Scientists have discovered a way to target elusive circular DNA fragments that drive survival of some of the most aggressive cancers, paving the way for future treatments.
In three groundbreaking papers published today in Naturescientists from the Cancer Grand Challenges eDyNAmiC team and their international collaborators at the Francis Crick Institute and University College London (UCL) shed light on the unique behavior of extrachromosomal DNA (ecDNA), the small, circular DNA structures common to some of the most difficult cancers to treat.
The papers identify, for the first time, how to target specific cancer cells that contain this malignant DNA, a finding that could make aggressive cancers – such as glioblastoma, triple-negative breast cancer or small cell lung cancer – much easier to treat in the future.
The research reveals how ecDNA is common to all types of cancer and explains how it allows tumors to rapidly change their genomes to resist treatment.
In one paper, the researchers identified a drug that specifically targets and kills cancer cells that contain ecDNA, while sparing normal cells.
Team eDyNAmiC is funded through Cancer Grand Challenges, a research initiative co-founded by Cancer Research UK and the National Cancer Institute in the US and produced by an international team including scientists at Stanford Medicine, the Francis Crick Institute and UCL.
The new publications reveal more about the structure of ecDNA and highlight how future cancer drugs may target it to stop the disease in its tracks.
Many of the most aggressive cancers depend on ecDNA for survival, and as these cancers progress, ecDNA increases their resistance to treatment, leaving patients with few options. By targeting ecDNA, we could cut off the lifeline of these relentless tumors, turning a dire prognosis into a treatable one.”
Dr David Scott, Director of Cancer Grand Challenges, Cancer Research UK
eDyNAmiC team leader and Professor of Pathology at Stanford Medicine, Dr Paul Mischel, said:
“We thought we understood the structure of cancer genomes, but in fact, something very important was missing. The discovery of extrachromosomal DNA, how common it really is and what it actually does, reveals a new layer of complexity in cancer development. Not only does it facilitate rapid genetic changes, but it also highlights the cunning strategies cancer cells use to evade treatment, suppress the immune system and provide a survival benefit for patients with the most aggressive forms of cancer.”
Our DNA is usually stored in structures called chromosomes and found in almost every cell in the body. They ensure that when cells divide, their DNA is accurately copied into new cells.
However, ecDNA exists outside the chromosomes in tiny circles of rogue genetic material. These escaped particles carry important cancer-causing genes and don’t follow the same rules as chromosomal DNA, allowing cancer cells to adapt quickly, evade treatments and grow out of control.
The presence of ecDNA is rare in normal human cells and when it occurs, it is often associated with certain diseases or abnormal cellular processes.
Dr Mischel’s lab at Stanford first discovered the critical role ecDNA plays in the progression and treatment resistance of aggressive cancers in a landmark paper published in 2014.
In 2022, the Cancer Grand Challenges (CGC) initiative awarded £20 million to Dr Mischel and a team of internationally recognized experts, including co-leads Dr Howard Chang and Dr Mariam Jamal-Hanjani, to improve our knowledge of the ecDNA. .
The papers published today represent some of the most important discoveries to come from the CGC eDyNAmiC team, which is made up of scientists from 13 research institutes around the world.
Key findings from each article:
Paper 1: THE UNIQUE BIOLOGY OF ECDNA
ecDNA plays a unique and chaotic role in cancer. Unlike the structured replication of normal DNA, ecDNA replicates in a rapid and unpredictable manner, dramatically changing its genetic makeup in just a few generations. This chaos benefits the tumor, allowing it to grow quickly, spread aggressively, and develop resistance to treatments.
- The open structure of ecDNA provides easy access to the cellular machinery responsible for converting genes into proteins that perform functions in the cell. This enhances the activity of cancer-promoting genes within the tumor.
- Some ecDNA can be passed on to new cells together, breaking the normal rules of genetic inheritance and allowing cells to inherit multiple benefits at once. In other cases, ecDNAs are unevenly distributed during cell division, creating greater diversity. Together, these processes help cancer cells adapt and grow faster than normal cells.
- The researchers found that ecDNA may contain “altruistic oncogenes” that exist only to promote the activity of other cancer genes.
- Overall, the flexibility and rapid structural changes of ecDNA make it a powerful tool for cancer cell adaptation and survival in challenging environments.
Presentation 2: THE IMPACT OF ECDNA IN THE CLINIC
Patients with ecDNA-containing cancers generally have worse outcomes, and the amount of ecDNA tends to increase during treatment, suggesting that ecDNA may play a role in treatment resistance.
Using data from Genomics England’s 100,000 Genomes Project housed at the National Genomics Research Library, whole genome sequence data from almost 15,000 cancer patients across 39 tumor types were analysed. Researchers from the Francis Crick Institute and eDyNAmiC discovered how important ecDNA is in cancer:
- Almost 17.1% of tumor samples from this data set contained ecDNA, with particularly high rates observed in breast cancer.
- Most of the cancers in this data set were early-stage, suggesting that the true prevalence of ecDNA may be even higher, as it tends to occur more frequently in later-stage cancers.
- Some mutational signatures found in tumor DNA, such as those associated with smoking, were positively associated with the presence of ecDNA.
- They found that ecDNAs don’t just carry cancer-promoting genes. they also harbor genes that help cancer cells evade the immune system. This has important implications for how well patients with high levels of ecDNA will respond to immunotherapies.
eDyNAmiC researcher at the Francis Crick Institute, Dr Chris Bailey, said:
“This work showed how common ecDNAs are in cancer and how their presence is often associated with poorer patient survival. We found that, in addition to increasing cancer, many ecDNAs carry genes that can suppress the immune system, possibly helping tumors to avoid immune detection. This work paves the way for future research aimed at limiting ecDNA replication, with the hope of improving outcomes for cancer patients.”
This work comes from the Cancer Evolution and Genome Instability Laboratory led by Professor Charles Swanton at the Francis Crick Institute, in collaboration with the eDyNAmiC group.
Paper 3: THE FIRST ECDNA-TARGETING DRUG
The unique biology of ecDNA provides significant advantages for resident tumors—but also paints a target on their backs. In this paper, the researchers identified a drug (BBI-2779, developed by the biotech company, Boundless Bio) that specifically targets and kills cancer cells that contain ecDNA, while protecting normal cells.
In tests with mice, BBI-2779 effectively reduced tumor growth and prevented resistance to another anticancer drug used in the study.
BBI-2779 works by targeting a protein called CHK1, which plays a protective role when ecDNA copies its own DNA.
Two molecular machines race along the ecDNA – one copies it, the other reads it to make proteins – but like two trains running along a track, they must take turns or risk colliding. In cancer cells with ecDNA, this delicate process is constantly at risk of causing severe DNA damage.
To prevent this, the cells rely heavily on CHK1, but when CHK1 is inhibited with BBI-2779, they are unable to repair the DNA damage, resulting in their death.
CHK1 inhibitors have been in clinical development for some time due to their ability to interfere with cell growth, but the development of BBI-2779 is particularly promising. It is more powerful and highly selective and could benefit patients with ecDNA by offering a clearer way to identify patients who may respond better. This advance could pave the way for more targeted treatment options for aggressive cancers.
Based on their work, the team is investigating how ecDNA turns off the immune system and exploring ways to reactivate it. They also reveal other complex mechanisms associated with ecDNA, in the hope that these could be targeted by new therapies.
Boundless Bio is continuing this research to determine whether BBI-2779 will have the same effect in human patients. ,
