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

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 (20 Gy given in 2 Gy daily fractions) to immune-deficient mice bearing Rh18 (embryonal) or a total of 30 Gy in 2 Gy 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, and TP53-responsive gene products (p21, PUMA, DDB2, MIC1) as well as markers of apoptosis, were analyzed. Results RG7388 showed no significant single agent antitumor activity. Twenty Gy 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 30 Gy 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.

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

“…For example, temozolomide was previously shown to act synergistically with RG7112 [37]. Other MDM2 inhibitors were shown to enhance sensitivity to radiation in human xenografts [38, 39]. In addition to confirming our data using other in vivo models, future studies will include testing of such combinations, as well as the evaluation of more potent MDM2 inhibitors including those in clinical trials (RG7388) [40, 41].…”

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

“…Our study also provides valuable PK and PD data to support paediatric clinical trials with an observed PK profile of RO6839921 consistent with IV administration, and compatible with recommended intermittent dosing schedules aimed to enable bone marrow recovery and overcome haematological toxicities. The PD profile was consistent with the PK profile, mechanism of action, and previous studies . The analysis of PD biomarkers of response to RO6839921 alone showed changes in MIC‐1, p21, p53 and Ki67, consistent with our previous in vitro observations of idasanutlin mediated anti‐tumour activity .…”

Evaluation of entinostat alone and in combination with standard‐of‐care cytotoxic agents against rhabdomyosarcoma xenograft models

“…For Rh10 and Rh65 xenografts, mice were treated as in the therapeutic protocol (2.5 mg/kg twice daily for 4 days) for up to three consecutive weeks. Tumors ( n = 3) were harvested at 4 hours after dose 7 (week 1), dose 15 (week 2), or dose 23 (week 3), and lysates prepared for immunoblotting as previously described . Antibodies used to detect PAX3 (#sc‐81351 mouse monoclonal, Santa Cruz Biotechnology, Dallas), acetyl‐histone H3(K9) rabbit monoclonal (#9649.…”