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The MDM2 small-molecule inhibitor RG7388 leads to potent tumor inhibition in p53 wild-type neuroblastoma
A Lakoma1, E Barbieri2, S Agarwal2
1Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
Neuroblastoma is an aggressive pediatric malignancy which is >98% p53 wild-type at diagnosis. As a primary repressor of p53 activity and part of a p53-activated negative feedback loop, targeting of mouse double minute 2 homolog (MDM2) is an attractive therapeutic approach to reactivation of p53. Since development of the first selective MDM2 inhibitor, Nutlin-3a, newer compounds have been developed for increased potency and improved bioavailability. Herein, we sought to determine the efficacy and specificity of a second-generation MDM2 inhibitor, RG7388, in neuroblastoma cell lines and xenografts and examine its effect on the p53-independent pathway of hypoxia-inducible factor-1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF). Cell viability and apoptosis studies were performed on the neuroblastoma cell lines, NGP, SH-SY5Y, LAN-5, LAN-5 si-p53 (p53 silenced), and SK-N-AS (p53 null). RG7388 potently decreased cell proliferation and activated p53-dependent apoptosis. Tumor-bearing mice treated with RG7388 demonstrated significant tumor inhibition by 59% in NGP (P = 0.003), 67% in SH-SY5Y (P = 0.006), and 75% in LAN-5 (P = 0.0019) p53 wild-type xenograft tumors, but no inhibitory effect on LAN-5 si-p53 or SK-N-AS p53-silenced/null xenograft tumors. Moreover, RG7388 was found to inhibit the p53-independent pathway of HIF-1α/VEGF with decreased gene expression and alteration of angiogenesis. Our study supports the further evaluation of RG7388 as a novel treatment option in p53 wild-type neuroblastoma at diagnosis and relapse.
Insights
The MDM2 inhibitor RG7388 effectively reduces neuroblastoma tumor growth by reactivating p53. This drug also impacts the HIF-1α/VEGF pathway, showing promise for p53 wild-type neuroblastoma treatment.
Area of Science:
- Oncology
- Pediatric Malignancies
- Molecular Therapeutics
Background:
- Neuroblastoma is a pediatric cancer with a high prevalence of wild-type p53.
- Targeting mouse double minute 2 homolog (MDM2) offers a therapeutic strategy to restore p53 tumor suppressor function.
- Second-generation MDM2 inhibitors like RG7388 exhibit enhanced potency and bioavailability.
Purpose of the Study:
- To evaluate the efficacy and specificity of RG7388 in neuroblastoma.
- To investigate RG7388's impact on the p53-dependent apoptosis pathway.
- To examine RG7388's effect on the p53-independent hypoxia-inducible factor-1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF) pathway.
Main Methods:
- RG7388 treatment on neuroblastoma cell lines (NGP, SH-SY5Y, LAN-5, LAN-5 si-p53, SK-N-AS).
- Cell viability and apoptosis assays.
- In vivo studies using p53 wild-type and p53-silenced/null neuroblastoma xenografts in mice.
- Analysis of HIF-1α/VEGF pathway gene expression and angiogenesis.
Main Results:
- RG7388 significantly reduced cell proliferation and induced p53-dependent apoptosis in p53 wild-type neuroblastoma cells.
- RG7388 demonstrated substantial tumor inhibition in p53 wild-type xenografts (59-75%).
- No significant tumor inhibition was observed in p53-silenced/null xenografts.
- RG7388 inhibited the HIF-1α/VEGF pathway, decreasing gene expression and altering angiogenesis.
Conclusions:
- RG7388 is a potent MDM2 inhibitor effective against p53 wild-type neuroblastoma.
- The drug's efficacy is dependent on p53 status.
- RG7388 also modulates the p53-independent HIF-1α/VEGF pathway.
- RG7388 warrants further investigation as a potential therapeutic for p53 wild-type neuroblastoma.
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