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Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma
Author(s) -
Chen Lindi,
Pastorino Fabio,
Berry Philip,
Bonner Jennifer,
Kirk Calum,
Wood Katrina M.,
Thomas Huw D.,
Zhao Yan,
Daga Antonio,
Veal Gareth J.,
Lunec John,
Newell David R.,
Ponzoni Mirco,
Tweddle Deborah A.
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32058
Subject(s) - temozolomide , neuroblastoma , medicine , prodrug , in vivo , pharmacology , pharmacokinetics , phases of clinical research , combination therapy , chemotherapy , oncology , biology , cell culture , microbiology and biotechnology , genetics
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.