Scientists have raised hopes of treating some of the most aggressive cases of cancer by targeting tiny fragments of rogue DNA that cause tumors to thrive and become resistant to chemotherapy.
The breakthrough emerged from a US and British study that found that many difficult-to-treat cancers contained loops of malignant genetic material that were crucial for the tumors to survive and resist treatment.
Tests on 39 different tumor types from almost 15,000 British patients found that more than one in six cancers had extrachromosomal DNA or ecDNA – the loops of genetic code that can make tumors harder to treat.
The analysis shed light on how ecDNA drives cancer growth and resistance and led researchers to identify, in early stages of clinical trials, a new drug that has the potential to selectively destroy affected cells and prevent tumors from growing rapidly. develop resistance.
“It’s an important discovery because this affects many people around the world,” said Paul Mischel, a professor of pathology at Stanford University. “These are the patients who are really suffering 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 located in the cell nucleus. But sometimes fragments break off the chromosomes and form circles of ecDNA that are loose from the chromosomes. Until recently, ecDNA was considered rare and unimportant in the development of cancer.
In three paper published In Nature, the researchers delve deeper into the origins and implications of ecDNA. They found that 17.1% of tumors studied contained ecDNA, with the harmful genetic material more common in certain types of breast, brain and lung cancer.
The ecDNA fragments carry cancer-causing genes and other genes that suppress the immune system. The former stimulate tumor growth, while the latter can help tumors evade the body’s natural defenses and resist modern immunotherapies that aim to focus the immune system’s firepower on cancer cells.
Rapid and chaotic replication of ecDNA also stimulates tumors, the researchers found. When a cancer cell divides, each resulting cell inherits the same number of chromosomes. But if the original cell contains multiple ecDNAs, they can be passed on unevenly, with one of the cells formed by division inheriting more than the other. This increases the genetic diversity of the tumor, increasing its resilience to cancer drugs.
The research, funded by Cancer Grand Challenges, an initiative co-founded by Cancer Research UK and the US National Cancer Institute, suggests that drugs called CHK1 inhibitors can selectively destroy tumor cells containing ecDNA. In experiments with a small number of mice, a CHK1 inhibitor developed by Boundless Bio, a start-up co-founded by Mischel, helped reduce tumors and prevent resistance when given alongside a traditional anti-cancer drug.
“This isn’t just a discovery about what can make cancer so bad, it actually points the way to a new line of therapies,” Mischel said. “There is a path forward for developing new treatments because this type of DNA is different and creates vulnerabilities that are different.”
David Scott, Director of Cancer Grand Challenges at Cancer Research UK, said: “Many of the most aggressive cancers rely on ecDNA for survival, and as these cancers develop, ecDNA drives their resistance to treatment, helping patients have few options left. By targeting ecDNA, we could cut the lifeline of these brutal tumors, turning a dire prognosis into a treatable one.”
Charles Swanton, deputy clinical director at the Francis Crick Institute in London and senior author of one of the papers, said: “This work demonstrates the importance of these circular DNA elements in cancer, and their emerging role in driving fitness of cancer. cells and supports their ability to evade the immune system. We hope that the work described in these three papers will help pave the way for new approaches to limit their origins and impact, ultimately improving sensitivity to cancer drugs and outcomes for patients.”