Imagine a world where a rare and devastating brain cancer in children could be effectively treated. That’s the promise of a groundbreaking discovery by researchers at St. Jude Children’s Research Hospital, who have identified a potential game-changer for atypical teratoid rhabdoid tumor (ATRT), a condition so rare it affects fewer than 100 children in the U.S. annually. But here’s where it gets even more compelling: their approach involves a combination therapy that not only shows promise in reducing tumor size and extending survival but also tackles the tricky issue of drug resistance head-on.
Published in Neuro-Oncology Pediatrics, the study reveals how the drugs idasantulin and selinexor work together to reactivate and maintain p53, a protein crucial for suppressing tumors. In a laboratory model, this combination was well-tolerated, significantly reduced tumor burden, and increased survival rates. But this is the part most people miss: the researchers also uncovered how cancer cells might develop resistance to this therapy and proposed strategies to counter it.
ATRT is notoriously difficult to treat, with current therapies falling short. As Dr. Martine Roussel, co-corresponding author and part of St. Jude’s Department of Tumor Cell Biology, bluntly puts it, “None of the treatments tried so far have worked.” The challenge is twofold: not only does the treatment need to cross the blood-brain barrier, but drugs like idasantulin, when used alone, have been known to induce resistance in tumors.
So, how does this combination therapy overcome these hurdles? Idasantulin blocks MDM2, a protein that breaks down p53, effectively boosting its levels. Meanwhile, selinexor prevents p53 from being exported out of the cell nucleus, ensuring it stays active. Together, these drugs attack the tumor through two distinct pathways, amplifying their effect on cancer cell death. “Our work confirmed that both drugs reach sufficient concentrations in the brain to trigger a strong p53 response,” explains Dr. Anang Shelat, co-corresponding author from St. Jude’s Department of Chemical Biology & Therapeutics.
But here’s the controversial part: while this therapy shows immense promise, it’s not without challenges. The researchers identified that long-term exposure to the combination could lead to resistance, mediated by the BCL-2 protein family. However, they’ve already outlined therapeutic strategies to mitigate this, raising the question: could this be the breakthrough ATRT patients have been waiting for?
The implications are vast. ATRT primarily affects very young children, and effective treatments are desperately needed. “The data we’ve seen is very convincing,” says Roussel, urging further investigation. Shelat adds a broader perspective: “Compared to adults, p53 mutations are much less common in children, so this combination therapy could have wide-ranging applications in pediatric cancer treatment.”
But what do you think? Is this combination therapy the future of treating ATRT, or are there still too many unknowns? Share your thoughts in the comments below.
The study was led by co-first authors Alaa Refaat, Justin Williams, Jennifer Stripay (St. Jude), and Hyekyung Cho (Vanderbilt University School of Medicine), with contributions from a multidisciplinary team of researchers. Funding was provided by Cookies for Kids, the National Institutes of Health, and the American Lebanese Syrian Associated Charities (ALSAC).
For more information, contact Chelsea Bryant at St. Jude Media Relations:
Desk: (901) 595-0564 | Cell: (256) 244-2048 | chelsea.bryant@stjude.org
St. Jude Children’s Research Hospital continues to pioneer advancements in pediatric medicine, with treatments developed here raising childhood cancer survival rates from 20% to 80% over the past six decades. To learn more about their work, visit stjude.org or follow @stjuderesearch on social media.
