Bold claim: A breakthrough combo therapy may change the game for a devastating pediatric brain cancer. That’s the core takeaway you’ll want to remember as you read on. But here’s where it gets controversial: can a two-drug strategy across the brain realistically overcome the barriers that have stymied prior efforts? Let’s dive in and unpack the latest findings, the practical hurdles, and what they might mean for families and clinicians.
Researchers at St. Jude Children’s Research Hospital have identified a promising combination approach to treat atypical teratoid rhabdoid tumor (ATRT), a rare yet highly aggressive pediatric brain cancer. In laboratory models, reactivating and sustaining the tumor-suppressing protein p53 with idasanutlin and selinexor, respectively, was well tolerated, reduced tumor burden, and extended survival. The team also mapped a potential resistance pathway and proposed strategies to counteract it. The work was published in Neuro-Oncology Pediatrics.
ATRT affects fewer than 100 children each year in the United States and carries historically poor outcomes, underscoring an urgent need for new treatments. Prior evidence showed that increasing p53 levels with idasanutlin can be effective against rhabdoid tumors outside the brain (malignant rhabdoid tumors, MRT), but ATRT presents an added challenge: the blood-brain barrier must be crossed to reach brain tumors. Additionally, single-agent use of idasanutlin has been linked to tumor resistance in other contexts, raising questions about durability.
Co-corresponding author Martine Roussel, PhD, from St. Jude’s Department of Tumor Cell Biology, summarized the current landscape: “None of the treatments tried so far have worked.” The new study proposes that combining two mechanisms to boost p53 activity could overcome some of these obstacles and yield meaningful tumor control.
Combination therapy increases tumor cell death
In ATRT and MRT mouse models, the combo therapy substantially improved survival. Idasanutlin inhibits MDM2, a protein that targets p53 for degradation; by preventing p53 turnover, the p53 pathway remains active. Selinexor blocks XPO1, a transport protein that shuttles p53 out of the nucleus. By hitting p53 from two angles, the researchers hypothesized a stronger and more durable anti-tumor effect.
Co-corresponding author Anang Shelat, PhD, noted that both drugs reached brain concentrations sufficient to trigger a robust p53 response, supporting the rationale for their combined use in brain tumors.
The team also examined how resistance might develop with prolonged exposure. They found that the BCL-2 family of proteins, which governs cell death, can mediate resistance to this combination. Importantly, they outlined therapeutic strategies to mitigate or overcome this resistance mechanism.
Implications and future directions
Taken together, the findings provide a compelling rationale for continuing investigation of this dual-drug approach for rhabdoid tumors, especially ATRT. Roussel stressed the urgency: ATRT is an intractable disease in very young children, and the current data are strong enough to warrant further pursuit of this therapy. She noted that the observed efficacy and brain penetrance are particularly noteworthy.
Shelat added that the incidence of p53 mutations is lower in children compared with adults. This suggests that combination strategies like the one studied could have broad applicability for pediatric cancers, potentially benefiting a larger group of young patients beyond ATRT.
Authors and funding
Co-first authors include Alaa Refaat, Justin Williams, and Jennifer Stripay (St. Jude); Hyekyung Cho (Vanderbilt University School of Medicine, formerly St. Jude). Additional St. Jude contributors 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. Santosh Upadhyaya (University of Michigan, formerly St. Jude) and Debolina Ganguly (AstraZeneca, formerly St. Jude) are also listed among the authors.
The study was supported by Cookies for Kids, the National Institutes of Health (grants CA-096832 and CA-02165), and ALSAC, the fundraising and awareness organization for St. Jude.
Context and continuing work
St. Jude Children’s Research Hospital remains at the forefront of pediatric cancer research, with a mission to turn scientific discoveries into practical treatments for children worldwide. The researchers’ next steps will likely involve refining dosing, optimizing brain delivery, and testing strategies to counteract resistance in preclinical models, with the goal of advancing toward clinical trials.
If you found this exploration provocative, you’re not alone. Do you think dual-targeted approaches like this should be prioritized in pediatric oncology research, even when they involve complex mechanisms and potential side effects? How should researchers balance aggressive innovation with careful safety monitoring when treating very young patients? Share your thoughts in the comments.
Media contact: St. Jude Media Relations, Chelsea Bryant (desk: 901-595-0564; cell: 256-244-2048; chelsea.bryant@stjude.org)
Notes
St. Jude emphasizes its role as a leading, NCI-designated Comprehensive Cancer Center dedicated to children, with a long history of advancing treatments that have improved survival rates from about 20% to 80% over six decades. For more information, visit stjude.org.
