Background
The ZERO Childhood Cancer Program, a national personalised medicine initiative has shown that molecular profiling identifies actionable alterations in approximately 70% of cases. However, approximately 30% of patients lack molecular biomarkers linked to potential drug sensitivities (Mayoh et al., 2023). This study will probe novel drug correlations using an innovative paediatric specific drug library.
Method
High-throughput screening (HTS) of an improved 150-drug library implementing clinically relevant drug concentration ranges was performed on ex vivo patient-derived high-risk tumours (brain tumour, n=27; sarcoma, n=38; solid other, n=4; haematological, n=11; neuroblastoma, n=4). Metabolic activity was measured 72 hours post-treatment by CellTiter-Glo. A custom-made ZERO script was used to establish area under the curve (AUC), half maximal inhibitory concentration (IC50) and half maximal lethal concentration (LC50) values were calculated. Pearson correlation was used to assess drug-drug interactions.
Results
Our comprehensive analysis revealed tumour type-specific vulnerabilities and novel drug-drug sensitivity correlations. Inhibitors targeting the same signalling pathways tended to cluster together, although this varied between tumour types. Notably, brain tumour samples demonstrated differential sensitivity to Mitogen-Activated Protein Kinase signalling pathway (MAPK) inhibitors with strong correlations observed with the JAK/STAT pathway inhibitor ruxolitinib and with xevinapant, a SMAC mimetic that targets anti-apoptotic signalling proteins (XIAP, cIAP1/2).
Conclusion
Our HTS pipeline revealed tumour-type specific sensitivities and novel drug-drug correlations, which may guide future combination efficacy testing and serve as predictive markers for potential drug responses. Further evaluation of the improved ZERO program will uncover additional drug correlations, paving the way for innovative therapies in paediatric cancer