Oncotarget

Research Papers:

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

Lindi Chen, Raphaël F. Rousseau, Steven A. Middleton, Gwen L. Nichols, David R. Newell, John Lunec and Deborah A. Tweddle _

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Oncotarget. 2015; 6:10207-10221. https://doi.org/10.18632/oncotarget.3504

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Abstract

Lindi Chen1, Raphaël F. Rousseau2, Steven A. Middleton3, Gwen L. Nichols3, David R. Newell1, John Lunec1 and Deborah A. Tweddle1

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 GI50 concentrations were determined in 21 p53-wt and mutant neuroblastoma cell lines of varying MYCN, MDM2 and p14ARF 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.


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