The majority of high-risk
neuroblastomas can be divided into three distinct molecular subgroups defined by the presence of MYCN amplification, upstream TERT rearrangements or alternative lengthening of telomeres (ALT). The common defining feature of all three subgroups is altered telomere maintenance; MYCN amplification and upstream TERT rearrangements drive high levels of
telomerase expression whereas ALT is a
telomerase independent telomere maintenance mechanism. As all three telomere maintenance mechanisms are independently associated with poor outcomes, the development of strategies to selectively target either
telomerase expressing or ALT cells holds great promise as a therapeutic approach that is applicable to the majority of children with aggressive disease.Here we summarise the biology of telomere maintenance and the molecular drivers of aggressive
neuroblastoma before describing the most promising therapeutic strategies to target both
telomerase expressing and ALT
cancers. For
telomerase-expressing
neuroblastoma the most promising targeted agent to date is
6-thio-2'-deoxyguanosine, however clinical development of this agent is required. In
osteosarcoma cell lines with ALT, selective sensitivity to ATR inhibition has been reported. However, we present data showing that in fact ALT
neuroblastoma cells are more resistant to the clinical ATR inhibitor
AZD6738 compared to other
neuroblastoma subtypes. More recently a number of additional candidate compounds have been shown to show selectivity for ALT
cancers, such as Tetra-Pt (bpy), a compound targeting the telomeric G-quadruplex and
pifithrin-α, a putative p53 inhibitor. Further pre-clinical evaluation of these compounds in
neuroblastoma models is warranted.In summary, telomere maintenance targeting strategies offer a significant opportunity to develop effective new
therapies, applicable to a large proportion of children with high-risk
neuroblastoma. In parallel to clinical development, more pre-clinical research specifically for
neuroblastoma is urgently needed, if we are to improve survival for this common poor outcome tumour of childhood.