Robert Beauchamp
Principal Investigator
Last active: 10/31/2018

Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma.

Rellinger EJ, Padmanabhan C, Qiao J, Craig BT, An H, Zhu J, Correa H, Waterson AG, Lindsley CW, Beauchamp RD, Chung DH
Oncotarget. 2017 8 (53): 91040-91051

PMID: 29207623 · PMCID: PMC5710904 · DOI:10.18632/oncotarget.19406

Neuroblastomas are the most common extracranial solid tumors in children and arise from the embryonic neural crest. -amplification is a feature of ∼30% of neuroblastoma tumors and portends a poor prognosis. Neural crest precursors undergo epithelial-to-mesenchymal transition (EMT) to gain migratory potential and populate the sympathoadrenal axis. Neuroblastomas are posited to arise due to a blockade of neural crest differentiation. We have recently reported effects of a novel MET inducing compound ML327 (-(3-(2-hydroxynicotinamido) propyl)-5-phenylisoxazole-3-carboxamide) in colon cancer cells. Herein, we hypothesized that forced epithelial differentiation using ML327 would promote neuroblastoma differentiation. In this study, we demonstrate that ML327 in neuroblastoma cells induces a gene signature consistent with both epithelial and neuronal differentiation features with adaptation of an elongated phenotype. These features accompany induction of cell death and G1 cell cycle arrest with blockage of anchorage-independent growth and neurosphere formation. Furthermore, pretreatment with ML327 results in persistent defects in proliferative potential and tumor-initiating capacity, validating the pro-differentiating effects of our compound. Intriguingly, we have identified destabilization of MYC signaling as an early and consistent feature of ML327 treatment that is observed in both -amplified and -single copy neuroblastoma cell lines. Moreover, ML327 blocked mRNA levels and tumor progression in established -amplified xenografts. As such, ML327 may have potential efficacy, alone or in conjunction with existing therapeutic strategies against neuroblastoma. Future identification of the specific intracellular target of ML327 may inform future drug discovery efforts and enhance our understanding of MYC regulation.

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