Table of Contents
- 0.1 Particularly common in aggressive types of cancer
- 0.2 Active brakes for the immune system
- 0.3 DNA rings act together
- 0.4 New active ingredient specifically kills ecDNA cancer cells
- 1 What are the potential ethical considerations surrounding the use of CHK1 inhibitors to target ecDNA, especially in light of their potential impact on healthy cells with ecDNA?
Cancer cells with helpers: Researchers have discovered why some cancer tumors barely respond to cancer therapies and the immune system. They contain small, extrachromosomal rings of DNA that make these cancer cells more resistant and aggressive. Because these DNA rings not only contain cancer genes and their amplifiers – they also inhibit the immune system and even act together. The good news: There is a drug that can eliminate this ecDNA along with its carrier cancer cells.
The genetic material of our cells actually lies in our chromosomes – they divide the almost two meter long DNA strand into packages and ensure that the genome is correctly distributed to both daughter cells during cell division. But in cancer cells there is also extrachromosomal DNA. Some of these ecDNA rings carry several cancer genes, others only carry regulatory sections or DNA of unknown function. What is striking, however, is that cancer tumors with many of these DNA rings often grow particularly aggressively and respond less well to cancer therapies.
A research team led by Paul Mischel from Stanford University has now explained why and how DNA rings can make cancer more stubborn and aggressive. For their study, they examined tumor cells from almost 15,000 cancer patients and 39 different types of cancer. They determined whether and which DNA rings were present in the cancer cells, what these extrachromosomal pieces of genetic code encode and how they behave during cell division.
Particularly common in aggressive types of cancer
The first result: Although the DNA rings only occur in around 17 percent of all cancer cells on average, they are significantly more common in some types of cancer. In aggressive HER2+ breast cancer, for example, almost half of the cancer cells carry this extrachromosomal DNA, as Mischel and his team found. The same applies to glioblastomas of the brain and the also aggressive, rapidly metastasizing liposarcoma. For intestinal adenocarcinomas it is a good 37 percent and for bladder cancer, ovarian cancer and some lung tumors it is a good 20 percent.
The analyzes also showed that cancer cells in later stages of tumor development and even after chemotherapy contain more DNA rings than before. Their presence is also usually associated with metastases and a poorer chance of survival, as the team determined. “This gives us a completely new view of a common and aggressive mechanism that drives cancer,” says Mischel.
Active brakes for the immune system
The second surprise: The DNA rings in the cancer cells not only contain cancer genes and amplifiers, but also gene sequences that actively inhibit the immune response to the cancer. “34 percent of tumors with ecDNA carry additional copies of immunomodulatory genes in the DNA rings,” report the researchers. These genes disrupt the activation of nearby lymph nodes, block immune messengers and inhibit the cancer-destroying T-killer cells.
DNA rings act together
The third surprise: The extrachromosomal DNA rings do not act individually, but can form groups that complement each other. “Several ecDNAs that originally emerged from different chromosomal loci can coexist in the same cancer cell and then often assemble into micrometer-sized clumps in the cell nucleus,” Mischel and his team explain. DNA rings with regulatory sequences have an activating effect on the ecDNA with cancer genes or immunomodulatory genes.
And that’s not all: These mutually supporting DNA rings are also disproportionately often inherited together when cancer cells divide. “That was a huge surprise,” says Mischel. “It contradicts Mendel’s rule, according to which genes that are not on a common chromosome are inherited independently of each other.” Instead, the cancer cells seem to prefer to pass on the ecDNA combinations that are favorable for them to daughter cells.
“Daughter cells that repeatedly inherit advantageous combinations of DNA rings should actually be rare if their inheritance is truly independent,” says co-senior author Howard Chang of Stanford University. “But we are seeing far more of these ‘jackpot events’. This has enormous benefits for the cancer cells.”
New active ingredient specifically kills ecDNA cancer cells
But there is also some positive news: Mischel and his team have also discovered how to kill tumor cells using extrachromosomal DNA. Because there is an active ingredient that exploits a weakness in the ecDNA-containing cancer cells. The code of their circular pieces of DNA is read almost constantly – even during cell division. This makes these cancer cells vulnerable to agents that inhibit a protein, CHK1, that is important for this process.
In initial tests, this CHK1 inhibitor inhibited the tumor growth of cancer cells containing ecDNA by 64 to 97 percent. “This suggests that the next generation of such CHK1 inhibitors could be a promising strategy against ecDNA-containing cancers,” write the researchers. The first clinical studies have already begun. (Nature, 2024; two: 10.1038/s41586-024-08107-3; two: 10.1038/s41586-024-07861-8; two: 10.1038/s41586-024-07802-5)
Quelle: Stanford Medicine
November 26, 2024 – Nadja Podbregar
What are the potential ethical considerations surrounding the use of CHK1 inhibitors to target ecDNA, especially in light of their potential impact on healthy cells with ecDNA?
## World Today News – Interview: Extrachromosomal DNA and the Future of Cancer Treatment
**Hosts:** Welcome to World Today News, where we delve into the latest scientific breakthroughs impacting our lives. Today, we’re discussing a groundbreaking discovery regarding cancer treatment: Extrachromosomal DNA (ecDNA) and its role in cancer aggression and resistance.
**Guests:** Joining us are Dr. Emily Carter, a leading oncologist specializing in aggressive cancers, and Dr. Alex Chen, a geneticist at the forefront of ecDNA research.
**Section 1: Understanding ecDNA**
* **Host:** Dr. Chen, could you explain what ecDNA is and how it differs from the DNA found in our chromosomes?
* [Dr. Chen explains ecDNA as separate, circular pieces of DNA outside the chromosomes, often containing cancer genes and amplifiers.]
* **Host:** This sounds incredibly complex. Dr. Carter, what is the significance of ecDNA in terms of cancer development and progression?
* [Dr. Carter discusses how ecDNA is linked to more aggressive cancers, resistance to therapies, and poorer patient outcomes.]
**Section 2: EcDNA’s Double Threat: Cancer Genes & Immune Suppression**
* **Host:** Dr. Chen, your research suggests that ecDNA does more than just carry cancer genes. Can you elaborate on its dual role in suppressing the immune system?
* [Dr. Chen explains how ecDNA contains genes that hinder immune cell activation and interfere with tumor recognition.]
* **Host:** Dr. Carter, how does this immune suppression impact treatment effectiveness?
* [Dr. Carter discusses how immune evasion by ecDNA-containing tumors makes traditional immunotherapy less effective.]
**Section 3: The Cooperative Nature of ecDNA**
* **Host:** One surprising finding is that ecDNA rings seem to work together. Dr. Chen, can you shed light on this phenomenon?
* [Dr. Chen explains the concept of ecDNA clumps and how different ecDNA rings can complement each other to further drive cancer growth and evade the immune system.]
* **Host**: Dr. Carter, what are the implications of this coordinated behavior for developing targeted therapies?
* [Dr. Carter discusses the challenges posed by this cooperative nature and the need for therapies that target multiple aspects of ecDNA.]
**Section 4: Targeting ecDNA: A New Hope?**
* **Host:** Dr. Chen, your research identified a potential vulnerability in ecDNA-carrying cancer cells. Can you tell us about this discovery?
* [Dr. Chen explains the exploitation of constant ecDNA replication through CHK1 inhibitors.]
* **Host:** Dr. Carter, what does this mean for patients facing aggressive cancers containing ecDNA?
* [Dr. Carter discusses the early clinical trials using CHK1 inhibitors and the potential of this new approach to combat ecDNA-driven cancers.]
**Host:** Thank you, Dr. Chen and Dr. Carter, for illuminating this cutting-edge research and offering a glimpse into the future of cancer treatment. This discovery of ecDNA’s role in cancer development opens up exciting new avenues for research and hope for patients battling this disease. And to our viewers, stay tuned to World Today News for more updates on this groundbreaking development.