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Down-regulation of MYCN protein by CX-5461 leads to neuroblastoma tumor growth suppression

Jordan S Taylor1, Jasmine Zeki1, Kimberly Ornell2

  • 1Department of Surgery, Stanford University, Stanford, CA.

Journal of Pediatric Surgery
|March 19, 2019
PubMed
Abstract

Insights

CX-5461 effectively suppressed neuroblastoma tumor growth by inhibiting ribosomal RNA synthesis and downregulating MYCN/MYC proteins. This small molecule inhibitor shows promise for treating neuroblastoma, particularly in cases with MYCN amplification.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • MYCN oncogene amplification is a key driver of aggressive neuroblastoma and predicts a poor prognosis.
  • CX-5461 is a novel small molecule inhibitor targeting ribosomal RNA synthesis initiation by RNA Polymerase I.
  • Downregulation of MYCN/MYC proteins by CX-5461 presents a potential therapeutic strategy for neuroblastoma.

Purpose of the Study:

  • To investigate the efficacy of CX-5461 in suppressing neuroblastoma tumor growth.
  • To evaluate the impact of CX-5461 on MYCN/MYC protein expression in neuroblastoma cells.
  • To assess the therapeutic potential of localized CX-5461 delivery using a sustained-release platform.

Main Methods:

  • Neuroblastoma cell lines with and without MYCN amplification were treated with CX-5461.
  • Western blot analysis was used to determine MYCN/MYC protein levels post-treatment.
  • Orthotopic neuroblastoma mouse models were established and treated with CX-5461-loaded silk films for local drug delivery.

Main Results:

  • CX-5461 demonstrated varying IC50 values across different neuroblastoma cell lines, with significant MYCN and MYC protein downregulation observed.
  • The silk film formulation provided sustained release of CX-5461 over 120 hours.
  • Local delivery of CX-5461 significantly suppressed orthotopic neuroblastoma tumor growth compared to control, with associated reduction in MYCN protein and nucleolar hypertrophy.

Conclusions:

  • Local administration of CX-5461 via a sustained-release system effectively inhibits orthotopic neuroblastoma tumor growth.
  • CX-5461 shows particular efficacy in neuroblastoma models overexpressing MYCN/MYC proteins.
  • These findings support CX-5461 as a promising therapeutic agent for neuroblastoma, especially in MYCN-amplified subtypes.
Keywords:
CX-5461Local drug delivery platformMYCMYCNNeuroblastomaOncogeneSilk fibroin

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