Abstract
Alteration of P53 pathway is one of the key molecular events involved in glioblastoma (GBM) biology. Genetic alterations which reduce TP53 function in GBM include MDM2 amplification (14% of patients), MDM4 amplification (7%), and TP53 gene mutations (35%), each of which is generally thought to be mutually exclusive. The study presented here aims to test the therapeutic activity of RG7112, a member of cis-imidazoline MDM2 inhibitors (Nutlins), in GBM cells according to their functional P53 pathway status. The effect of RG7112 was assessed in a panel of eleven GBM patient-derived cell lines (PDCLs) genetically selected to assess the drug response of the different alterations of P53 pathway. RG7112 was found to be able to induce cell death in all cell lines tested, with the highest cytotoxic efficacy against MDM2/MDM4-amplified GBM PDCL. Indeed, GBM cell lines carrying MDM2 or MDM4 gene amplification were 10 to 20 times more sensitive to the inhibitor than the other lines. TP53 mutant lines were the least sensitive lines. RG7112 treatment restored P53 and P21 protein levels in MDM2-amplified GBM cells. Most importantly, treatment of MDM2-amplified GBM orthotopic patient derived xenograft (PDX) bearing mice with 100 mg/kg RG7112 (Q5Dx3) reduced tumor growth rate and significantly increased survival duration compared to vehicle-treated mice. This data supports the research towards the development of RG7112 for clinical testing in MDM2/4-amplified glioblastoma patients. Studies assessing the capacity of RG7112 compound to cross the blood-brain barrier in healthy and GBM tumor tissue are currently ongoing.
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