p53 non-genotoxic activation and mTORC1 inhibition lead to effective combination for neuroblastoma therapy.

Purpose: mTORC1 inhibitors are promising agents for neuroblastoma therapy, however they have shown limited clinical activity as monotherapy, thus rational drug combinations need to be explored to improve efficacy. Importantly, neuroblastoma maintains both an active p53 and an aberrant mTOR signaling. <br /><br />Experimental Design: Using an orthotopic xenograft model and modulating p53 levels, we investigated the anti-tumor effects of the mTORC1 inhibitor temsirolimus in neuroblastoma expressing normal, decreased, or mutant p53, both as single agent and in combination with first and second generation MDM2 inhibitors to reactivate p53. <p>Results: Non-genotoxic p53 activation suppresses mTOR activity. Moreover, p53 reactivation via RG7388, a second generation MDM2 inhibitor, strongly enhances the in vivo anti-tumor activity of temsirolimus. Single agent temsirolimus does not elicit apoptosis, and tumors rapidly re-grow after treatment suspension. In contrast, our combination therapy triggers a potent apoptotic response in wild-type p53 xenografts and efficiently blocks tumor re-growth after treatment completion. We also found that this combination uniquely led to p53-dependent suppression of survivin whose ectopic expression is sufficient to rescue the apoptosis induced by our combination.</p> <br />Conclusions: Our study supports a novel highly effective strategy that combines RG7388 and temsirolimus in wild-type p53 neuroblastoma, which warrants testing in early-phase clinical trials.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2wZnHhO