Glioblastoma (GBM) has the highest prevalence and mortality of all primary brain tumours. New treatments are urgently needed, but more than 90% of novel GBM drugs fail in clinical trials, which is partially due to challenges in preclinical modelling of the blood–brain barrier (BBB). Researchers now endeavour to improve patient-derived orthotopic xenograft (PDOX) models of GBM for rapid screening of novel therapeutics and potential use in “co-clinical trials” to stratify patients for personalised medicine.
Chengjian Zhao and colleagues have thoroughly examined zebrafish GBM xenograft models to assess their validity as drug screening platforms or tools for co-clinical trials. First, the authors injected three established GBM cell lines into zebrafish larvae brain and demonstrated that these cells could robustly propagate in the brain and mirror the infiltration and angiogenic properties that are apparent when the same cells are xenografted into rodent brains. They then examined the zebrafish BBB using fluorescent tracers and single-cell RNA sequencing to conclude that it recapitulates the functional and molecular integrity of human and rodent BBB, as well as the structural changes observed in rodent BBB when interacting with GBM xenografts. Interestingly, the authors treated the zebrafish GBM models with six anticancer drugs and were able to accurately identify known BBB-penetrating drugs that repressed tumour growth.
The authors then proceeded to generate a robust protocol for xenografting primary GBM cells in zebrafish. The zebrafish GBM PDOX (zPDOX) models phenocopied the differing infiltration properties of GBM cells from two patients and unveiled intratumour heterogeneity. They then generated zPDOX models from five patient samples to assess sensitivity to temozolomide, a chemotherapeutic often used to treat GBM. Importantly, short-term exposure to temozolomide in zPDOX was able to accurately predict long-term patient responses to this drug.
Zebrafish have many unique advantages that can complement rodent models of disease. They have immune tolerance, optic transparency allowing in vivo microscopy, and can rapidly generate large cohorts. Zhao and colleagues have now demonstrated that this versatile model can robustly recapitulate human and rodent GBM and GBM–BBB interactions. By expanding these findings with more patient samples, the powerful properties of this model can be harnessed in preclinical and co-clinical trials. This can enable rapid and accurate screening of novel drugs or drug combinations and advance precision medicine for GBM patients.