High-risk neuroblastoma is an aggressive, highly chemoresistant childhood tumour. These patients will receive intensive, multi-modal therapy, although relapse with treatment resistant disease occurs in up to 50% of cases.
We recently utilised mathematical modelling and longitudinal single-cell imaging to demonstrate that a non-genetic form of chemoresistance can arise in neuroblastoma through the impact of gene expression noise upon the stochastic nature of apoptotic signalling (Hastings*, Latham*, 2023, Science Advances). Within treatment naïve neuroblastomas, priming with the histone deacetylase (HDAC) inhibitor Vorinostat could overcome this chemoresistance and sensitise tumours to treatment with specific standard-of-care chemotherapies.
In order to further rationalise the inclusion of HDAC inhibitors with a wider range of standard-of-care chemotherapy treatments for high-risk neuroblastoma patients, we have now undertaken a functional analysis of a panel FDA-approved HDAC inhibitors. By using established high content imaging and applying multi-omics approaches, this analysis has demonstrated that HDAC inhibitors with differing specificity are capable of eliciting a diverse range of cell behaviour in neuroblastoma tumours, which impacts the manner in which they should be deployed in a clinical setting.
A key observation from this study was that the HDAC inhibitors Belinostat and Vorinostat did not directly induce apoptosis, but readily primed the cells to allow for sensitisation to standard-of-care chemotherapies. These differing functional outcomes were also associated with unique histone acetylation patterns and mechanistically coherent transcriptional changes as determined by RNAseq analysis.
These mechanistic insights are now being leveraged to design rationalised treatment regimens that combine these HDAC inhibitors with standard-of-care chemotherapies. These optimal combinations are currently being tested within patient derived xenograft models, in order to identify approaches capable of improving survival outcomes for high-risk neuroblastoma patients.