Abstract
Abstract Pediatric brain cancers cause the highest rate of mortality amongst all childhood cancers. Most high-grade gliomas are difficult to treat mainly due to impermeability across the blood-brain barrier, or systemic toxicity. Here, we explore the benefits of zebrafish to assess drug toxicity, orthotopic pediatric brain cancer model development and drug screening. We assessed the toxicity of eight anti-cancer drugs with diverse mechanisms of action. In addition to the survival assay (LC50), we analyzed other teratogenic characteristics to demonstrate the detrimental developmental toxicity, which was critical in determining drug safety for future human usage. To develop fast and reproducible orthotopically xenografted pediatric brain cancer models, we injected approximately 80-100 mCherry expressing JHH-NF1-PA1 and TM-31 cells into the midbrain of 2 days post-fertilization (dpf) zebrafish embryos and imaged daily for next 4 days to monitor the survival, progression, and invasion of the injected cells. Our results show that both cell types were engrafted successfully and multiplied inside the developing zebrafish brain. As compared to JHH-NF1-PA1 cells, which mostly migrated caudally within the developing spinal cord, TM-31 migrated in multiple directions and metastasized five times more rapidly. To check the efficiency of VAL-083 and AZD-1775 in high-grade glioma, 2 dpf zebrafish embryos were injected with mCherry expressing HGG cells, SF8628. At one day post-injection (dpi), the xenografted embryos were exposed to different combinations of Val-083 and AZD-1775 for 72 hours. After 4 dpi, tumor cell invasion and migration in zebrafish were quantified. We found that the combination group had the lowest tumor burden with significantly lower fluorescence intensity, total area of migration, and reduced number of metastatic cells (p<0.001) compared to single or no drug treatment groups. Our study showed that zebrafish is a valuable, rapid, and cost-effective in-vivo pediatric brain cancer pre-clinical model to assess tumor proliferation, metastasis, and rapid drug screening.
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