New biomarker predicts therapy response for hard-to-treat childhood cancers
· News-MedicalA study by researchers at the University of Birmingham has identified a new biomarker for response to a specific cancer therapy, treating children with Ewing Sarcoma and other tumor types.
The study, which is a Phase I/II treatment arm within the eSMART Trial, carried out at the Cancer Research UK Clinical Trials Unit (CRCTU) with Gustave Roussy as international sponsor, recruited 70 patients, and of those 66 were treated across four countries (the UK, France, the Netherlands and Spain). All these patients had solid tumors, 36 had Ewing Sarcoma and 34 had various other tumor types, mainly types of sarcoma and central nervous system tumors.
Patients' tumors included Ewing Sarcoma and other cancers such as:
- osteosarcoma, a type of bone cancer,
- neuroblastoma, a tumor arising from the adrenal gland or sympathetic chain,
- rhabdomyosarcoma, a tumor arising from the soft tissue mimicking skeletal muscle,
- nephroblastoma, a tumor of the kidney,
- medulloblastoma, a tumor of the brain, and
- choroid plexus carcinoma, a much rarer brain tumor affecting 4 patients per year in the UK.
The chances of a cure for these types of tumors significantly decreases to less than 30% if the cancer has spread or recurs - when patients were enrolled in eSMART they had relapsed several times and although the trial may induce some response, a cure was not expected.
Researchers wanted to understand if the combination of a low dose or irinotecan (a chemotherapy drug commonly used in pediatric cancers) and a PARP inhibitor (a DNA repair inhibitor used in treatment of various cancer in adults) would be tolerated and effective in treating pediatric cancers. The researchers also wanted to investigate if there was a particular sensitivity in tumors with alterations in genes, which may cause faulty DNA repair in Ewing sarcoma, a cancer shown to have similar faulty DNA repair in the lab as adult cancers which respond to PARP inhibitors.
The study found that 12 patients benefitted from this therapy across the different tumor types, either responding with partial or complete tumor shrinkage or showing stable disease for more than six months. Importantly, gene alterations which predicted faulty DNA repair or Ewing sarcoma itself did not predict benefit from therapy.
Crucially, however, retrospective analysis of the patients' tumors who benefitted and the remaining 49 patients' tumors without benefit revealed that a certain change of the tumor genome called aneuploidy was distributed differently between all patients, with those patients whose cancers had a high aneuploidy score significantly more likely to benefit from therapy.
The impact of this study lies in its potential to change how clinicians approach treatment for children with high-risk, relapsed cancers; clinicians may now be able to determine in advance whether advanced therapies-specifically PARP inhibitors-will be effective for a specific child." Dr Louise Hopkins, Trial Management Team Leader for the Children's Cancer Trial Team at the Cancer Research UK Clinical Trials UnitThis study is a major breakthrough in pediatric oncology because it provides a potential roadmap for personalising treatment in some of the most difficult-to-treat childhood cancers.
Dr Susanne Gatz, Associate Clinical Professor in Pediatric Oncology in the Department of Cancer and Genomic sciences at the University of Birmingham, said: "These are really exciting data, and we are grateful to all the patients and families who enrolled into this study.
"Whilst treatment with specific DNA repair inhibitors such as PARP inhibitors is fully established in specific adult cancer types with specific gene alterations as part of standard of care treatment, we have not yet identified such specific cancer groups in pediatric cancer.
"Having identified high aneuploidy score as a potential biomarker for benefit to DNA repair inhibitor trials in pediatric cancers could identify such a specific cancer group. More research is needed to see if this finding can be translated to other DNA repair inhibitor trials, and to better understand the link between high aneuploidy score and treatment benefit."
This is the first time that aneuploidy score has been associated with response to therapy in a pediatric cancer trial. The high score did not correlate with specific tumor types, but with benefit from this specific therapy, which suggests that a high aneuploidy score could potentially emerge as a biomarker for benefit for other DNA repair inhibitor trials in pediatric cancer. The team hope that this high aneuploidy score could be a wider applicable biomarker, not only for pediatric cancer but also for trials for adult cancers.
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