Abstract 1821: <i>In vivo</i> synergy is observed with AMG-232 and radiotherapy in endometrial cancer

Abstract Background: Approximately 15% of high-grade TP53-mutated endometrial cancers (EC) are heterozygous and retain wild-type (WT) signaling. Our previous in vitro findings nominated MDM2 inhibitors as potential radio-sensitizing strategies that leverage TP53 WT signaling. Here, we further explore this radio-sensitizing role for one particular inhibitor, AMG-232, in an in vivo xenograft model with a TP53 WT EC cell line. Methods: To evaluate the radio-sensitizing potential of AMG-232 in vivo, we utilized a xenograft tumor model with the JHUEM-2 (TP53 WT) cell line. Cells (2x106) were injected subcutaneously in the bilateral flanks of 6-8 week old female NSG mice. Mice were separated into 4 treatment groups and 6 mice (n= 12 tumors) were included in each group: Vehicle, Radiation (RT), AMG-232, and Combination. Once the largest tumors were 200-300mm3 in size, mice were given either Vehicle or AMG-232 (30 mg/kg) by gavage for 9 days. In the RT and Combination groups, a single dose of 1 Gy of radiation was given 24 hours following first drug dose. Assessment of treatment synergy was carried out using both the Highest Single Agent (HSA) and Bliss Independence models with bootstrap analysis at either single timepoints, or over the entire growth curve based on area under the curve (AUC). Synergy scores were calculated as a measure of deviation from additivity, with positive values indicating synergy. Synergy analyses were carried out using the invivoSyn package in R software. Results: AMG-232 and RT together significantly suppressed tumor growth at treatment days 7 and 9 compared to either RT alone (P= 0.004 and P= 0.0014, respectively) or AMG-232 alone (P= 0.003 and P= 0.0061, respectively). Synergy analysis of growth inhibition at treatment day 9 using both the HSA and Bliss models showed significant synergy in the combination group, with mean synergy scores of 27 (P= 0) and 25 (P= 0.003), respectively. Entire growth curve AUC analysis also showed synergy only in the less stringent HSA model, with synergy score of 37.5 (P= 0.033). Conclusions: Overall, these findings further support the use of MDM2 inhibitors to improve radiotherapy response in EC. The improved tumor response that we observed at clinically relevant doses further highlights the potential of these agents to either enhance responses to current therapeutic strategies, or to lower the radiotherapy dose necessary for complete response. Citation Format: Aaron P. Petty, Yvonne Parker, Daniel Lindner, Roberto Vargas. In vivo synergy is observed with AMG-232 and radiotherapy in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1821.