High-risk neuroblastoma is an aggressive, childhood tumour with high rates of chemoresistance. These patients receive an intensive regimen of multi-agent chemotherapy, although ~15% of patients will not respond to treatment, and a further 40-50% of patients will relapse following an initial response.
Aiming to understand the mechanisms underlying this chemoresistance, we previously demonstrated that in silico, patient-specific modelling of chemotherapy-induced apoptotic JNK signalling can stratify neuroblastoma patient cohorts and provide robust biomarkers of patient survival (Fey et al., 2015, Science Signaling). More recently, we adapted this patient-level model to provide single-cell simulations of drug response (Hastings*, Latham* et al., Science Advances, in revision). By combining these simulations with high-content biosensor imaging, we revealed that populations of individual cells within neuroblastoma tumours are innately JNK-impaired and chemoresistant.
Through single-cell drug screens, we also demonstrated that priming treatment naïve neuroblastomas with the HDAC inhibitor Vorinostat can sensitise these JNK-impaired cells to chemotherapy, but this drug-resistant state becomes enriched and intractable within relapsed tumours. Therefore, we have now performed in depth drug screening using a panel of FDA-approved HDAC inhibitors within high content imaging-based functional assays, along with the quantification of histone acetylation, RNAseq and ChIPseq, to delineate the mechanism of action through which HDAC inhibitors sensitise neuroblastoma cells to chemotherapy.
Importantly, this work has identified an alternative class of HDAC inhibitors that are capable of directly inducing apoptosis in neuroblastoma cells in a manner that bypasses the need for JNK activation. We are now using this data to develop a rationalised guide towards personalised epigenetic drug combinations that can improve chemotherapy response in both primary and relapse settings for high-risk neuroblastoma patients.