Promising Drug Combination Offers New Hope for Rare Pediatric Brain Cancer ATRT
A novel combination therapy is showing significant promise in the fight against atypical teratoid rhabdoid tumor (ATRT), a rare and aggressive pediatric brain cancer. Scientists at St. Jude Children’s Research Hospital have identified a strategy to reactivate and maintain the function of a crucial tumor suppressor protein, p53, leading to reduced tumor growth and increased survival in laboratory models.
Fewer than 100 children in the United States are diagnosed with ATRT each year, and the prognosis is often poor, making the search for effective treatments a critical priority. The research, published in Neuro-Oncology Pediatrics on December 16, 2025, details how the drugs idasanutlin and selinexor, when used in combination, can overcome the challenges of treating this devastating disease.
The Challenge of ATRT and the Role of p53
ATRT affects the central nervous system and is notoriously difficult to treat. A key obstacle lies in the fact that “None of the treatments tried so far have worked,” according to a leading researcher involved in the study. The team focused on p53, a protein often referred to as the “guardian of the genome” due to its role in preventing cancer development. In many cancers, p53 is deactivated, allowing tumors to grow unchecked.
The researchers aimed to restore p53 function, but faced a unique hurdle with ATRT: delivering the drugs effectively across the blood-brain barrier. Furthermore, single-agent use of drugs like idasanutlin has previously been shown to induce resistance in tumors.
Combination Therapy Boosts Tumor Cell Death
The breakthrough came with the realization that combining idasanutlin and selinexor could synergistically boost p53 activity and overcome these limitations. Idasanutlin works by blocking MDM2, a protein that degrades p53, effectively preventing its breakdown. Selinexor, on the other hand, inhibits XPO1, a protein responsible for transporting p53 out of the cell’s nucleus – the control center of the cell.
“If p53 levels increase through two different pathways, we hypothesized a much greater effect on tumor cell death,” explained a senior researcher. The results in mouse models of both ATRT and malignant rhabdoid tumors (MRT), a related cancer occurring in soft tissues, were compelling, demonstrating significantly extended survival rates.
Overcoming Drug Resistance
Recognizing that tumors can develop resistance to treatment over time, the team also investigated potential mechanisms of resistance to the combination therapy. They discovered that resistance was linked to the BCL-2 protein family, which regulates cell death. Importantly, they identified therapeutic strategies to counteract this resistance, offering a potential path to long-term efficacy.
“Notably, our work confirmed that both drugs achieve sufficient concentrations in the brain to induce a strong p53 pathway response,” added a co-corresponding author. This finding is crucial, as it addresses the previous challenge of drug delivery to the central nervous system.
Implications for Pediatric Cancer Treatment
The findings offer a strong rationale for further investigation of this combination therapy, particularly for ATRT. Researchers are optimistic about its potential, given the limited treatment options currently available.
“ATRT is an intractable disease in very young children, so we hope there will be interest in pursuing this combination therapy,” stated a researcher. “The data we have seen in support of this is very convincing.”
Furthermore, the approach may have broader implications for treating childhood cancers. “Compared to adults, mutations in p53 are much less frequent in children, and combination strategies like ours might have broad applicability to treat children with cancer,” noted a scientist.
More information: Alaa Refaat et al, Targeting the p53 Pathway to Treat Atypical Teratoid Rhabdoid Tumors, Neuro-Oncology Pediatrics (2025). DOI: 10.1093/neuped/wuaf018.
