None of the treatments tried so far have worked.
Each year, fewer than a hundred American children are handed a diagnosis that has historically offered little more than grief — atypical teratoid rhabdoid tumor, a brain cancer that has resisted nearly every treatment medicine has tried. Researchers at St. Jude Children's Research Hospital have now identified a two-drug combination that reawakens the body's own cellular defenses, achieving meaningful results in laboratory models and opening a path toward clinical trials. In the long human struggle against childhood cancer, this moment represents not a victory, but a credible reason to keep fighting.
- A cancer affecting fewer than a hundred children a year has remained stubbornly lethal, leaving families and physicians with almost nowhere to turn.
- Two drugs — idasantulin and selinexor — work in tandem to restore p53, the cell's natural tumor-suppressing guardian that this cancer effectively silences.
- Both drugs were confirmed to cross the blood-brain barrier and reach therapeutic concentrations, a critical hurdle that has defeated many promising treatments before them.
- In mouse models, tumors shrank and survival extended significantly, giving researchers enough confidence to begin planning clinical trials.
- The team also mapped the resistance pathways most likely to emerge — proteins in the BCL-2 family — and proposed strategies to block them before they can undermine the therapy's gains.
Fewer than a hundred children in the United States are diagnosed each year with atypical teratoid rhabdoid tumor, a brain cancer so aggressive that doctors have largely exhausted their options. Now researchers at St. Jude Children's Research Hospital have found something that works in the laboratory: a two-drug combination that reactivates the body's own tumor-suppressing machinery and, in mouse models, extends survival significantly.
The drugs are idasantulin and selinexor, and together they target a protein called p53 — a cellular guardian that this cancer effectively silences. Idasantulin blocks MDM2, which normally degrades p53, while selinexor blocks XPO1, which expels p53 from the cell nucleus where it does its work. By attacking the problem from two angles, the researchers built p53 to levels sufficient to kill tumor cells. Critically, both drugs were confirmed to cross the blood-brain barrier and reach effective concentrations — a challenge that has defeated many candidates before them.
Rather than stopping at promising results, the team looked ahead to the problem of resistance. They identified BCL-2 proteins as a likely escape mechanism and outlined strategies to block that route, laying groundwork for a more durable treatment. Co-author Martine Roussel noted that nothing tried so far has worked, while co-author Anang Shelat observed that because p53 mutations are rare in children, this approach could have applications well beyond this single disease. The data, Roussel said, is convincing enough to pursue clinical trials — and for the families who receive this devastating diagnosis each year, that possibility represents something that has been scarce: hope.
Fewer than a hundred children in the United States are diagnosed each year with atypical teratoid rhabdoid tumor, a brain cancer so aggressive and so resistant to treatment that doctors have largely exhausted their options. The disease strikes young children. The outcomes have been grim. Now researchers at St. Jude Children's Research Hospital have found something that works in the laboratory: a two-drug combination that reactivates the body's own tumor-suppressing machinery and, in mouse models, extends survival significantly.
The drugs are idasantulin and selinexor. Together, they work on a protein called p53, which normally acts as a cellular guardian, stopping tumors before they start. In atypical teratoid rhabdoid tumors, this guardian has been silenced. Idasantulin blocks a protein called MDM2, which ordinarily breaks down p53 and removes it from circulation. Selinexor blocks a different protein, XPO1, which shuttles p53 out of the cell nucleus where it does its work. By attacking the problem from two angles at once, the researchers reasoned, they could build up p53 to levels high enough to kill tumor cells.
The challenge with treating brain tumors is getting drugs across the blood-brain barrier, the body's natural filter that keeps most medications from reaching the brain. Idasantulin has already shown promise against rhabdoid tumors that occur outside the central nervous system, in soft tissues. But brain tumors are different. The St. Jude team confirmed that both drugs achieve sufficient concentrations in the brain to trigger a strong p53 response. In their mouse models of both brain and soft-tissue rhabdoid tumors, the combination therapy worked. Tumors shrank. Survival improved.
But the researchers did not stop at success. They looked ahead to the problem that has plagued single-drug treatments: resistance. Over time, tumor cells adapt and learn to survive the assault. The team identified the mechanism by which cells might develop resistance to this combination—a family of proteins called BCL-2 that regulate whether cells live or die. They also outlined strategies to block that escape route, laying groundwork for a more durable treatment.
Martine Roussel, a co-author of the study published in Neuro-Oncology Pediatrics, put the stakes plainly: none of the treatments tried so far have worked. Anang Shelat, another co-author, noted that mutations in p53 are far less common in children than in adults, which means this kind of combination strategy might have applications far beyond atypical teratoid rhabdoid tumors. The data, Roussel said, is convincing enough to pursue this approach in clinical trials. For the fewer than a hundred families each year who receive a diagnosis of this intractable disease, that possibility represents something that has been scarce: hope.
Citas Notables
ATRT is an intractable disease in very young children, so we hope there will be interest in pursuing this combination therapy. The data we have seen in support of this is very convincing.— Martine Roussel, St. Jude Department of Tumor Cell Biology
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.— Anang Shelat, St. Jude Department of Chemical Biology & Therapeutics
La Conversación del Hearth Otra perspectiva de la historia
Why does the blood-brain barrier matter so much here? Idasantulin already works against rhabdoid tumors outside the brain.
Because the brain is sealed off. Most drugs can't cross that barrier. You can have a perfect drug that works everywhere else in the body and it just bounces off the brain. That's why the researchers had to verify that both drugs actually reach the tumor in sufficient amounts.
So they proved the drugs get there. But why combine them instead of using one?
Single drugs fail because tumors adapt. They develop resistance. By hitting p53 from two different angles at once—blocking the protein that destroys it and blocking the protein that exports it—you're making it much harder for the cancer to escape. You're not just raising p53 levels, you're raising them through redundant pathways.
The researchers found a resistance mechanism anyway. Doesn't that undermine the whole approach?
Actually, it strengthens it. They didn't just identify the problem—they outlined how to block it. They're not pretending this is a silver bullet. They're showing they understand the next move the cancer will try to make, and they have strategies ready.
What makes this different from other pediatric cancer research?
Children rarely have p53 mutations. Adults with cancer often do. That means this strategy might work across many childhood cancers, not just this one rare tumor. You're potentially unlocking a whole class of treatments.
How close are we to actual patients?
This is still laboratory work—mouse models. But the data convinced the researchers it's time to move toward clinical trials. For a disease where nothing has worked, that's significant.