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

Lindi Chen, Fabio Pastorino, Philip Berry, Jennifer Bonner, Calum Kirk, Katrina M. Wood, Huw D. Thomas, Yan Zhao, Antonio Daga, Gareth J. Veal, John Lunec, David R. Newell, Mirco Ponzoni, Deborah A. Tweddle

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)3146-3159
Number of pages14
JournalInternational Journal of Cancer
Volume144
Issue number12
DOIs
Publication statusPublished - Jun 15 2019

Fingerprint

temozolomide
Neuroblastoma
Prodrugs
Liquid Chromatography
Mass Spectrometry
Neoplasms
Therapeutics
Pharmacokinetics
Enzyme-Linked Immunosorbent Assay
Clinical Trials
Drug Therapy
Survival
Growth

Keywords

  • idasanutlin (RG7388)
  • MDM2 antagonists
  • neuroblastoma
  • RO6839921 (RG7775)
  • temozolomide

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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

In: International Journal of Cancer, Vol. 144, No. 12, 15.06.2019, p. 3146-3159.

Research output: Contribution to journalArticle

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 2019, 'Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma', International Journal of Cancer, vol. 144, no. 12, pp. 3146-3159. https://doi.org/10.1002/ijc.32058
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. / Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma. In: International Journal of Cancer. 2019 ; Vol. 144, No. 12. pp. 3146-3159.
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