Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma

Doris Phelps, Kathryn Bondra, Star Seum, Christopher Chronowski, Justin Leasure, Raushan T. Kurmasheva, Steven Middleton, Dian Wang, Xiaokui Mo, Peter J. Houghton

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Background: Curative therapy for childhood sarcoma presents challenges when complete resection is not possible. Ionizing radiation (XRT) is used as a standard modality at diagnosis or recurrence for childhood sarcoma; however, local recurrence is still problematic. Most childhood sarcomas are TP53 wild type at diagnosis, although approximately 5-10% have MDM2 amplification or overexpression. Procedures: The MDM2 inhibitor, RG7388, was examined alone or in combination with XRT (20Gy given in 2Gy daily fractions) to immune-deficient mice bearing Rh18 (embryonal) or a total of 30Gy in 2Gy fractions to mice bearing Rh30 (alveolar) rhabdomyosarcoma xenografts. RG7388 was administered by oral gavage using two schedules (daily ×5; schedule 1 or once weekly; schedule 2). TP53-responsive gene products (p21, PUMA, DDB2, and MIC1) as well as markers of apoptosis were analyzed. Results: RG7388 showed no significant single agent antitumor activity. Twenty Grays XRT induced complete regressions (CR) of Rh18 with 100 percent tumor regrowth by week 7, but no tumor regrowth at 20 weeks when combined with RG7388. RG7388 enhanced time to recurrence combined with XRT in Rh30 xenografts compared to 30Gy XRT alone. RG7388 did not enhance XRT-induced local skin toxicity. Combination treatments induced TP53 responsive genes more rapidly and to a greater magnitude than single agent treatments. Conclusions: RG7388 enhanced the activity of XRT in both rhabdomyosarcoma models without increasing local XRT-induced skin toxicity. Changes in TP53-responsive genes were consistent with the synergistic activity of RG7388 and XRT in the Rh18 model.

Original languageEnglish (US)
Pages (from-to)1345-1352
Number of pages8
JournalPediatric Blood and Cancer
Volume62
Issue number8
DOIs
StatePublished - Aug 1 2015

Keywords

  • Childhood sarcoma
  • MDM2 inhibitor
  • Radiation treatment

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

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