New study explains why neuroblastoma returns years later

Cancer is the leading cause of disease-related death in childhood. This is in part due to cancer-associated genes called oncogenes that can be found far from chromosomes in cell nuclei on ring-shaped DNA inside tumor cells.

Circular extra-chromosomal DNA elements (ecDNA) are pieces of DNA that have broken off normal chromosomes and then been wrongly stitched together by DNA repair mechanisms. This phenomenon leads to circular DNA elements floating around in a cancer cell.

We have shown that these ecDNAs are much more abundant in solid pediatric tumors than we previously thought. And we have also shown that they are associated with very poor outcomes."

Lukas Chavez, PhD, Associate Professor, Cancer Genome and Epigenetics Program, Sanford Burnham Prebys

An international team of scientists published findings on August 7th, 2025, in Cancer Discovery, helping to explain why a common form of pediatric cancer called neuroblastoma is often treated successfully with chemotherapy but prone to relapse in several years.

Cancer cells with many copies of the MYCN oncogene on ecDNA grow quickly but are more easily destroyed by chemotherapy. Tumor cells with fewer copies of the oncogene located on ecDNA enter a zombie-like state known as senescence where they persist but no longer divide to make new cells. These zombie cells are unaffected by chemotherapy and can be reactivated a year or two later, triggering the cancer to relapse.

The researchers demonstrated that combining standard chemotherapy with a secondary therapy able to target senescent cancer cells led to dramatically improved outcomes in tests on mouse models of neuroblastoma.

Ashley Hui, a graduate student in the Chavez lab, contributed to this study by showing that the phenomenon of zombie cells with low amounts of ecDNA carrying MYCN can also be observed in medulloblastoma, the most common malignant brain tumor type in children.

"By integrating genomic analyses of tumor DNA with hypothesis-driven functional experiments and high-throughput drug screening, we aim to discover new drugs and drug combinations that halt tumor growth by eliminating these oncogenic DNA circles," said Chavez, a co-author of the study.

"Ultimately, our goal is to translate these scientific advances into more effective therapies and lasting cures for children with brain cancer."