Nervous system cancers, leukemias, and sarcomas are the most prevalent cancer types in children and adolescents, and they contribute significantly to increasing their mortality.
Pediatric cancers exhibit differences at the genetic level compared to the same form of adult disease, which may influence the selected treatment. Children and adolescents lack robust preclinical models to replicate the pathologies and provide precise and targeted therapies. This is why not many Pharma companies specifically specialize in discovering and developing pediatric cancer treatments; a great example of advancing new therapies for childhood cancer is the biotech Oncoheroes.
How can research boost the discovery of specific therapies for childhood and adolescent cancers?
Zebrafish Pioneers Advance in Pediatric Cancer Research and Treatment
Increasing the survival rate is the primary goal when screening for cancer drugs. Some pediatric cancers, such as leukemias, present a high survival percentage with the available treatment regimens but cause systemic toxicities, and a subset of patients eventually relapse.
Zebrafish have high genetic homology with humans (>70%), allowing them to develop histologically and genetically similar tumors. This New Alternative Model (NAM) provides a platform for High-Content Screening through disease modeling through the transplantation of primary patient tumors into immunocompromised lines. Zebrafish models have been developed for pediatric leukemia, brain tumors, sarcomas, germ-cell tumors, or neuroblastoma.
A drug developed to treat pediatric hematopoietic malignancies is one of the first treatments discovered in Zebrafish that has reached the bedside. This treatment was developed by performing a chemical screening on zebrafish. Leonard Zon’s research group, an expert in Zebrafish research at Harvard Medical School, and a doctor at Boston’s Children’s Hospital found that prostaglandins upregulate blood stem cells, boosting their engraftment after transplantation. This drug, ProHema®, is now in phase II clinical trial to improve engraftment of hematopoietic stem cells upon bone marrow transplant.
Zebrafish Xenografts for Pediatric Cancers: Where Are We?
Patient-derived xenografts (PDXs) go one step further and generate a patient’s avatar mimicking their tumor in vivo in the whole animal environment. They are valuable for evaluating potential therapeutic interventions and advancing our understanding of tumor behavior. They consist of the implantation of human-established cancer cells, patient-derived cancer cells, or tumor tissues into an animal model.
Mice are the gold standard for PDX generation, but some limitations open the door to using NAMs), such as Zebrafish.
As of 2023, there are more than 40 genetically engineered tumor models and numerous zebrafish xenograft models, encompassing patient-derived xenografts implanted in embryos and adult fish.
If we talk specifically about PDX for pediatric cancers, the models developed are few. However, Zebrafish continues to provide reliable evidence to position as a strong NAM, and new PDXs for common cancers in childhood have been created to help mimic their specific response better.
The first orthotopic xenograft model of pediatric brain tumors in zebrafish was generated in 2015. Mouse cancer cells of various types, including glioma, were implanted into the cerebrum via intranasal route of a 30 days post-fertilization (dpf), immunosuppressed zebrafish. Diverse studies have followed using human transplanted cells into zebrafish to mimic glioblastoma, central nervous system tumors, or medulloblastoma, most in embryo/larvae stage at 2 dpf.
These studies affirm the zebrafish xenografts as a robust model for comprehending the fundamental mechanisms behind the development of pediatric tumors. Additionally, they function as a highly effective screening platform for assessing new therapeutic agents or more personalized treatments.
Mouse vs. Zebrafish PDXs for Cancer Modeling
Nowadays, thinking about xenograft for cancer modeling unequivocally leads to thinking about immunodeficient mice for cancer cell transplantations. Although murine models are highly extended, the immunosuppression process takes 2-8 months before treatments. In the case of zebrafish embryos, the adaptative immune system is not fully developed until four weeks post-fertilization, which provides a short window, up to 7-10 days, for studying human cancer development.
Tumor establishment is also time-consuming in murine models, from weeks to months, while zebrafish offer a tumor development process that takes days to weeks. More time equals more resources and elevated costs, turning Zebrafish into a time and cost-effective alternative. Murine xenografts also require a large number of patient samples for engraftment. Zebrafish require much less material to assess the drug toxicity and efficacy, and their easy breading and rearing allow High-Content Screenings, helping to speed up the selection of promising anticancer drugs.
Zebrafish cost-effectivity is also supported by its transparency, which allows in vivo tracking of the engrafted cells at high resolution, directly by microscopy. Murine models require creating a surgical image window for long-term intravital imaging and using multi-photon imaging techniques, which increases costs.
The most important benefit of the Zebrafish system to pediatric cancer research is the ability to develop rare tumor subtypes in a timely and affordable manner for preclinical Drug Discovery.
Conclusion
Integrating Zebrafish models in pediatric cancer research marks a transformative stride toward more effective and tailored treatments. Their unique advantages, including genetic similarity to humans, rapid tumor development, and time and cost-effectiveness, position them as great New Alternative Models for oncology, especially pediatric oncology.
As we navigate the complexities of these challenging diseases, zebrafish provide a practical and efficient platform for research and promise to significantly impact the trajectory of treatment outcomes for young patients. The Zebrafish xenografts study advances our understanding and fosters innovation in pursuing improved care and, ultimately, better lives for affected children and adolescents.
Sources
Basheer F, Dhar P, Samarasinghe RM. Zebrafish Models of Paediatric Brain Tumours. IJMS. 2022;23(17):9920.
Casey MJ, Stewart RA. Pediatric Cancer Models in Zebrafish. Trends in Cancer. 2020;6(5):407-18.
Yin J, Zhao G, Kalirai H, Coupland SE, Jochemsen AG, Forn-Cuní G, et al. Zebrafish Patient-Derived Xenograft Model as a Preclinical Platform for Uveal Melanoma Drug Discovery. Pharmaceuticals. 2023;16(4):598.
