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.

通过同源重组 (HR) 修复双链断裂 (DSB) 对于维持细胞的基因组稳定性至关重要。HR 通路中的突变会增加患乳腺癌、卵巢癌、胰腺癌和前列腺癌的风险。PARP 抑制剂 (PARPi) 是专门针对 HR 缺陷肿瘤的化合物。新型 PARPi 正在不断开发中，但研究仍主要集中在体外数据上，小鼠异种移植物仅用于开发后期。需要能够：1) 提供体内数据，2) 在新型 PARPi 开发过程的早期，3) 提供快速结果和 4) 以可承受的成本提供的分析。这里我们建议结合体内斑马鱼测定以准确量化 PARP 抑制剂的功效。我们表明 PARPi 在斑马鱼中显示出功能效应，通常与它们的 PARP 捕获能力相关。此外，我们展示了 olaparib 介导的放射增敏在我们的斑马鱼模型中是如何保守的。这些测定可以通过提供早期的体内数据来帮助开发新型 PARPi 。此外，使用斑马鱼可以对联合疗法进行高通量测试，以寻找新的治疗策略。