Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma

S L George,P Angelini,Y Jamin,V Parmar,F Lorenzi,E Poon,L Chesler,L V Marshall

doi:10.1186/s13046-020-01582-2

Abstract

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.

Highlights

Neuroblastoma is a common childhood malignancy arising from the sympathetic nervous system
In 2015 it was reported that aggressive neuroblastoma can be divided into 3 almost mutually exclusive subgroups with either MYCN amplification, rearrangements upstream to the telomerase reverse transcriptase (TERT) gene or alternative lengthening of telomeres (ALT) [4, 5]
Data far indicates that subgroups of neuroblastoma are driven by either telomerase or ALT activation, it is highly likely that a selective pressure targeting one telomere maintenance mechanism (TMM) will support the emergence of an alternative mechanism

Summary

Introduction

Neuroblastoma is a common childhood malignancy arising from the sympathetic nervous system. In the absence of an ATRX alteration the underlying drivers of ALT neuroblastoma are currently unknown, and somatic alterations in other genes, known to be associated telomere maintenance with a specific focus on the potential relevance to patients with neuroblastoma. Data is accumulating to support the hypothesis that TMMs are the common defining molecular feature of aggressive disease in the majority of children with clinical high-risk neuroblastoma.

Results

Conclusion