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

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.

Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer

“…AP is a potent and selective inhibitor of p53-MDM2 interaction to activate p53 pathway and associates with cell-cycle arrest and/ or apoptosis. In a preclinical trial, intravenous (IV) RG7775 (RO6839921) showed anti-tumor effects in osteosarcoma and AML in immunocompromised mice model (Chen et al, 2019). In a phase I study (NCT02098967), RG7775 was investigated for its safety, tolerability, and pharmacokinetics in patients with advanced malignancies (Abdul et al, 2019).…”

Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists

“…Temozolomide (TMZ), which delivers methyl groups to purine bases of DNA, results in the formation of N7-methylguanine and N3-methyladenine. TMZ was evaluated in combination with RG7775 ( idasanutlin prodrug) to treat neuroblastoma [55]. The combined treatment has led to the inhibition of tumor growth, which was correlated with the upregulation of genes involved in apoptosis and signal transduction and downregulation of genes involved in DNA replication, mitosis, cell cycle progression and cell division [55].…”

“…TMZ was evaluated in combination with RG7775 ( idasanutlin prodrug) to treat neuroblastoma [55]. The combined treatment has led to the inhibition of tumor growth, which was correlated with the upregulation of genes involved in apoptosis and signal transduction and downregulation of genes involved in DNA replication, mitosis, cell cycle progression and cell division [55]. In another study, TMZ showed an additive antiproliferative effect with HDM2 antagonist CGM097 in neuroendocrine tumor model [32].…”

Molecular targeting therapies for neuroblastoma: Progress and challenges

“…Treatment of NB cells with wild‐type p53 using RG7388 induces p53 activation and apoptosis 182 . Other MDM2 antagonists which have been demonstrated anticancer activity in NB models include SAR405838 (MI‐77301), 216 MK‐8242, 217 MI‐63, 218 RG7112, 219 and RG7775 220 . In addition, a study by Giustiniano et al 221 has shown that “compound 12” acts as a dual inhibitor of MDM2/p53 and MDM4/p53 complexes and enhances the p53 protein levels in human SHSY‐5Y NB cells.…”