Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma

• Published in: Oncotarget 2015-04, Vol.6 (12), p.10207-10221
• Main Authors: Chen, Lindi, Rousseau, Raphaël F, Middleton, Steven A, Nichols, Gwen L, Newell, David R, Lunec, John, Tweddle, Deborah A
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Neuroblastoma - drug therapy; Neuroblastoma - metabolism; para-Aminobenzoates - administration & dosage; para-Aminobenzoates - pharmacology; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - metabolism; Pyrrolidines - administration & dosage; Pyrrolidines - pharmacology; Research Paper; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3504

Neuroblastoma is a predominantly p53 wild-type (wt) tumour and MDM2-p53 antagonists offer a novel therapeutic strategy for neuroblastoma patients. RG7388 (Roche) is currently undergoing early phase clinical evaluation in adults. This study assessed the efficacy of RG7388 as a single-agent and in combination with chemotherapies currently used to treat neuroblastoma in a panel of neuroblastoma cell lines. RG7388 GI50 concentrations were determined in 21 p53-wt and mutant neuroblastoma cell lines of varying MYCN, MDM2 and p14(ARF) status, together with MYCN-regulatable Tet21N cells. The primary determinant of response was the presence of wt p53, and overall there was a >200-fold difference in RG7388 GI50 concentrations for p53-wt versus mutant cell lines. Tet21N MYCN+ cells were significantly more sensitive to RG7388 compared with MYCN- cells. Using median-effect analysis in 5 p53-wt neuroblastoma cell lines, selected combinations of RG7388 with cisplatin, doxorubicin, topotecan, temozolomide and busulfan were synergistic. Furthermore, combination treatments led to increased apoptosis, as evident by higher caspase-3/7 activity compared to either agent alone. These data show that RG7388 is highly potent against p53-wt neuroblastoma cells, and strongly supports its further evaluation as a novel therapy for patients with high-risk neuroblastoma and wt p53 to potentially improve survival and/or reduce toxicity.