Fertility-Linked Gene Drives Glioblastoma Cells to Weather Chemotherapy
Glioblastomas stand as one of the deadliest brain cancers, with a median survival hovering around 15 months. New findings from researchers at the University of Sydney offer a possible explanation for why these tumors often return after treatment. The study is detailed in a Nature Communications paper titled “Histone methyltransferase PRDM9 promotes survival of drug-tolerant persister cells in glioblastoma.”
The researchers identified a small subset of drug-tolerant cells, termed persister cells, that rewire their metabolism to endure chemotherapy. This resilience hinges on a gene typically active in reproductive cells—PRDM9. Lead author Lenka Muñoz, PhD, head of cancer research at the University of Sydney’s School of Medical Sciences, explains that discovering how cancer cells co-opt a fertility gene to survive treatment opens the door to safer, more effective therapies.
Glioblastomas account for roughly half of brain tumor cases and cause an estimated 200,000 deaths worldwide. Even after aggressive treatment combining surgery, radiation, and chemotherapy, tumor relapse is nearly universal. In this study, persister cells under chemotherapy conditions hijack PRDM9 to drive the production of cholesterol, which aids their survival against damage.
Using glioblastoma models, the team found that inhibiting PRDM9 or disrupting the cholesterol supply eliminated persister cells. When these strategies were paired with chemotherapy, survival in mouse models improved markedly.
PRDM9 is not active in most normal tissues, which makes it an unusually selective and promising cancer therapy target. If researchers can eradicate the stubborn cancer cells that linger after treatment, the chances of glioblastoma returning could rise substantially, argues George Joun, PhD, the paper’s first author and a research fellow in the School of Medical Sciences.
To translate these findings further, the team has developed a brain-penetrant chemotherapy agent named WJA88, combined with a cholesterol-lowering drug that has already been evaluated in humans. Preclinical results show that this combination reduces tumor size and extends survival with minimal side effects. Looking ahead, the researchers are collaborating with Australian biotech company Syntara to create PRDM9 inhibitors for additional animal testing, with aims to begin human trials within a few years.
Beyond glioblastoma, Muñoz, Joun, and colleagues suspect persister cells may underlie treatment resistance in other hard-to-treat cancers. They plan to test this idea in models of ovarian cancer next.
“Cancer relapse remains one of oncology’s biggest hurdles. Our work suggests that directly targeting persister cells could prevent relapse in preclinical models,” Muñoz states. The study encourages scientists to examine not just the bulk tumor, but the rare persister cells that drive recurrence, and to consider post-treatment dynamics as well as drug exposure during therapy.
Would you agree that focusing on persister cells could reshape how we approach cancer treatment, or do you think alternative strategies hold more promise? Share your thoughts in the comments.
