Healthcare (Commonwealth Union) – Groundbreaking research from the University of Sydney, released today, has identified a process that could explain why glioblastoma often returns after treatment, providing fresh insights for potential therapies. The team will now explore these findings further through an Australian industry partnership.
Glioblastoma is among the most aggressive forms of brain cancer, with an average survival time of just 15 months. Despite extensive efforts—including surgery, chemotherapy, and over 1,250 clinical trials in the past two decades—improvements in survival have remained limited.
Published in Nature Communications, the study reveals that a small subset of drug-tolerant cells, called “persister cells,” adapt their metabolism to withstand chemotherapy. Surprisingly, they exploit a fertility-related gene, PRDM9, as a kind of camouflage to evade treatment.
The lead author Professor Lenka Munozfrom the Charles Perkins Centre at the University of Sydney indicated that it is a world-first discovery that makes a change to our current knowledge about glioblastoma.
She further indicated that by finding out the way these cancer cells recruit a fertility gene to survive treatment, they have paved the way for new approaches that they hope could bring about safer, and more effective therapies.
The research team is collaborating with Australian biotech firm Syntara to create PRDM9 inhibitors for testing in animal models, with the ultimate goal of advancing to human trials. The next phase will explore whether these inhibitors can eliminate persister cells and stop glioblastoma from recurring. Human trials remain several years away, depending on the successful completion of preclinical studies assessing safety and effectiveness.
Glioblastoma, which accounts for roughly half of all brain tumours, causes up to 200,000 deaths worldwide and about 1,000 deaths in Australia each year. Despite surgery, radiation, and chemotherapy, the cancer almost always comes back. Doctors refer to this as “minimal residual disease,” meaning the small number of cancer cells that survive treatment eventually regrow into a tumour.
Professor Munoz, who is the co-lead the research alongside Dr George Joun from the School of Medical Sciences in the Faculty of Medicine and Health indicated for patients and their family’s facing glioblastoma, recurrence is highly likely and the research gives hope for new treatment strategies where none had occurred on prior occasions.
The process of glioblastoma exploiting the fertility genes was explored by the team who discovered that under the stress of chemotherapy, glioblastoma cells can hijack the fertility gene PRDM9 to produce cholesterol, which helps persister cells survive and ultimately allows the tumour to return. Until now, PRDM9 was only recognized for its role in reproductive cells at the very beginning of egg and sperm formation, long before fertilization.
“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,” explained Professor Munoz.
By inhibiting PRDM9 or disrupting the tumour’s access to cholesterol, scientists successfully eliminated hard-to-kill persister cells in laboratory experiments and animal studies. When used alongside standard chemotherapy, this strategy led to a marked increase in survival among mice.
The researchers also created a new chemotherapy compound capable of crossing the blood–brain barrier, known as WJA88, and combined it with a cholesterol-reducing drug that has already been tested in people. In preclinical models, the dual treatment reduced tumour size and significantly prolonged survival, while causing few side effects.
“PRDM9 isn’t active in most normal tissues, which makes it an incredibly selective and promising target for cancer therapy,” explained Dr Joun, the first author and 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.”
