Research ArticleCancer

Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth

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Science Translational Medicine  19 Feb 2020:
Vol. 12, Issue 531, eaax8694
DOI: 10.1126/scitranslmed.aax8694

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Interrupting a vicious cycle

Neuroblastoma is a relatively common pediatric neuroendocrine tumor. Although some neuroblastomas spontaneously regress, others can be deadly and difficult to treat, especially when they are associated with MYCN amplifications. MYCN itself has proven difficult to target, but Guo et al. have found that it may be possible to intervene indirectly, by targeting aldehyde dehydrogenase family 18 member A1 (ALDH18A1). The authors identified a positive feedback loop between ALDH18A1 and MYCN, as well as a chemical inhibitor of ALDH18A1 that can interrupt the cycle and effectively treat neuroblastoma in mouse models.

Abstract

MYCN-amplified neuroblastoma (NB) is characterized by poor prognosis, and directly targeting MYCN has proven challenging. Here, we showed that aldehyde dehydrogenase family 18 member A1 (ALDH18A1) exerts profound impacts on the proliferation, self-renewal, and tumorigenicity of NB cells and is a potential risk factor in patients with NB, especially those with MYCN amplification. Mechanistic studies revealed that ALDH18A1 could both transcriptionally and posttranscriptionally regulate MYCN expression, with MYCN reciprocally transactivating ALDH18A1 and thus forming a positive feedback loop. Using molecular docking and screening, we identified an ALDH18A1-specific inhibitor, YG1702, and demonstrated that pharmacological inhibition of ALDH18A1 was sufficient to induce a less proliferative phenotype and confer tumor regression and prolonged survival in NB xenograft models, providing therapeutic insights into the disruption of this reciprocal regulatory loop in MYCN-amplified NB.

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