The pathogenic role of the PHOX2B gene in
neuroblastoma is indicated by heterozygous mutations in
neuroblastoma patients and by gene overexpression in both
neuroblastoma cell lines and
tumor samples. PHOX2B encodes a
transcription factor which is crucial for the correct development and differentiation of sympathetic neurons. PHOX2B overexpression is considered a prognostic marker for
neuroblastoma and it is also used by clinicians to monitor
minimal residual disease. Furthermore, it has been observed that neuronal differentiation in
neuroblastoma is dependent on down-regulation of PHOX2B expression, which confirms that PHOX2B expression may be considered a target in
neuroblastoma. Here, PHOX2B promoter or
3' untranslated region were used as molecular targets in an in vitro high-throughput approach that led to the identification of molecules able to decrease PHOX2B expression at transcriptional and likely even at post-transcriptional levels. Further functional investigations carried out on PHOX2B
mRNA levels and biological consequences, such as
neuroblastoma cell apoptosis and growth, showed that
chloroquine and
mycophenolate mofetil are most promising agents for
neuroblastoma therapy based on down-regulation of PHOX2B expression. Finally, a strong correlation between the effect of drugs in terms of down-regulation of PHOX2B expression and of biological consequences in
neuroblastoma cells confirms the role of PHOX2B as a potential molecular target in
neuroblastoma.