Abstract 1614: Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma
Authors: Houghton Peter J. , Phelps Doris A. , Bondra Kathryn , Seum Star , Chronowski Christopher , Leasure Justin , Kurmasheva Raushan T. , Middleton Stephen , Wang Dian , Mo Xiaokui 
Published: August 2015

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, and approximately 5-10 per cent have MDM2 amplification or overexpression. Thus, reconstitution of a functional TP53 pathway, through inhibition of MDM2-mediated TP53 degradation, is an attractive anticancer strategy to enhance the activity of cytotoxic therapies that induce apoptosis through TP53-dependent pathways. RG7388, is a second generation MDM2 inhibitor. However, combining MDM2 inhibitors with myelosuppressive therapies may be problematic as the p53-MDM2 auto-regulatory loop in normal megakaryocytopoiesis suggests that thrombocytopenia may be an on-target toxicity. Here we have evaluated the antitumor activity of RG7388 alone or in combination with XRT in two rhabdomyosarcoma xenografts (Rh18 [embryonal], and Rh30 [alveolar]).

RG7388 was administered at 80 mg/kg daily x 5 (schedule 1) or 100 mg/kg BID q7 days x 2 (schedule 2). XRT (2 Gy daily fractions) was given to a cumulative dose of 20 Gy (Rh18) or 30 Gy (Rh30). XRT (20 Gy) induced complete regressions of Rh18 xenografts followed by regrowth of all tumors with the median event time of 89.6 days compared 9.5 days for control or RG7388 treated tumors (P = 0.0287). The combination of XRT with RG7388 on either schedule induced complete regressions with no tumor regrowth (19 weeks observation). Thus, RG7388 given on either schedule significantly potentiated XRT (P&lt;0.0003) for both schedules). RG7388 slightly potentiated XRT against Rh30 xenografts where the cumulative tumor volumes at the end of the period of observation (day 134) was significantly smaller for the combination group in Schedule 1 (P = 0.0005) and Schedule 2 (P = 0.0029) when compared with tumors receiving 30 Gy alone. Local XRT-induced skin toxicity was not enhanced by RG7388.

Tumor samples were derived from untreated tumors, or tumors following 2, 4 or 6 Gy XRT and 24 and 48 Hr after the last XRT fraction with or without RG7388, or at the same time points from mice treated for 3 days with RG7388 alone (80 mg/kg). RG7388/XRT increased p21 levels over the 3 days of treatment, to a greater extent than XRT alone whereas p21 induction in tumors treated with RG7388 alone was lowest. Both XRT and combination treatments induced PARP cleavage over the first 48 hr.

Although additional models should be examined to see whether the synergistic activity of XRT combined with RG7388 occurs frequently, these initial results suggest that the combination may provide more effective local control for pediatric soft tissue sarcoma.

Citation Format: Peter J. Houghton, Doris A. Phelps, Kathryn Bondra, Star Seum, Christopher Chronowski, Justin Leasure, Raushan T. Kurmasheva, Stephen Middleton, Dian Wang, Xiaokui Mo. Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1614. doi:10.1158/1538-7445.AM2015-1614