Targeting the apoptosis pathway to treat tumours of the paediatric nervous system

Abstract

New, more effective therapeutics are required for the treatment of paediatric cancers. Current treatment protocols of cytotoxic treatments including chemotherapy trigger cancer-cell death by engaging the apoptosis pathway, and chemotherapy efficacy is frequently impeded by apoptosis dysregulation. Apoptosis dysregulation, through genetic or epigenetic mechanisms, is a feature of many cancer types, and contributes to reduced treatment response, disease progression and ultimately treatment resistance. Novel approaches are required to overcome dysregulated apoptosis signalling, increase the efficacy of cancer treatment and improve patient outcomes. Here, we provide an insight into current knowledge of how the apoptosis pathway is dysregulated in paediatric nervous system tumours, with a focus on TRAIL receptors, the BCL-2 proteins and the IAP family, and highlight preclinical evidence demonstrating that pharmacological manipulation of the apoptosis pathway can restore apoptosis signalling and sensitise cancer cells to treatment. Finally, we discuss the potential clinical implications of these findings.

Fig. 1. Schematic representation of the extrinsic and intrinsic apoptosis pathways, indicating pharmacological agents and their therapeutic targets.

Proteins mediating similar functions are indicated by shading, while green shaded boxes highlight pharmacological agents. ↑ and ↓ indicates that the target is upregulated or downregulated by the drug, respectively. --| indicates inhibition of the target protein by the specified protein/drug. Created with BioRender.com.

Fig. 2. The structure of BCL-2 protein family members.

TM denotes the transmembrane domain.

Fig. 3. BCL-2 protein family interactions.

The BCL-2 protein family interactions mediate BAX/BAK-induced mitochondrial outer membrane permeabilisation (MOMP). Created with BioRender.com.

Fig. 4. The structure of IAP family members.

IAP members all have at least one baculoviral IAP repeat (BIR) domain that facilitates their interaction with other proteins. Some IAPs contain a Really Interesting New Gene (RING) domain that mediates E3 ligase activity. cIAP1/2 additionally contains a CAspase Recruitment Domain (CARD) which functions in protein-protein interactions.