A new study has identified a strong connection between circular extra-chromosomal DNA (ecDNA) and poor outcomes in solid pediatric tumors, including neuroblastoma and medulloblastoma. The findings, published August 7 in Cancer Discovery, provide a mechanistic explanation for why some childhood cancers respond initially to chemotherapy yet recur years later.
EcDNA are ring-shaped fragments that form when DNA breaks away from chromosomes and is incorrectly reassembled by repair machinery. These elements can carry multiple copies of oncogenes, such as MYCN, driving aggressive tumor growth. Lukas Chavez, associate professor at Sanford Burnham Prebys, said, “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.”
In neuroblastoma, cells harboring high ecDNA MYCN copy numbers proliferate rapidly but are more susceptible to chemotherapy-induced cell death. Cells with fewer MYCN copies on ecDNA enter a senescent state, halting division yet remaining metabolically active. These “zombie” cells evade chemotherapy and can reactivate months or years later, triggering relapse.
Using mouse models, researchers tested a two-pronged treatment: conventional chemotherapy followed by a senolytic therapy to eliminate senescent tumor cells. This combination markedly improved survival compared to chemotherapy alone. Graduate researcher Ashley Hui extended the work to medulloblastoma, showing that ecDNA-linked senescence also occurs in this tumor type.
“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. This study suggests that targeting ecDNA-associated senescence could be a promising strategy for reducing relapse in pediatric cancers that initially respond to treatment.
Publication Details
Montuori G, et al. Extrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers. Cancer Discov 2025; https://doi.org/10.1158/2159-8290.CD-24-1738
EcDNA are ring-shaped fragments that form when DNA breaks away from chromosomes and is incorrectly reassembled by repair machinery. These elements can carry multiple copies of oncogenes, such as MYCN, driving aggressive tumor growth. Lukas Chavez, associate professor at Sanford Burnham Prebys, said, “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.”
In neuroblastoma, cells harboring high ecDNA MYCN copy numbers proliferate rapidly but are more susceptible to chemotherapy-induced cell death. Cells with fewer MYCN copies on ecDNA enter a senescent state, halting division yet remaining metabolically active. These “zombie” cells evade chemotherapy and can reactivate months or years later, triggering relapse.
Using mouse models, researchers tested a two-pronged treatment: conventional chemotherapy followed by a senolytic therapy to eliminate senescent tumor cells. This combination markedly improved survival compared to chemotherapy alone. Graduate researcher Ashley Hui extended the work to medulloblastoma, showing that ecDNA-linked senescence also occurs in this tumor type.
“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. This study suggests that targeting ecDNA-associated senescence could be a promising strategy for reducing relapse in pediatric cancers that initially respond to treatment.
Publication Details
Montuori G, et al. Extrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers. Cancer Discov 2025; https://doi.org/10.1158/2159-8290.CD-24-1738