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Updated: Nov 25, 2025
Small Molecule Screening and Toxicity Testing in Early-stage Zebrafish Larvae
Published on: March 7, 2025
Zebrafish as an in vivo screening tool to establish PARP inhibitor efficacy
Jeroen Vierstraete1, Charlotte Fieuws2, Andy Willaert3
1Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Department of Human Structure and Repair, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University and Ghent University Hospital, Ghent, Belgium.
Abstract:
Double strand break (DSB) repair through Homologous Recombination (HR) is essential in maintaining genomic stability of the cell. Mutations in the HR pathway confer an increased risk for breast, ovarian, pancreatic and prostate cancer. PARP inhibitors (PARPi) are compounds that specifically target tumours deficient in HR. Novel PARPi are constantly being developed, but research is still heavily focussed on in vitro data, with mouse xenografts only being used in late stages of development. There is a need for assays that can: 1) provide in vivo data, 2) early in the development process of novel PARPi, 3) provide fast results and 4) at an affordable cost. Here we propose a combination of in vivo zebrafish assays to accurately quantify PARP inhibitor efficacy. We showed that PARPi display functional effects in zebrafish, generally correlating with their PARP trapping capacities. Furthermore, we displayed how olaparib mediated radiosensitization is conserved in our zebrafish model. These assays could aid the development of novel PARPi by providing early in vivo data. In addition, using zebrafish allows for high-throughput testing of combination therapies in search of novel treatment strategies.
Insights
Zebrafish models offer a fast, affordable way to test new cancer drugs. These in vivo assays can evaluate PARP inhibitors (PARPi) early in development, aiding the discovery of novel cancer treatments.
Area of Science:
- Genomic stability and cancer biology
- Pharmacology and drug development
Background:
- Homologous Recombination (HR) is crucial for repairing DNA double-strand breaks (DSBs) and maintaining genomic stability.
- Defects in HR increase susceptibility to various cancers, including breast, ovarian, pancreatic, and prostate.
- Poly(ADP-ribose) polymerase inhibitors (PARPi) target HR-deficient tumors, but their development relies heavily on early-stage in vitro data.
Purpose of the Study:
- To develop and validate in vivo zebrafish assays for early, rapid, and cost-effective evaluation of PARP inhibitor (PARPi) efficacy.
- To assess the utility of zebrafish models for preclinical testing of novel PARPi and combination therapies.
Main Methods:
- Utilized in vivo zebrafish assays to quantify the functional effects of PARP inhibitors (PARPi).
- Correlated observed effects with the PARP trapping capacities of tested PARPi.
- Investigated the conservation of olaparib-mediated radiosensitization in the zebrafish model.
Main Results:
- PARPi demonstrated measurable functional effects in zebrafish, generally aligning with their PARP trapping potencies.
- Olaparib-induced radiosensitization was successfully replicated in the zebrafish model, confirming its utility.
- Zebrafish assays provide early in vivo data crucial for novel PARPi development and high-throughput screening of combination therapies.
Conclusions:
- In vivo zebrafish assays offer a valuable platform for the early assessment of PARP inhibitor (PARPi) efficacy.
- This model facilitates rapid, cost-effective evaluation, potentially accelerating the development of new cancer therapeutics.
- Zebrafish enable high-throughput screening for combination therapies, paving the way for novel treatment strategies against HR-deficient cancers.
