Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma. Issue 12 (9th January 2019)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: International journal of cancer. Volume 144:Issue 12(2019)
• Page Start: 3146
• Page End: 3159
• Publication Date: 2019-01-09
• Subjects: neuroblastoma -- MDM2 antagonists -- idasanutlin (RG7388) -- RO6839921 (RG7775) -- temozolomide; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32058
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : 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. Abstract : What's new? Long‐term survival of high‐risk neuroblastoma patients currently averages than 50%. New therapies that both improve survival and reduce treatment toxicity are urgently needed. MDM2 antagonists are a novel class of anti‐cancer agents that stabilize the p53 pathway and lead to tumour suppression. In this preclinical study, the authors tested a prodrug of the MDM2 inhibitor idasanutlin in mice. They found that this compound inhibited tumour growth and increased survival, especially in combination with temozolomide. These results support the further development of idasanutlin plus temozolomide in clinical trials for neuroblastoma.