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Published on: April 10, 2020
Developing a Novel Embryo-Larval Zebrafish Xenograft Assay to Prioritize Human Glioblastoma Therapeutics
Leah Christine Wehmas1, Robert L Tanguay1, Alex Punnoose2
11 Department of Environmental and Molecular Toxicology, Oregon State University , Corvallis, Oregon.
Abstract:
Glioblastoma is an aggressive brain cancer requiring improved treatments. Existing methods of drug discovery and development require years before new therapeutics become available to patients. Zebrafish xenograft models hold promise for prioritizing drug development. We have developed an embryo-larval zebrafish xenograft assay in which cancer cells are implanted in a brain microenvironment to discover and prioritize compounds that impact glioblastoma proliferation, migration, and invasion. We illustrate the utility of our assay by evaluating the well-studied, phosphatidylinositide 3-kinase inhibitor LY294002 and zinc oxide nanoparticles (ZnO NPs), which demonstrate selective cancer cytotoxicity in cell culture, but the in vivo effectiveness has not been established. Exposures of 3.125-6.25 μM LY294002 significantly decreased proliferation up to 34% with concentration-dependent trends. Exposure to 6.25 μM LY294002 significantly inhibited migration/invasion by ∼27% within the glioblastoma cell mass (0-80 μm) and by ∼32% in the next distance region (81-160 μm). Unexpectedly, ZnO enhanced glioblastoma proliferation by ∼19% and migration/invasion by ∼35% at the periphery of the cell mass (161+ μm); however, dissolution of these NPs make it difficult to discern whether this was a nano or ionic effect. These results demonstrate that we have a short, relevant, and sensitive zebrafish-based assay to aid glioblastoma therapeutic development.
Insights
A new zebrafish xenograft model accelerates glioblastoma drug discovery. This assay rapidly identifies compounds impacting cancer growth and spread, offering a faster path to new brain cancer therapeutics.
Area of Science:
- Neuroscience
- Oncology
- Biotechnology
Background:
- Glioblastoma is an aggressive brain cancer with limited treatment options.
- Current drug discovery timelines are lengthy, delaying patient access to novel therapies.
- Zebrafish xenograft models offer a promising avenue for accelerating drug development.
Purpose of the Study:
- To develop and validate a novel embryo-larval zebrafish xenograft assay for glioblastoma.
- To assess the assay's utility in discovering and prioritizing therapeutic compounds.
- To evaluate the effects of LY294002 and zinc oxide nanoparticles (ZnO NPs) on glioblastoma in vivo.
Main Methods:
- Development of an embryo-larval zebrafish xenograft model with implantation in the brain microenvironment.
- Quantification of glioblastoma proliferation, migration, and invasion in response to tested compounds.
- Evaluation of a phosphatidylinositide 3-kinase inhibitor (LY294002) and ZnO NPs.
Main Results:
- LY294002 significantly decreased glioblastoma proliferation (up to 34%) and inhibited migration/invasion (∼27-32%).
- ZnO NPs unexpectedly enhanced glioblastoma proliferation (∼19%) and migration/invasion (∼35%).
- The observed effects of ZnO NPs require further investigation to distinguish nano- vs. ionic effects.
Conclusions:
- The developed zebrafish xenograft assay is a rapid, relevant, and sensitive tool for glioblastoma drug development.
- The assay can effectively prioritize compounds for further therapeutic investigation.
- Findings highlight the potential and challenges of using nanoparticles in glioblastoma treatment.
