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

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.

How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?

“…George et al [101] recently evaluated the clinical ATR inhibitor AZD6738 in a panel of telomerase-and ALT-positive NB and non-NB cell lines, and found that ALT-positive cells were generally not more sensitive to ATR inhibition than telomerase-positive cells are following ATR inhibition. These findings provide support for differences in ATR inhibitor sensitivity not being related to ATRX-deficient ALT [100].…”

Molecular targeting therapies for neuroblastoma: Progress and challenges

“…This review provides an overview of the current state‐of‐the‐art molecular understanding of the development and progression of NB, with a particular emphasis on genetic aberrations and disrupted molecular pathways. As noted, several excellent reviews have been published, covering recent advances made in pathogenesis, diagnosis, and clinical management of NB and interested readers are referred to those excellent publications 4,9,22,29,42,46–72 . In this review, we will emphasize how these advances in knowledge about molecular pathogenesis can be translated to developing molecular targeted therapies for NB management, especially personalized therapies.…”

Neuroblastoma Risk Assessment and Treatment Stratification with Hybrid Capture-Based Panel Sequencing

“…Further probes were selected to detect ALK mutations or amplifications [19,20,45], focusing on the most common druggable mutations present in neuroblastoma, and genes involved in the p53/MDM2-and Ras/MAPK-pathway, as mutations of these genes have been previously shown to define a group of UHR neuroblastomas [13]. Finally, we included probes covering additional genes previously found mutated in neuroblastoma [9][10][11][12][13]18,46], and with potential relevance for neuroblastoma tumor biology or targeted therapies, including ATM [47] and ATR [48,49] (Table S1). The NB-HCPS assay includes 4516 single probes that cover 2484 genomic regions, including 55 genes (Figure 1A, Tables S1 and S2), 736694 base pairs (bp) in total, as well as 65 additional probes across the genome serving as a reference for copy number analysis.…”