Neuroblastoma treatment in the post-genomic era

Abstract

Neuroblastoma is an embryonic malignancy of early childhood originating from neural crest cells and showing heterogeneous biological, morphological, genetic and clinical characteristics. The correct stratification of neuroblastoma patients within risk groups (low, intermediate, high and ultra-high) is critical for the adequate treatment of the patients.High-throughput technologies in the Omics disciplines are leading to significant insights into the molecular pathogenesis of neuroblastoma. Nonetheless, further study of Omics data is necessary to better characterise neuroblastoma tumour biology. In the present review, we report an update of compounds that are used in preclinical tests and/or in Phase I-II trials for neuroblastoma. Furthermore, we recapitulate a number of compounds targeting proteins associated to neuroblastoma: MYCN (direct and indirect inhibitors) and downstream targets, Trk, ALK and its downstream signalling pathways. In particular, for the latter, given the frequency of ALK gene deregulation in neuroblastoma patients, we discuss on second-generation ALK inhibitors in preclinical or clinical phases developed for the treatment of neuroblastoma patients resistant to crizotinib.We summarise how Omics drive clinical trials for neuroblastoma treatment and how much the research of biological targets is useful for personalised medicine. Finally, we give an overview of the most recent druggable targets selected by Omics investigation and discuss how the Omics results can provide us additional advantages for overcoming tumour drug resistance.

Keywords: Neuroblastoma; Omics; Personalised medicine; Targeted therapy.

Fig. 1

Schematic presentation of current pre-clinically tested drugs in neuroblastoma. A discussed anti-tumor drugs used against neuroblastoma in vitro and/or in vitro, and their targets are presented. In addition, a connection between the molecular targets is determined by the arrows. Legend shows a type of interaction described between the molecules a Indicates targeting of MYCN and P53/MDM dependent pathways. b Depicts drugs against ALK, Trk and PI3K/AKT/mTOR pathway. c Illustrates a targeting of main anti-apoptotic molecules. Gene symbol and its corresponding protein: NTRK1 – TrkA; NTRK2 – TrkB; PIK3CA - PI3K, BIRC5 – Survivin (Data resource: http://www.pathwaycommons.org/)

Fig. 2

Flow chart of Omics data integration for personalised treatment. At the top of the figure, schematic presentation of Omics data processing, the assortment and analyses is shown. Once collected, omic technologies data obtained by studying tumor material or CTC from blood, have to be integrated to allow the extraction and selection of the druggable single target or molecular pathways. This step proceeds by the screening of the most reliable drug or drug combination that would assure optimal chances for tumour defeating. Some of the compounds are listed in the figure: MYCN, ALK, AURORA A, TrkB. In the lower part of the figure is shown the liquid biopsy as a procedure to use at the follow-up in order to understand how disease behaves due to treatment. In the case of neuroblastoma, integration of liquid biopsy for the follow-up of molecular biomarkers during therapy might be a winning strategy for early detection of possible drug resistance that could allow clinicians to change current therapeutic strategy