World-first research published today by University of Sydney scientists has uncovered a mechanism that may explain why glioblastoma returns after treatment, offering new clues for future therapies which they will now investigate as part of an Australian industry collaboration.
Glioblastoma is one of the deadliest brain cancers, with a median survival rate of just 15 months. Despite surgery and chemotherapy, more than 1250 clinical trials over the past 20 years have struggled to improve survival rates.
Published in Nature Communications, the study shows that a small population of drug-tolerant cells known as “persister cells” rewires its metabolism to survive chemotherapy, using an unexpected ally as an invisibility cloak: a fertility gene called PRDM9.
“This is a world-first discovery that changes what we know about glioblastoma,” said lead author Professor Lenka Munozfrom the Charles Perkins Centre at the University of Sydney. “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.”
The researchers are now working with Australian biotech company Syntara to develop PRDM9 inhibitors for further testing in animal models, with the hope to eventually progress to human studies. The next steps are to determine whether these inhibitors can eliminate persister cells and prevent glioblastoma from returning. Trialling this in humans is likely several years away, pending successful completion of preclinical safety and efficacy studies.
Accounting for about half of all brain tumours, glioblastoma claims the lives of up to 200,000 people globally and around 1000 Australians each year. Even after surgery, radiation and chemotherapy, recurrence is almost universal. Clinicians call this “minimal residual disease”, meaning the few hidden cancer cells that survive treatment eventually regrow the tumour.
“For patients and their families facing glioblastoma, recurrence is inevitable. This research offers hope for new strategies in the future where none existed,” said Professor Munoz, who co-led the study with Dr George Joun from the School of Medical Sciences in the Faculty of Medicine and Health.
How glioblastoma uses a fertility gene to cheat chemotherapy
The researchers found that while the body undergoes chemotherapy stress, glioblastoma cells are able to hijack PRDM9 to churn out cholesterol, helping persister cells withstand damage and eventually allowing the tumour to return. Previously, PRDM9 was only known as a fertility gene, active in reproductive cells at the very start of egg and sperm formation, long before fertilisation.
“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,” said Professor Munoz.
