Scientists have raised hopes of treating some of the most aggressive cancers by targeting small fragments of rogue DNA that help tumors thrive and become resistant to chemotherapy.
The breakthrough arose from a US-UK study which found that many hard-to-treat cancers contained loops of malignant genetic material that were essential for the tumors to survive and resist treatment.
Tests on 39 different tumor types from nearly 15,000 UK patients revealed that more than one in six cancers extrachromosomal DNAor ecDNA – the loops of genetic code that can make tumors more difficult to treat.
The analysis shed light on how ecDNA drives cancer growth and resistance and led researchers to identify a new drug, already in early-stage clinical trials, that has the potential to selectively destroy affected cells and prevent tumors from rapidly growing develop resistance.
“This is an important discovery because it affects many people around the world,” said Paul Mischel, a professor of pathology at Stanford University. “These are the patients who really suffer because they don’t respond to our current therapies and their tumors are so aggressive.”
Most genes in human cells are carried on 23 pairs of chromosomes that sit inside the cell nucleus. But sometimes fragments break off the chromosomes and form circles of ecDNA that sit apart from the chromosomes. Until recently, ecDNA was considered rare and unimportant in the development of cancer.
In three papers published in Nature, the researchers take a deep dive into the origins and implications of ecDNA. They found that 17.1% of the tumors studied contained ecDNA, with the rogue genetic material being more common in specific forms of breast, brain and lung cancer.
The ecDNA fragments carry cancer-driving genes and other genes that suppress the immune system. The former encourages tumor growth while the latter can help tumors evade the body’s natural defenses and resist modern immunotherapies aimed at directing the immune system’s firepower at cancer cells.
Rapid and chaotic replication of ecDNA also drives tumors, the researchers found. When a cancer cell divides, each resulting cell inherits the same number of chromosomes. But if the initial cell contains multiple ecDNAs, it can be passed on unevenly, with one of the cells formed by division inheriting more than the other. This increases the tumor’s genetic diversity, increasing its resilience to cancer drugs.
Funded by Cancer Grand Challenges, an initiative jointly founded by Cancer Research UK and the US National Cancer Institute, the research suggests that drugs called CHK1 inhibitors can selectively destroy tumor cells that contain ecDNA. In experiments on a small number of mice, a CHK1 inhibitor developed by Boundless Bio, a start-up founded by Mischel, helped shrink tumors and prevent resistance when combined with a traditional anti – cancer drug is given.
“This is not only a discovery about what can make cancer so bad, it actually points the way to a new set of therapies,” Mischel said. “There is a way forward for the development of new treatments because this type of DNA is different and it creates vulnerabilities that are different.”
David Scott, the director of Cancer Grand Challenges at Cancer Research UK, said: “Many of the most aggressive cancers depend on ecDNA for survival, and as these cancers progress, ecDNA drives their resistance to treatment, leaving patients with few options late. By targeting ecDNA, we can cut the lifeline of these relentless tumors, turning a dire prognosis into a treatable one.
Charles Swanton, the deputy clinical director at the Francis Crick Institute in London and a senior author on one of the papers, said: “This work demonstrates the importance of these circular DNA elements in cancer, and their emerging role in the driving the fitness of cancer cells and supporting their ability to evade the immune system We hope that the work outlined in these three papers will help pave the way for new approaches to limiting their origin and impact, to ultimately improve cancer drug sensitivity and outcomes for patients.”
