Toggle Main Menu Toggle Search

Open Access padlockePrints

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma

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

Downloads


Licence

This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC High-risk neuroblastoma, a predominantly TP53 wild-type (wt) tumour, is incurable in >50% patients supporting the use of MDM2 antagonists as novel therapeutics. Idasanutlin (RG7388) shows in vitro synergy with chemotherapies used to treat neuroblastoma. This is the first study to evaluate the in vivo efficacy of the intravenous idasanutlin prodrug, RO6839921 (RG7775), both alone and in combination with temozolomide in TP53 wt orthotopic neuroblastoma models. Detection of active idasanutlin using liquid chromatography-mass spectrometry and p53 pathway activation by ELISA assays and Western analysis showed peak plasma levels 1 h post-treatment with maximal p53 pathway activation 3–6 h post-treatment. RO6839921 and temozolomide, alone or in combination in mice implanted with TP53 wt SHSY5Y-Luc and NB1691-Luc cells showed that combined RO6839921 and temozolomide led to greater tumour growth inhibition and increase in survival compared to vehicle control. Overall, RO6839921 had a favourable pharmacokinetic profile consistent with intermittent dosing and was well tolerated alone and in combination. These preclinical studies support the further development of idasanutlin in combination with temozolomide in neuroblastoma in early phase clinical trials.


Publication metadata

Author(s): Chen L, Pastorino F, Berry P, Bonner J, Kirk C, Wood KM, Thomas HD, Zhao Y, Daga A, Veal GJ, Lunec J, Newell DR, Ponzoni M, Tweddle DA

Publication type: Article

Publication status: Published

Journal: International Journal of Cancer

Year: 2019

Volume: 144

Issue: 12

Pages: 3146-3159

Print publication date: 15/06/2019

Online publication date: 11/12/2018

Acceptance date: 13/11/2018

Date deposited: 08/04/2019

ISSN (print): 0020-7136

ISSN (electronic): 1097-0215

Publisher: John Wiley & Sons, Inc.

URL: https://doi.org/10.1002/ijc.32058

DOI: 10.1002/ijc.32058


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share