Abstract 1366: Mdm2 antagonist RG7388 does not interfere with tumor angiogenesis in vitro and in vivo

Abstract

Abstract MDM2 interacts with the transcription factor p53 via its N-terminal domain and is the most prominent and best described natural inhibitor of the p53 tumor suppressor pathway. Apart from this very well investigated function, MDM2 has been reported to be involved in angiogenesis via various mechanisms. Published data indicate that MDM2 interacts directly with and activates HIF1a but can also display HIF1a independent effects such as VEGF mRNA stabilization or regulation of ERK1/2 signaling. Taken together, these reports suggest that MDM2 antagonists might have the potential to inhibit tumor-angiogenesis or age-related macular degeneration. In order to test the potential anti-angiogenic activity of interfering with MDM2-p53 binding, we utilized the highly selective, clinical stage MDM2 antagonist RG7388. First, it was tested if RG7388 influences the induction of response to hypoxic conditions using a HRE-reporter cell line, followed by analyzing the interference of RG7388 with human endothelial cell tubule formation. The in-vitro results showed no statistically significant inhibition of HIF1a facilitated GFP reporter activation nor any effect on HUVEC tubule formation, viability or proliferation. In a mouse cornea pocket assay in-vivo, systemic administration of a MDM2 antagonist did not prevent VEGF-A or FGF-2 induced vessel formation. Finally, RG7388 and vehicle treated SJSA xenograft tumors were explanted and analyzed in detail for changes in vessel architecture. No effects on microvascular density or vessel structure were observed. Taken together, these data indicate that RG7388, a highly selective MDM2 antagonist that binds to the p53-binding pocket of MDM2 and prevents interaction of MDM2 with p53, is not suitable for anti-angiogenic treatment. One possible explanation for the lack of anti-angiogenic activity is the increased potency/specificity of RG7388 resulting in higher selectivity and fewer off target effects compared to Nutlin-3a. Citation Format: Christian Lehmann, Thomas Friess, Erica Lorenzon, Frank Herting, Markus Dangl. Mdm2 antagonist RG7388 does not interfere with tumor angiogenesis in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1366. doi:10.1158/1538-7445.AM2015-1366