Abstract C103: Pediatric Preclinical Testing Program (PPTP) Stage 1 evaluation of the p53-MDM2 antagonist RG7112: Early evidence for high activity against MLL-rearranged leukemias.

Abstract

Abstract Introduction: Tumor suppressor p53 is a pro-apoptotic molecule frequently inactivated in cancer by gene mutations or defective signaling. Mutated p53 is uncommon in many childhood cancers and hence agents able to free p53 from inhibitory mechanisms may have therapeutic benefit in the pediatric setting. RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 is a member of the Nutlin family of MDM2 antagonists that has improved potency and pharmacological properties. Methods: RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hour exposure at concentrations from 1 nM to 10 μM. RG7112 was tested against the PPTP in vivo panel focusing on p53 wild type (WT) xenografts at a dose of 100 mg/kg daily for 14 days followed by 4 weeks observation. MDM2 and p53 expression for the PPTP models tested were available through Affymetrix U133 Plus 2.0 arrays (Clin Cancer Res 2008:14:4572–83). Results: In vitro, RG7112 produced treated to control (T/C) ratios approaching 0% for most p53 WT cell lines at the highest concentration tested. The median IC50 for RG7112 was ∼0.4 μM on p53 WT cell lines versus > 10 μM on p53 mutant cell lines. RG7112 was well tolerated in vivo, with 44 of 45 xenograft models evaluable for efficacy. RG7112 induced significant differences in EFS (event-free survival) distribution compared to control in 15 of 27 (56%) evaluable p53 WT solid tumor xenografts. RG7112 induced a twofold or greater delay in time to event in 10 of 25 (40%) p53 WT solid tumor xenografts, including: 2/2 rhabdoid tumor, 2/2 Wilms tumor, 2/3 Ewing, 3/6 rhabdomyosarcoma models, but no neuroblastoma (n=5) or osteosarcoma (n=6) models. Objective responses were observed in 5 solid tumor xenografts: maintained complete response (MCR) or complete response (CR) for a medulloblastoma and an alveolar rhabdomyosarcoma, respectively, and partial responses (PR) for a Wilms tumor, rhabdoid tumor, and Ewing tumor xenograft. For the systemic-disease ALL panel, among 13 xenografts there were 11 CR, 1 MCR and 1 PR. Each of the 7 ALL xenografts with MLL rearrangement was sensitive to RG7112 with 6 CR and 1 MCR. Two additional MLL-rearranged xenografts (MV4;11 and RS4;11) grown subcutaneously were also tested, with the former showing MCR and the latter tumor growth delay. Solid tumor xenografts with mutant p53 (Rh30R and EW5) showed no in vivo response to RG7112 as expected. The osteosarcoma xenografts were p53 WT, but had very low p53 expression and low MDM2 expression, and they failed to respond to RG7112. The ALL xenografts expressed the highest levels of p53 and MDM2 among the PPTP panels and showed the most consistent responses to RG7112. Conclusions: RG7112 induced tumor regressions in one xenograft line from the rhabdomyosarcoma, medulloblastoma, Wilms tumor, Ewing and rhabdoid tumor panels and induced CRs or MCRs for most ALL xenografts. The consistent high level activity of RG7112 against leukemia models with MLL-rearrangement was particularly notable. This high level of activity supports prioritization of RG7112 for further evaluation. Preclinical evaluations of RG7112 with standard agents are planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C103.