Combining inhibitors of Brd4 and cyclin-dependent kinase can decrease tumor growth in neuroblastoma with MYCN...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• High-risk neuroblastoma presents a significant clinical challenge with poor prognoses often linked to MYCN-amplification and TERT-overexpression.
• Gene Set Enrichment Analysis (GSEA) offers a potential method to uncover biological pathways associated with these poor prognostic markers.

Purpose of the Study:

• To identify pathways dysregulated in MYCN-amplified neuroblastoma using GSEA.
• To evaluate the therapeutic potential of inhibiting identified pathways in preclinical models of neuroblastoma.

Main Methods:

• GSEA was performed on the Neuroblastoma-Kocak dataset (GSE45547) to identify gene sets associated with MYCN-amplification.
• In vitro cytotoxicity assays and in vivo orthotopic xenograft models (PDX) were used to test selected inhibitors, including Brd4 inhibitors (JQ1, AZD5153) and a CDK inhibitor (dinaciclib).
• Tumor growth was monitored via ultrasound, and histological analysis (H&E staining) assessed treatment effects.

Main Results:

• GSEA revealed significant enrichment of MYC targets, cell cycle genes, TERT-associated genes, RB1 loss, and E2F targets in MYCN-amplified tumors.
• Bromodomain-containing protein 4 (Brd4) and cyclin-dependent kinase (CDK) pathways emerged as potential therapeutic targets.
• Combination therapy with dinaciclib and AZD5153 demonstrated synergistic cytotoxicity in vitro and significantly reduced tumor volume, increased lymphocyte infiltration, and induced necrosis in vivo.

Conclusions:

• GSEA is a valuable tool for identifying actionable molecular targets in complex cancers like neuroblastoma.
• The combination of dinaciclib and AZD5153 shows promise as an effective therapeutic strategy for MYCN-amplified and TERT-overexpressing neuroblastoma.