Abstract
Researchers have developed an immune-deficient adult zebrafish model that engrafts a variety of human cancers, allowing them to visualize tumor growth at single-cell resolution and track responses to drug therapy. Using the model, they identified a possible treatment for rhabdomyosarcoma.
Researchers at the Massachusetts General Hospital Research Institute in Boston have developed an immune-deficient zebrafish model that engrafts a variety of human cancers, allowing them to see tumor growth at single-cell resolution and track responses to drug therapy. Using the model, they identified a possible treatment for rhabdomyosarcoma, an aggressive form of cancer that develops in skeletal muscles, with the vast majority of cases occurring in people 18 years old or younger (Cell 2019 Apr 25 [Epub ahead of print]).
The team, led by David Langenau, PhD, and Chuan Yan, PhD, developed a zebrafish deficient in prkdc and il2rga, resulting in a lack of T, B, and natural killer (NK) cells.
“The major innovation was making a compound-mutant zebrafish that lacked both adaptive and NK immune cells—and raising fish at temperatures conducive to human tumor growth,” says Langenau. “It's the first immune-compromised zebrafish model that can robustly engraft and grow human cancers and allows for accurate oraldrug dosing similar to what is achievedin the clinic.”
Human cancers grow with similar kinetics and histology when engrafted into prkdc−/−, il2rga−/− zebrafish. Because the fish are transparent, researchers can assess tumor growth as well as responses to treatment.
Previous studies have shown that human cancers can be engrafted in larval zebrafish prior to development of the adaptive immune system, says Langenau. However, these models sustain tumor growth for only 7 to 10 days, after which immune responses kill off engrafted cells. In addition, larval fish engraft only a small number of cells and are typically raised at lower temperatures than necessary for human tumor growth (<35°C vs. 37°C), so they cannot replicate what happens in humans.
Immune-deficient mouse models are the gold standard for studies involving xenotransplantation, but the animals have inherent limitations, including being expensive to maintain and having fur, which complicates imaging. Using the prkdc−/−, il2rga−/− zebrafish, Langenau's team tested a combination of the PARP inhibitor olaparib (Lynparza; AstraZeneca) plus temozolomide chemotherapy to treat rhabdomyosarcoma and found that it halted tumor growth. They repeated the study in mouse models and got the same results.
Researchers are now trying to add patients with rhabdomyosarcoma to an ongoing phase II trial that's evaluating the drug combination in patients with Ewing sarcoma.
The prkdc−/−, il2rga−/− zebrafish could dramatically lower the cost and scale of large drug studies, notes Cecilia Moens, PhD, of Fred Hutchinson Cancer Research Center in Seattle, WA. Besides being less expensive to maintain compared with immune-compromised mouse models, zebrafish are translucent, allowing researchers to see drug activity in the animals' bodies in real time.
“The ability to image tumor cells while animals are still alive—and monitor how they respond to treatment—is extremely powerful,” she says. “In addition, working with adult fish opens up new opportunities for us to visualize tumor–host interactions throughout both the innate and adaptive immune systems.”
The findings also have significant implications for the future of personalized therapy, says Langenau. “The dream is to be able to implant a patient's own tumor into zebrafish, treat them with available therapies, and return that information to clinicians to inform clinical care,” he says. “It's precision-guided medicine using zebrafish avatars.” –Janet Colwell
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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