A study co-led by researchers at The Hospital for Sick Children (SickKids) and the University of Toronto’s Temerty Faculty of Medicine sheds light on why some very-high-risk childhood brain tumors resist radiation—and outlines a strategy to overcome it. Published in Cell Reports Medicine (2025; DOI: 10.1016/j.xcrm.2025.102202), and reported by MSN.com, the work targets medulloblastoma, the most common malignant brain tumor in children, where treatment options have changed little in decades and radiation has been a mainstay since the 1950s.
While often effective initially, radiation can lose potency when tumors recur, a problem that is especially pronounced in high-risk medulloblastomas within the SHH subgroup that harbor TP53 mutations. The team aimed to re-sensitize these tumors to radiation. To uncover the root of resistance, the researchers collaborated across disciplines to adapt CRISPR-Cas9 screening so it could be performed under radiation exposure—enabling a genome-wide search for genes that drive radioresistance.
Strikingly, the screen identified a single culprit: loss of TP53 conferred radiation resistance in medulloblastoma cells, mirroring clinical observations in patients with TP53-mutated tumors. Building on this, the team ran a second CRISPR-Cas9 screen to identify vulnerabilities that could reverse resistance. They found three genes whose disruption re-sensitized cancer cells to radiation, all within a pathway responsible for repairing DNA breaks—the very damage radiation is designed to inflict.
In follow-up experiments, the researchers showed that peposertib—a drug targeting one of these genes—was sufficient to make TP53-deficient medulloblastoma cells responsive to radiation again. The effect held up in lab-grown tumor cells and in rodent models derived from patient tumors.
Peposertib is already being tested in multiple clinical trials as an add-on intended to heighten the impact of radiation and chemotherapy in some adult cancers. If it similarly sensitizes pediatric brain tumors, clinicians may gain an option for patients whose cancers have stopped responding to radiation. It could also enable lower radiation doses, potentially reducing the long-term toxicities that currently burden many survivors.
Those late effects are substantial: survivors of childhood medulloblastoma face high rates of severe, lasting consequences, including increased incidence of stroke and hearing loss, and greater reliance on disability support. The authors suggest their findings may extend to other high-risk pediatric brain tumors that lack effective therapies, and they underscore how clinician–basic scientist collaboration can accelerate such advances—an example, they argue, of the “out-of-the-box” thinking needed to move the field forward.
