Zebrafish could help researchers develop treatments for childhood cancers
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James Amatruda, MD, PhD, never set out to become a fish farmer.
“My goal is not to cure a fish; it’s to cure a child,” Amatruda, head of basic and translational research for the Cancer and Blood Disease Institute and Dr. Kenneth O. Williams chair in cancer research at Children’s Hospital Los Angeles, told Healio. “I see the impact these cancers have on children and their families every day, and that spurs to us to go back to the laboratory and work that much harder.”
As it turns out, much of the hard work at Amatruda’s lab involves some incidental fish farming — in fact, his 3,000-square-foot facility is designed to house up to 120,000 zebrafish. The cancer researcher chose the zebrafish model for its anatomical similarity to humans, a fact that may surprise some.
“The more we look at it, the more we realize just how similar humans and zebrafish are,” Amatruda said. “About 80% of human genes have a direct equivalent in the zebrafish and when we look at disease-causing genes, the similarities are even greater.”
Amatruda spoke with Healio about the value of zebrafish models in understanding pediatric cancers, the major progress that has been made in treating these cancers, and the potential future implications of his research.
Healio: You have said that progress in treating pediatric solid tumor cancers has hit a plateau. Why do you think that is?
Amatruda: Through many careful studies and clinical trials and the introduction of new chemotherapy drugs and combinations of chemotherapy, radiation and surgery, the survival rates and outcomes for these solid tumors in children have improved dramatically. However, we’re getting to the point where we can’t increase the intensity of those therapies much more because of concerns about toxicity and side effects. These are short- and long-term effects that will impact the quality of life of children who have survived cancer. So, although we’re very grateful to be able to apply these therapies, we really need to do better in curing patients and minimizing toxicity in tumors that can be treated effectively with chemotherapy.
Healio: What makes zebrafish such a good model for studying the development of tumors during childhood?
Amatruda: Cancers in children are often related to problems during fetal development of organs such as the kidney or liver, or bone or muscle. Under normal circumstances, that growing tissue is supposed to slow down and start taking on the mature function of a muscle cell, or kidney or liver cells. In childhood cancers, very often that process is somehow disrupted, which can lead to a tumor. By studying those mechanisms even in normal development, we can gain incredible insight into how cancers develop. That’s really what led us to using the zebrafish as a model system, because that experimental model organism is extremely well-suited to studying the process of normal development. We can literally start with the first cell and watch that development happen. We can mimic what we think are the causes of childhood cancer and watch those same types of tumors develop in the fish. The zebrafish is very similar to humans in terms of its anatomy, physiology and disease susceptibility. The zebrafish can be models not only of cancer, but also of diabetes, neurodegeneration, inflammatory diseases, infections, skeletal problems and cardiovascular defects.
Healio: Can you describe the work you have done on fusion oncogenes?
Amatruda: Fusion genes is the term we use when two pieces of different DNA chromosomes break apart and then fuse together. When that happens, very often an abnormal protein is made, one that’s never present in normal cells but combines parts of two different proteins. It becomes a new protein that can act as a cancer driver gene. These occur both in leukemia and solid tumors. We have been studying the ones that occur in sarcomas. In the past, we’ve done some work on rhabdomyosarcoma, which is caused by the PAX3-FOXO1 fusion gene. In that case, we used the zebrafish system to learn how those tumors develop. More recently, we focused on Ewing sarcoma, which is the tissue often found in bone and sometimes in soft tissue. This is caused by the EWS-FLI1 fusion oncogene.
EWS-FLI1 was discovered about 30 years ago and, unfortunately, we still don’t have a very specific treatment that targets it. We discovered that, under certain conditions, introducing the EWS-FLI1 gene into zebrafish will cause them to develop a tumor that is strikingly similar to human Ewing sarcoma. So, that’s a very exciting advance.
We’re using this system now for several purposes; one is to study how these tumors developed, starting at a single-cell level all the way up to a fully formed tumor. We are also looking at how the tumor interacts with surrounding nontumor cells, and we can use this system to test new potential therapies. The fish are small, they grow quickly, and we have the potential to grow hundreds of thousands of fish. We are fortunate to work not only within our own lab, but as part of a large international cooperative group trying to attack this problem. Now, we can bring to the table this unique animal model that mimics so many features of the human disease.
We’re working with collaborators, for example, at The University of Texas Southwestern Medical Center in Dallas, where they are searching large chemical laboratories for potential inhibitors of EWS-FLI1. Our goal is to apply those inhibitors to the fish model to validate whether it has an impact on the tumors.
Healio: What is next in your research with this system?
Amatruda: I think we are almost at the starting line of using this model to drive progress in the field. We’re taking on several parallel tracks, one of which is screening any available drugs that might be effective therapies for Ewing sarcoma.
We also now have a unique chance to look at how the immune system might affect the growth and spread of Ewing sarcoma tumors. Immuno-oncology has been incredibly important in childhood leukemia and in lung cancer, melanoma and some other tumors. It’s never worked very well for Ewing sarcoma or other cancers, and we don’t know enough about why that is. So, we are quite dedicated to using this model to study the impact of the immune system on growth of the tumors.
Lastly, one of the biggest problems we face in the clinic is taking care of children in whom the tumor has metastasized to other tissues. Those tumors are very difficult to treat and do not respond well to our current therapy. We are thinking about ways we can use the zebrafish system to study how it is that the metastatic cell is able to break away from the main tumor, move to a different part of the body, and “set up shop” to grow a secondary tumor there. We’d like to understand how that process occurs so we can design better treatments to target it. The fish system enables us to study very directly the interaction of a tumor cell with the cells around it. We also want to study the signaling events that allow the tumor cells to adapt and survive. We think that knowledge may also tell us something about metastasis in other cancer types.
For more information:
James Amatruda, MD, PhD, can be reached at Children’s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027.
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