ecDNA: A New Frontier in Understanding and Treating Cancer

Recent advancements in cancer research have shed light on a cunning trick that tumors use to evade treatment and thrive. This trick involves storing cancer-driving genes in extrachromosomal DNA, or ecDNA, which exists outside the traditional chromosomes. New findings are offering a deeper understanding of how ecDNA not only defies genetic norms but also provides hope for novel treatments to tackle the toughest cancers.

Cancer’s Unconventional Tactics: Using ecDNA to Cheat the System

Cancer has long been known as a disease that "cheats" the body, using various tactics to proliferate despite immune defense mechanisms. One such audacious trick involves cancer-driving genes being stored in circular pieces of DNA outside chromosomes—extrachromosomal DNA (ecDNA). This form of genetic material gives tumors an advantage by boosting the activity of oncogenes that promote growth and resilience. Recent research led by physician-scientist Howard Y. Chang and Paul Mischel, supported by Cancer Grand Challenges and published in a trio of papers on November 6, 2024, illustrates the magnitude of this advantage. Unlike regular human cells that keep their DNA within chromosomes, ecDNA operates in defiance of the traditional genetic rules, significantly contributing to cancer aggressiveness.

The Role of ecDNA in Tumor Growth and Resilience

Normal cells maintain DNA in their chromosomes, but ecDNA circumvents these norms. Chang and Mischel's research team has shown that ecDNA enhances tumor growth by allowing genes to be expressed at levels far higher than if they were on chromosomes. Specifically, they discovered that ecDNA copies of oncogenes produce mRNA four times more effectively compared to those in chromosomes. This enhanced transcription is facilitated through ecDNA's ability to form hubs, where separate molecules of ecDNA interact closely, amplifying gene expression through cooperative mechanisms. This type of behavior helps to fuel cancer growth, making it more resilient to treatment.

Challenging Mendelian Genetics

One of the fascinating aspects of ecDNA is its disregard for Mendel’s third law of independent assortment, which states that genes on the same chromosome are inherited together, while genes on different chromosomes assort independently. Unlike chromosomes, ecDNA lacks centromeres, resulting in a chaotic inheritance process. Surprisingly, Chang and Mischel observed that when cancer cells divide, ecDNA is often inherited together, maintaining the toxic synergy between different oncogenes. This inheritance mechanism gives cancer cells a dangerous edge, allowing them to keep their oncogene copies intact through generations.

Turning Cancer's Strength into Its Weakness

While ecDNA gives cancer a formidable advantage, the research team has also uncovered a potential vulnerability. Chang and Mischel discovered that by inhibiting a cellular enzyme called CHK1, they could disrupt ecDNA’s ability to replicate effectively. This CHK1 inhibitor was found to selectively destroy cancer cells containing ecDNA, especially when combined with the drug infigratinib. This discovery highlights a promising strategy to convert ecDNA’s strength into a weakness, targeting the very transcription machinery that makes it effective. The biotech company Boundless Bio, founded by Chang and Mischel, is already developing therapies focused on this mechanism and is recruiting patients for clinical trials to explore the impact of CHK1 inhibitors in treating advanced cancers.

Implications for Future Cancer Treatments

(photo by National Cancer Institute ) The implications of these findings are significant. The fact that ecDNA is present in over 17% of tumor types, far more than previously thought, suggests that targeting ecDNA could play an essential role in improving cancer outcomes, especially for aggressive cancers that resist conventional treatments. The diversity of ways in which ecDNA contributes to malignancy, from housing oncogenes to including immune-regulating elements, underscores its complexity as a therapeutic target.   Ongoing work by Team eDyNAmiC, including studies into ecDNA in fungi and other systems, aims to further unravel the mysteries of ecDNA and develop new approaches to combat cancer. As research continues, the hope is that these discoveries will translate into real-world solutions for patients who desperately need more effective cancer treatments. Keep an eye on biomed field. As always, investors should conduct their own due diligence and consider their risk tolerance before making investment decisions.