A study by researchers at the University of Birmingham has identified new biomarkers that indicate response to certain cancer treatments for treating children with Ewing’s sarcoma and other tumor types.
The study, the Phase I/II treatment arm of the eSMART trial, was conducted at the Cancer Research UK Clinical Trials Unit (CRCTU) with international sponsor Gustave Roussy and recruited 70 patients, 66 of whom were treated in four countries (UK, France, Netherlands and Spain). All of these patients had solid tumors, with 36 having Ewing’s sarcoma and 34 having various other tumor types, primarily sarcomas and central nervous system tumors.
The patient’s tumors included Ewing’s sarcoma and other cancers, including:
- Osteosarcoma, a type of bone cancer
- neuroblastoma, a tumor arising from the adrenal gland or sympathetic chain;
- rhabdomyosarcoma, a tumor that arises from soft tissue that mimics skeletal muscle;
- nephroblastoma, kidney tumor,
- medulloblastoma, brain tumor,
- Choroid plexus cancer is an extremely rare brain tumor that affects four people a year in the UK.
If the cancer metastasizes or comes back, the chance of cure for these types of tumors is significantly reduced to less than 30%. When the patient was enrolled in eSMART, he had relapsed several times, and while this trial might induce some kind of response, there was no hope of a cure.
Researchers wanted to understand whether the combination of low-dose irinotecan (a chemotherapy drug commonly used in childhood cancers) and PARP inhibitors (DNA repair inhibitors used to treat a variety of cancers in adults) would be tolerated and effective in treating childhood cancers. The researchers also wanted to investigate whether tumors with genetic changes had a particular susceptibility. Ewing’s sarcoma, which has been shown in the lab to have DNA repair defects similar to adult cancers that respond to PARP inhibitors, can cause DNA repair defects.
The study found that 12 patients benefited from this therapy across a variety of tumor types, responding with partial or complete tumor regression or exhibiting stable disease for more than six months. Importantly, genetic changes that predicted DNA repair defects or Ewing’s sarcoma itself did not predict benefit from treatment.
Importantly, however, a retrospective analysis of the tumors of patients who responded and the remaining 49 patients who did not respond revealed that certain changes in the tumor genome, called aneuploidy, were distributed differently among all patients, with patients whose cancers had higher aneuploidy scores responding significantly better to treatment.
This study is a major advance in pediatric oncology because it provides a potential roadmap to personalize treatment in some of the most difficult-to-treat childhood cancers.
The impact of this study is that it could change the way clinicians approach treatment for children with high-risk, recurrent cancer. Clinicians may now be able to determine in advance whether advanced therapies, particularly PARP inhibitors, will work for a particular child. ”
Dr Louise Hopkins, Trial Management Team Leader, Children’s Cancer Trials Team, Cancer Research UK Clinical Trials Division
Dr Suzanne Gatz, Clinical Associate Professor, Pediatric Oncology, School of Cancer and Genome Sciences, University of Birmingham, said: “These are really interesting data and we are grateful to all the patients and families who took part in this study.”
“While treatment with specific DNA repair inhibitors, such as PARP inhibitors, is well established as part of standard of care in certain adult cancer types with specific genetic mutations, we have not yet identified such specific groups of cancers in childhood cancers.
“The identification of high aneuploidy scores as a potential biomarker of benefit for DNA repair inhibitor testing in pediatric cancers may help identify such specific cancer groups. Further research is needed to see if this finding can be applied to other DNA repair inhibitor testing and to better understand the association between high aneuploidy scores and treatment efficacy.”
This is the first time that aneuploidy score has been associated with response to treatment in a pediatric cancer clinical trial. Although this high score did not correlate with a specific tumor type, it did correlate with benefit from this particular therapy, suggesting that high aneuploidy scores may emerge as a biomarker of benefit for other DNA repair inhibitor trials in childhood cancers. The research team hopes that this high aneuploidy score may become a more broadly applicable biomarker not only for pediatric cancers but also for adult cancer clinical trials.
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Reference magazines:
Guts, SA, others. (2026). Phase I/II study of the PARP inhibitors olaparib and irinotecan in children and young adults with relapsed/refractory malignancies: Arm D of the AcSé-ESMART trial. Clinical cancer research. DOI: 10.1158/1078-0432.CCR-25-3767. https://aacrjournals.org/clincancerres/article-abstract/32/7/1210/775515/Phase-I-II-Study-of-the-PARP-Inhibitor-Olaparib?redirectedFrom=fulltext
