Neuroblastoma: clinical outcomes and experimental studies on cell signalling

Abstract

Neuroblastoma (NBL) is a solid childhood malignancy associated with survival rate of <50%. The most frequently diagnosed extracranial tumour in the paediatric age group, NBL is widely renowned for its heterogeneity as the tumour exhibits a spectrum of clinical behaviour from chemotherapy resistance to spontaneous regression. In this thesis, firstly, clinical outcomes for NBL are reviewed at a leading UK Children’s Cancer and Leukaemia Group (Alder Hey Children’s Hospital, Liverpool) in the context of evolving therapies for this enigmatic disease. In the second part of this work, building on previous knowledge linking the transcription factor nuclear factor kappa B (NF-κB) with the development of chemoresistance in NBL, this thesis highlights a series of laboratory experiments where a selection of novel pharmacological compounds are screened for their effects on the NF-κB pathway and their ability to induce cell death in NBL cells. A potential synergistic interaction between an NF-κB inhibitor and conventional chemotherapeutic agent is also investigated. The past two decades have observed dramatic intensification of therapy for moderate to high-risk NBL. The clinical outcomes study has highlighted that 5-year survival for advanced stage 3 NBL patients has improved from 25 to 80% over two comparative treatment eras 1985-1994 and 1995-2005. Current opinion is widely divided in the international community over the role of aggressive surgery in highrisk NBL. This study has shown that although we observed a trend towards improved clinical outcomes by achieving complete resection, the benefits were marginal. Experiments on NF-κB manipulation yielded the discovery that inhibition of NF-κB through various pharmacological compounds induced NBL cell death. A potentially synergistic interaction between cancer chemotherapy agent etoposide and an NF-κB inhibitor, H26(S), was observed. Further mechanistic investigations will be required to exploit the therapeutic potential herein described in this work.