Bold claim: a gene tied to fertility may be helping the deadliest brain cancer dodge chemotherapy. That unsettling possibility is at the heart of new research from the University of Sydney, which sheds light on why glioblastomas almost always come back after treatment. The team reports their findings in Nature Communications in a paper titled “Histone methyltransferase PRDM9 promotes survival of drug-tolerant persister cells in glioblastoma.”
Glioblastoma multiforme remains one of the most lethal brain cancers, with a median survival around 15 months in many estimates. The new study focuses on a small subset of tumor cells that survive initial chemotherapy, called persister cells. These cells seem to rewire their metabolism to endure damage, and they do so with help from PRDM9, a gene normally active during the earliest stages of egg and sperm development. In short, a fertility-related gene gets repurposed to help cancer cells resist treatment.
The researchers used glioblastoma models to probe the mechanism. They found that inhibiting PRDM9 or cutting off cholesterol production—an essential byproduct of the persister cells’ altered metabolism—can eradicate these resilient cells. When combined with standard chemotherapy, this strategy substantially extended survival in mouse models.
“PRDM9 isn’t typically active in most normal tissues, which makes it a highly selective and promising target for cancer therapy,” said Lenka Muñoz, PhD, the study’s lead author and head of cancer research at the University of Sydney. “If we can remove the last cancer cells that remain after treatment, we may prevent recurrence.”
As a next step, the team has developed a brain-penetrant chemotherapy candidate named WJA88 and paired it with a cholesterol-lowering drug that has previously reached human trials. In preclinical assessments, this combination reduced tumor size and improved survival with minimal side effects. The researchers are collaborating with Australian biotech firm Syntara to develop PRDM9 inhibitors for further animal testing and, they hope, human studies in a few years.
Beyond glioblastoma, Muñoz, Joun, and colleagues speculate that persister cells could underlie relapse in other tough-to-treat cancers. They plan to test this idea in ovarian cancer models next.
Relapse remains one of oncology’s biggest hurdles. The study implies that targeting persister cells directly—studying them alongside the broader tumor population and considering post-treatment biology—could help prevent recurrence in preclinical settings. The broader takeaway is provocative: looking beyond the tumor’s bulk to the rare cells driving return may unlock new strategies to improve long-term outcomes. Do you think this focus on persister cells could reshape how we approach cancer therapy, or might it raise new risks or trade-offs in treatment planning?
