(MEMPHIS, Tenn. – December 16, 2025) St. Jude Children's Research Hospital scientists identified a promising combination approach to treat a rare, but catastrophic pediatric brain cancer called atypical teratoid rhabdoid tumor (ATRT). Reactivating and maintaining p53, a protein responsible for tumor suppression, using the drugs idasantulin and selinexor, respectively, was well-tolerated, reduced tumor burden and increased survival in a laboratory model. Further, the researchers identified a route by which cells may develop resistance to the combination and outlined strategies to offset this phenomenon. The findings were published in Neuro-Oncology Pediatrics.
Fewer than 100 children in the U.S. are diagnosed annually with ATRT. These tumors have poor outcomes, and new treatments are desperately needed. Increasing p53 levels using idasantulin has demonstrated efficacy against extra-CNS (outside the central nervous system) rhabdoid tumors, which occur in soft tissues, called malignant rhabdoid tumors (MRT). However, this is confounded in ATRT due to the additional complexity of needing to get these treatments across the blood-brain barrier. Moreover, drugs like idasanutlin have been shown to induce resistance in tumors when used as single agents.
Summing up the problem, co-corresponding author Martine Roussel, PhD , St. Jude Department of Tumor Cell Biology ,stated simply, "None of the treatments tried so far have worked."
Combination therapy boosts tumor cell death
The researchers found that the combination therapy significantly extended survival in ATRT and MRT mouse models. "Idasantulin blocks MDM2, a protein responsible for turning over p53, and if you prevent p53 turnover, you increase the p53 pathway," Roussel explained. "Selinexor blocks XPO1, a shuttling protein that exports p53 out of the nucleus. So, if p53 levels increase through two different pathways, we hypothesized a much greater effect on tumor cell death."
"Notably, our work confirmed that both drugs achieve sufficient concentrations in the brain to induce a strong p53 pathway response," added co-corresponding author Anang Shelat, PhD , St. Jude Department of Chemical Biology & Therapeutics .
Further, the researchers identified cells where drug resistance could be acquired against the combination therapy following long-term exposure. They found that resistance was mediated by the BCL-2 protein family, which helps regulate cell death, and could be mitigated therapeutically.
The findings provide a strong rationale for continuing investigation into this treatment approach for rhabdoid tumors, especially ATRT. "ATRT is an intractable disease in very young children, so we hope there will be interest in pursuing this combination therapy," Roussel said. "The data we have seen in support of this is very convincing."
Shelat noted that "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."
Authors and funding
The study's co-first authors are Alaa Refaat, Justin Williams and Jennifer Stripay, St. Jude; and Hyekyung Cho, Vanderbilt University School of Medicine, formerly of St. Jude. The study's other authors are Kaley Blankenship, Kimberly Mercer, Rebekah DeVries, Michele Connelly, Sarah Robinson, Evan Savage, Nathaniel Twarog, Ayush Attery, Dipranjan Laha, Kaiwen Yu, Suresh Poudel, Sandeep Dhanda, Clinton Stewart, Burgess Freeman III, Charles Roberts, Christopher Tinkle and Elizabeth Stewart, St. Jude; Santosh Upadhyaya, University of Michigan, formerly of St. Jude; and Debolina Ganguly, AstraZeneca, formerly of St. Jude.
The study was supported by Cookies for Kids, the National Institutes of Health (CA-096832 and CA-02165) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
