A study co-led by researchers at The Hospital for Sick Children (SickKids) and the University of Toronto's Temerty Faculty of Medicine has uncovered why some very-high-risk brain tumours are resistant to radiation - and identified a promising new strategy to overcome it.
The findings, published in Cell Reports Medicine , could help improve the effectiveness of radiation therapy in treating medulloblastoma and other brain tumours, enabling children with these cancers to live longer and better lives.
"These high-risk tumours still have vulnerabilities and if we can identify those vulnerabilities, we can potentially find therapies that we could bring to the clinic," says Alexandria DeCarlo, co-lead author on the study and a PhD student in the lab of Vijay Ramaswamy, scientist and pediatric neuro-oncologist at SickKids.
Treatment options for medulloblastoma - the most common malignant brain tumour in children - have remained largely unchanged over the past 40 years, with radiation being a cornerstone of therapy since the 1950s. Despite its initial effectiveness, radiation therapy often loses its potency if the tumour recurs. This is especially true for high-risk medulloblastomas that belong to the SHH subgroup and have mutations in the TP53 gene.
"We wanted to sensitize these cancer cells to radiation because radiation is the only treatment that works in medulloblastoma," says Ramaswamy, an associate professor of paediatrics and medical biophysics at Temerty Medicine.
To do this, DeCarlo first needed to figure out what was making the tumours resistant to radiation. She and Ramaswamy reached out to Stephane Angers, director of the Donnelly Centre for Cellular and Biomolecular Research and a professor of biochemistry at Temerty Medicine, to learn about a technique called CRISPR-Cas9 screening. In a screen, CRISPR-Cas9 gene editing tools are used to systematically knock out every gene in a cell to determine which genes contribute to a specific trait - in this case, radiation resistance.
DeCarlo worked with co-lead author Graham MacLeod, a senior research associate in Angers' lab, to develop a new method to integrate radiation treatment into their CRISPR-Cas9 screening approach, which they had not previously done. Their efforts identified a single gene, TP53, whose loss conferred radiation resistance to the medulloblastoma cells, confirming clinical observations of patients with TP53-mutated tumours.
"It was quite remarkable that it was just one gene, and it was the gene that, biologically, makes the most sense," says Ramaswamy.
The researchers then conducted another CRISPR-Cas9 screen to look for genes that could overcome radiation resistance. They found three different genes that contributed to making the cancer cells sensitive to radiation; interestingly, all three genes were part of a pathway that repairs DNA breaks, such as those caused by radiation exposure.
In follow-up experiments, the researchers showed that treatment with a new drug called peposertib - which targets one of the three genes - was enough to make the medulloblastoma susceptible to radiation again. They replicated their findings in both lab-grown tumour cells and rodent models of patient-derived tumours.
Ramaswamy notes that peposertib is currently being tested in several clinical trials as an add-on treatment to make radiation and chemotherapy more effective in treating some types of adult cancer.
By making tumours more sensitive to radiation, this strategy could offer new therapeutic options for patients whose cancers have previously been unresponsive to radiation. It could also help lower the dose of radiation that's needed, thereby reducing the risk and severity of long-term side effects.
"One of the challenges of treating children with brain tumours is that we need to irradiate them. Even though survival rates are 50 to 60 per cent, the survivors are left with long-term severe consequences from their treatment," says Ramaswamy.
In a 2023 study that examined the health of childhood medulloblastoma survivors in Ontario, Ramaswamy and his colleagues found that survivors experienced a higher incidence of stroke and hearing loss and were more frequently dependent on disability supports.
He believes that their findings may also be relevant to other high-risk childhood brain tumours - many of which lack effective treatment options - and offer new hope for those children.
"This is some of the best data we have so far for this group of patients," he says.
For both Ramaswamy and Angers, the study highlights the impact of working across disciplines to address complex health questions.
"We desperately need out-of-the-box thinking to come up with new treatments and new approaches for these patients," says Angers. "If clinician scientists collaborate with basic scientists and leverage the considerable expertise that exists in the Toronto ecosystem, we're going to be able to move mountains."
This study was funded by Brain Canada, the Canadian Cancer Society and the Meagan Bebenek Foundation.
