“PBT-SCREEN”, a high-throughput screening platform to identify new therapeutic agents for Medulloblastoma Group 3

Abstract

Abstract Background Pediatric brain tumors (PBTs) represent about 25% of all pediatric cancers and are the most common solid tumors in children and adolescents. Medulloblastoma (MB) is the most frequently occurring malignant PBT, accounting for almost 10% of all pediatric cancer deaths. MB Group 3 (MB G3) accounts for 25–30% of all MB cases and has the worst outcome, particularly when associated with MYC amplification. However, no targeted treatments for this group have been developed so far. PBTs differ significantly from their adult counterparts in terms of driver genetic mutations, origin, and tumor microenvironment. As a result, drugs approved for adults often fail to be effective or lead to undesirable toxicity in children. Methods We have used a broad panel of pediatric MB G3 and healthy human cell lines to develop in vitro efficacy and toxicity assays, both in 2D and 3D and in high-throughput screening (HTS) format. A pilot HTS campaign with 1.280 lead-like compounds was performed to validate the screening platform. Results We have set up, optimized, and validated 2D and 3D efficacy and toxicity models ensuring that they correctly identify positive and negative compounds, and a high reproducibility, so they could be used in our screening platform. PBT-SCREEN was further validated by conducting a pilot HTS campaign, detecting 8 active compounds against MB cell lines. All detected hits were acting via caspase activation. Compounds targeted 6 MB-related cancer targets, some of them currently approved or in clinical trials in pediatric patients with PBTs, including MB. Hits were then combined, identifying 3 synergistic combinations, one currently being studied in the clinics for recurrent MB and other PBTs. Conclusion We have set up and validated PBT-SCREEN, an HTS pediatric platform specifically designed to identify new therapies for MB G3 patients. PBT-SCREEN accounts for tumor heterogenicity, limited efficacy, and unacceptable toxicity from the very early stage of drug development, which makes it an ideal in vitro tool to develop new drugs that are not only effective but safer for children with medulloblastoma. Its versatility extends to various PBTs, therefore providing targeted therapies to pediatric brain tumors that are crucial.