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In vivo evaluation of the intravenous MDM2-p53 antagonist RO6839921 alone and in combination with temozolomide in TP53 wild-type orthotopic models of neuroblastoma

Lookup NU author(s): Dr Lindi Chen, Philip Berry, Dr Jennifer Bonner, Dr Katrina Wood, Professor Gareth Veal, Professor John Lunec, Emeritus Professor Herbie Newell, Professor Deborah Tweddle

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Abstract

Background. Neuroblastoma is a predominantly TP53 wt tumor which supports the use of MDM2-p53 antagonists as a novel therapy for neuroblastoma patients. This is the first study to evaluate the efficacy of RO6839921, an IV prodrug of RG7388, alone and in combination with temozolomide in TP53 wild-type orthotopic models of neuroblastoma.Methods. Studies were conducted using a well-established orthotopic model of neuroblastoma, implanted with SHSY5Y-Luc (TP53 wt; non-MYCN amplified) and NB1691-Luc (TP53 wt; MYCNand MDM2 amplified) cells, and randomized into control, intravenous RO6839921, oral temozolomide or RO6839921 and temozolomide in combination. Tumor growth was monitored using bioluminescence imaging. Active RG7388 in plasma and tumor samples were detected using liquid chromatography-mass spectrometry, and p53 pathway activation assessed by MIC-1 ELISA assays, Western analysis and/or immunohistochemistry for p53, p21 and cleaved caspase 3.Results. Pharmacokinetic and pharmacodynamic analysis of RO6839921 observed peak plasma levels of active RG7388 at 1h posttreatment with maximal activation of the p53 pathway observed 3-6h posttreatment. RO6839921 had a favorable pharmacodynamic profile consistent with intermittent dosing. Assessment of anti-tumor efficacy demonstrated that RO6839921 was as effective as temozolomide and that RO6839921 in combination with temozolomide led to significantly greater tumor growth inhibition and survival than either agent given alone. RO6839921 alone and in combination with temozolomide was well tolerated.Conclusions. These preclinical studies support the evaluation of combining RO6839921 with temozolomide in early phase clinical trials of neuroblastoma patients with wt TP53.


Publication metadata

Author(s): Chen L, Pastorino F, Berry P, Bonner J, Wood K, Veal G, Ponzoni M, Lunec J, Newell DR, Tweddle DA

Publication type: Conference Proceedings (inc. Abstract)

Publication status: Published

Conference Name: AACR Annual Meeting 2017

Year of Conference: 2017

Pages: Abstract LB-300

Online publication date: 01/07/2017

Acceptance date: 01/07/2017

ISSN: 1538-7445

Publisher: American Association for Cancer Research

URL: https://doi.org/10.1158/1538-7445.AM2017-LB-300

DOI: 10.1158/1538-7445.AM2017-LB-300


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