title: Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma.
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 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.
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom.
authors.forename: Lindi
authors.initials: L
authors.lastname: Chen
authors.affiliation: Genentech Inc., South San Francisco, CA, USA.
authors.forename: Raphaël F
authors.initials: RF
authors.lastname: Rousseau
authors.affiliation: Hoffmann-La Roche Inc., Nutley, NJ, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Middleton
authors.affiliation: Hoffmann-La Roche Inc., Nutley, NJ, USA.
authors.forename: Gwen L
authors.initials: GL
authors.lastname: Nichols
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Lunec
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Tweddle
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062366:para-Aminobenzoates / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D011759:Pyrrolidines; C586849:RG7388; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D062366:para-Aminobenzoates; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Calcusyn; MDM2-p53 antagonists; RG7388; combination therapy; neuroblastoma
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