Researchers have discovered increased amounts of a specific type of DNA known as extrachromosomal DNA (ecDNA) in tumors that are more aggressive and at advanced stages of cancer, suggesting these could be potential targets for new treatments. They observed that tumors from patients who had previously undergone treatment contained significantly higher levels of ecDNA, which may provide those tumors with a survival advantage.
Researchers from Yale School of Medicine have identified that advanced and aggressive cancers possess a higher level of extrachromosomal DNA (ecDNA), which could make them candidates for new therapeutic approaches.
By analyzing data from resources such as The Cancer Genome Atlas, the International Cancer Genomics Consortium, the Hartwig Medical Foundation, and the Glioma Longitudinal Analysis Consortium, the researchers examined over 8,000 tumor samples. These samples included both newly diagnosed untreated tumors and those that had undergone past treatments like chemotherapy and radiation. They found that ecDNA levels were significantly elevated in tumors from previously treated patients, leading to the hypothesis that ecDNA may provide these tumors with a competitive advantage in surviving.
“Our research indicates that ecDNA contributes to the aggressiveness of tumors,” explained Roel Verhaak, the study’s senior author and the Harvey and Kate Cushing Professor of Neurosurgery at Yale School of Medicine, who is also affiliated with the Yale Cancer Center. “EcDNA has a unique mechanism and is influential across various cancer types, not just breast or lung cancer.”
This study highlighted that ecDNA is more frequently found after taxol-based treatments, including docetaxel and paclitaxel, which are common in multiple cancer therapies. Moreover, the researchers noted that in longitudinal studies of the same cancer, ecDNA was more likely to persist compared to changes in standard chromosomes.
In the advanced cancers examined, ecDNA was seen to undergo rapid mutations. The researchers propose that these “hypermutations” could explain why certain cancers become increasingly aggressive and harder to treat over time. The mutations present in ecDNA may enable cancer cells to adapt and thrive better than normal cells. The aim is that this research can contribute to the creation of more effective cancer treatments.
“In our laboratory, we are leveraging drug libraries to identify agents that specifically target cells containing ecDNA,” stated Verhaak. “Our goal is to uncover vulnerabilities in tumors with ecDNA, as therapies directed at ecDNA could potentially help a third of all cancer patients.”
Verhaak also mentioned that there are clinical trials currently underway that focus on therapies specifically designed to target ecDNA in tumors.
Kevin Johnson from the Yale Cancer Center collaborated with Verhaak as a co-author on this study. Soyeon Kim and Hoon Kim, a former postdoctoral researcher in the Verhaak lab and now a professor at Sungkyunkwan University in Seoul, South Korea, were also significant contributors to this research.
