it with a cholesterol-lowering agent that has already been tested in humans. In preclinical models, this combination shrank tumors and extended survival with minimal side effects.
A key advantage of targeting PRDM9 is its selectivity. The gene is not active in most normal tissues, which could reduce the risk of harming healthy cells.
“PRDM9 isn’t active in most normal tissues, which makes it an incredibly selective and promising target for cancer therapy,” added first author George Joun, a research fellow in the School of Medical Sciences. “If we can eliminate the last cancer cells standing, we can stop glioblastoma from returning. That would be a game changer for patients and families.”
For now, the work remains at the preclinical stage. The researchers are partnering with Australian biotech company Syntara to develop PRDM9 inhibitors and test them further in animal models. Only after successful safety and efficacy studies could the approach move into human trials, a process likely to take several years.
Still, for a disease where options have barely improved despite more than 1,250 clinical trials over the past two decades, the discovery offers a rare sense of momentum.
“For patients and their families facing glioblastoma, recurrence is inevitable. This research offers hope for new strategies in the future where none existed,” Munoz added.
The implications may extend beyond brain cancer. Because PRDM9 has now been linked to cancer for the first time, the team believes a similar mechanism could be at work in other hard-to-treat tumors. They plan to test their approach in ovarian cancer next.
More broadly, the study adds weight to a growing shift in oncology: focusing not just on the bulk of a tumor, but on the rare, resilient cells that drive relapse.
“Cancer relapse is one of the biggest challenges in oncology. Our research shows that by directly targeting persister cells, relapse may be preventable in preclinical models,” added Munoz. “We now need to look beyond the bulk of the tumour and study rare persister cells that drive recurrence, as well as what happens after treatment ends rather than only during drug exposure,” she added.
If future trials confirm that shutting down PRDM9 and its cholesterol lifeline can clear out the last surviving cancer cells, it could reshape how doctors think about treating glioblastoma — and possibly other stubborn cancers — from the ground up.
Source: University of Sydney