Zebrafish as an in vivo screening tool to establish PARP inhibitor efficacy

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.

Keywords: Homologous Recombination; Irradiation; PARP inhibitor; Zebrafish.