Groundbreaking research reveals how to target malignant DNA in aggressive cancers

Scientists have discovered a way to target the elusive circular pieces of DNA that determine the survival of some of the most aggressive cancers, paving the way for future therapies.

In three groundbreaking papers published today in Naturescientists from the Cancer Grand Challenges eDyNAmiC team and their international collaborators from the Francis Crick Institute and University College London (UCL) are shedding lithe on the unique behavior of extrachromosomal DNA (ecDNA), diminutive, circular DNA structures that are common in some of the most difficult-to-treat cancers.

The papers show for the first time how to target cancer cells containing this malignant DNA. This discovery may significantly facilitate the future treatment of aggressive cancers such as glioblastoma multiforme, triple-negative breast cancer and diminutive cell lung cancer.

The study reveals how common ECDNA is in various types of cancer and explains how it enables tumors to rapidly change their genome to resist treatment.

In one paper, researchers identified a drug that specifically targets and kills ecDNA-containing cancer cells while sparing normal cells.

The eDyNAmiC team is funded by Cancer Grand Challenges, a research initiative co-founded by Cancer Research UK and the National Cancer Institute in the US, and developed by an international team including scientists from Stanford Medicine, the Francis Crick Institute and UCL.

The up-to-date papers reveal more about the structure of ecDNA and highlight how future cancer drugs could target it to stop the disease.

Many of the most aggressive cancers depend on ECDNA for survival, and as these cancers progress, ECDNA makes them more resistant to treatment, leaving patients with few options. By targeting ecDNA, we could cut the slack for these inexorable cancers, turning a terrible 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 we were missing something very essential. The discovery of extrachromosomal DNA – how common it really is and what it actually does – reveals a up-to-date level of complexity in cancer evolution. It not only facilitates rapid genetic changes, but also highlights the clever strategies cancer cells apply to evade treatment, suppress the immune system and outlive the benefits for patients suffering from the most aggressive forms of cancer.”

Our DNA is usually stored in structures called chromosomes, which are found in almost every cell in the body. They ensure that when cells divide, their DNA will be accurately copied into up-to-date cells.

However, ecDNA exists outside the chromosomes, in diminutive circles of false genetic material. These escaped particles carry essential cancer-causing genes and do not follow the same rules as chromosomal DNA, allowing cancer cells to adapt quickly, evade treatment and grow uncontrolled.

The presence of ecDNA in normal human cells is sporadic, and when it occurs, it is often associated with certain diseases or abnormal cellular processes.

Dr. Mischel’s lab at Stanford University first discovered the key role that ecDNA plays in the evolution and treatment resistance of aggressive cancers in a groundbreaking 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-authors Dr Howard Chang and Dr Mariam Jamal-Hanjani, to advance our understanding of ecDNA .

The papers published today highlight some of the most essential discoveries made by the CGC eDyNAmiC team, which includes scientists from 13 research institutes around the world.

Key takeaways from each article:

Article 1: UNIQUE ECDNA BIOLOGY

ecDNA plays a unique and cluttered role in cancer. Unlike the structural 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 cancer by allowing it to grow rapidly, spread aggressively, and develop resistance to treatment.

• The open structure of ecDNA allows uncomplicated access to the cellular machinery responsible for transforming 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 up-to-date cells together, breaking the usual rules of genetic inheritance and allowing cells to inherit multiple benefits at once. In other cases, ecDNAs are distributed unevenly during cell division, causing greater differentiation. Together, these processes facilitate cancer cells adapt and grow faster than normal cells.
• Scientists have determined that ecDNA may contain “altruistic oncogenes” that exist only to promote the activity of other cancer genes.
• Overall, ecDNA’s flexibility and rapid structural changes make it a powerful tool that enables cancer cells to adapt and survive in challenging environments.

Article 2: ECDNA IMPACT ON THE CLINIC

Patients with ECDNA-containing tumors generally have worse outcomes, and the amount of ECDNA tends to raise during treatment, suggesting that ECDNA may play a role in treatment resistance.

Using data from Genomics England’s 100,000 Genomes Project at the National Genomics Research Library, whole genome sequence data from almost 15,000 cancer patients across 39 cancer types were analyzed. Scientists from the Francis Crick Institute and eDyNAmiC have discovered how essential ecDNA is in cancer:

• Nearly 17.1% of tumor samples from this dataset contained ecDNA, with a particularly high percentage observed in breast cancer.
• Most of the cancers included in this dataset were early-stage, suggesting that the true prevalence of ecDNA may be even higher because it is more common in later-stage cancers.
• Certain mutational signatures found in tumor DNA, such as those associated with smoking, correlated positively with the presence of ecDNA.
• They found that ecDNAs not only carry cancer-promoting genes; they also contain genes that facilitate cancer cells evade the immune system. This has essential implications for the response of patients with high ecDNA levels to immunotherapy.

eDyNAmiC researcher at The Francis Crick Institute, Dr Chris Bailey, said:

“This work has shown how common ecDNA is in cancer and how its presence is often associated with poorer patient survival. “We found that in addition to fueling tumor growth, many ecDNAs contain genes that can suppress the immune system, possibly helping tumors evade. This work paves the way for future research aimed at limiting ecDNA replication, with the hope of improving treatment 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 team.

Article 3: FIRST ECDNA-AFFECTING DRUG

The unique biology of ecDNA provides significant benefits to the tumors in which they live, but it also puts a target on their backs. In this paper, researchers identified a drug (BBI-2779, developed by the biotechnology company Boundless Bio) that specifically targets and kills ecDNA-containing cancer cells while sparing normal cells.

In tests in mice, BBI-2779 was effective in reducing tumor growth and preventing 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 DNA.

Two molecular machines move around ecDNA – one copies it and the other reads it to make proteins – but like two trains running on the same track, they must take turns or risk colliding. In cancer cells with ecDNA, this exquisite process is constantly at risk of causing severe DNA damage.

To prevent this, cells rely heavily on CHK1, but when CHK1 is inhibited by BBI-2779, they are unable to repair DNA damage, leading to their death.

CHK1 inhibitors have been in clinical development for some time due to their potential to interfere with cell growth, but the development of BBI-2779 is particularly promising. It is more effective and highly selective and may benefit ecDNA patients by offering a clearer way of identifying patients who may respond best. These advances could pave the way for more targeted treatment options for aggressive cancers.

Building on their work, the team is investigating how ecDNA shuts down the immune system and exploring ways to reactivate it. They are also discovering other convoluted mechanisms related to ecDNA, hoping to find applications in up-to-date treatments.

Boundless Bio is continuing this research to determine whether BBI-2779 will have the same effect in humans. ​