High-risk neuroblastoma is an aggressive and invasive paediatric malignancy, with few actionable somatic mutations. As such, intense multi-agent chemotherapy remains the standard-of-care. Unfortunately, only half these children are cured and survivors are at increased risk of serious complications such as deafness, infertility and secondary cancers. As such, there is an urgent need for predictive markers of therapeutic response, to guide rationalised treatment of high-risk neuroblastoma patients.
Failure to effectively activate apoptosis, or the ability to evade apoptosis, has been established as a key mechanism of chemoresistance in neuroblastoma. Despite this, there is little understanding of the apoptotic mechanism-of-action of current standard-of-care drugs, let alone their combined mechanism of action, nor any potential for synergistic/antagonistic interactions. Therefore, the aim of this project is to apply a network-wide, systems level approach to defining the apoptotic mechanisms activated by each of the main standard-of-care neuroblastoma drugs in order to identify patient-specific, synergistic drug combinations, that will be validated in vitro and in PDX models.
The application of such a systems biology approach to innovatively combine pathway-focused patient stratification and mechanism-based drug selection will address fundamental questions about the network level functioning of apoptotic signalling pathways. This will also inform the development of a precision medicine approach that will aim to improve outcomes for high-risk neuroblastoma patients.