Targeting of epigenetic regulators in neuroblastoma

Abstract

Approximately 15,000 new cases of pediatric cancer are diagnosed yearly in Europe, with 8-10% corresponding to neuroblastoma, a rare disease with an incidence of 8-9 cases per million children <15 years of age. Although the survival rate for low-risk and intermediate-risk patients is excellent, half of children with high-risk, refractory, or relapsed tumors will be cured, and two-thirds of the other half will suffer major side effects and life-long disabilities. Epigenetic therapies aimed at reversing the oncogenic alterations in chromatin structure and function are an emerging alternative against aggressive tumors that are or will become resistant to conventional treatments. This approach proposes targeting epigenetic regulators, which are proteins that are involved in the creation, detection, and interpretation of epigenetic signals, such as methylation or histone post-translational modifications. In this review, we focused on the most promising epigenetic regulators for targeting and current drugs that have already reached clinical trials.

Fig. 1. Main epigenetic targets.

Current inhibitors act on three different epigenetic levels: DNA methylation, histone methylation or acetylation, and chromatin reading. This scheme highlights the most promising drugs that target proteins involved in these processes with a subset already under clinical trials or even approved for treatment of certain malignancies

Fig. 2. Schematic representation of members of the main epigenetic regulator families and subfamilies.

Representative members of a DNMT, b HMT, c HDM, d HAT, e HDAC, and f BRD-containing proteins are included, showing their domain configurations and indicating the catalytic region, which is the main target of epigenetic drugs. Sources: UniProt, InterPro

Fig. 3. In silico analysis of HAT and BRD-containing protein expression in NB.

mRNA expression levels from 39 different BRD-containing proteins and 16 histone acetyltransferases were analyzed in neuroblastoma samples from the E-GEOD-3960 (n = 101) dataset. Samples were sorted according to disease stage and MYCN status. Heatmap represents the differentially expressed genes (p < 0.05) between the groups of patients with poor prognosis (stage 4, MYCN amplification) versus the remainder of patients (i.e., stage 1, 3, and 4 MYCN non-amplified)