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

Abstract

// Lindi Chen 1 , Raphaël F. Rousseau 2 , Steven A. Middleton 3 , Gwen L. Nichols 3 , David R. Newell 1 , John Lunec 1 and Deborah A. Tweddle 1 1 Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom 2 Genentech Inc., South San Francisco, CA, USA 3 Hoffmann-La Roche Inc., Nutley, NJ, USA Correspondence to: Deborah A. Tweddle, email: // Keywords : neuroblastoma, MDM2-p53 antagonists, RG7388, combination therapy, Calcusyn Received : December 17, 2014 Accepted : February 17, 2015 Published : March 10, 2015 Abstract 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 GI 50 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 GI 50 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.