Abstract 1124: Prevention of radiation-induced malignancies in Li-Fraumeni syndrome

Abstract PURPOSE: Li-Fraumeni Syndrome (LFS) is a genetic disorder associated with a significant risk of early-onset cancer. This condition is driven by germline mutations in the TP53 gene which plays a primary role in the regulation of the radiation response. Aberrant TP53 function contributes to radiation vulnerability and a greater risk of secondary, radiation-induced malignancies (RIMs). As a result, therapeutic options for LFS patients are often limited to exclude radiotherapy (RT), which may otherwise be beneficial for the treatment of certain primary tumors. Data from our lab demonstrate an aberrant transcriptomic response to irradiation (IR) in mutant p53 patient skin fibroblasts compared to wildtype; however, it is unknown whether reprogramming this radiation response can decrease the risk of RIM in LFS. Metformin, a commonly prescribed anti-diabetic drug, is associated with lower cancer incidence and may decrease cancer-related mortality in murine LFS models. In addition to its potential anti-tumorigenicity, studies have shed light on the ability of metformin to prevent IR-induced damage in normal tissue; hence, we hypothesize that metformin can reprogram the radiation response to protect against radiation injury and delay the onset of RIM in LFS. METHODS: To establish a murine model of RIM in LFS, and to investigate whether metformin can delay tumor onset in this model, whole-body or localized IR were administered to mice harboring a hotspot Trp53R172H/+ mutation in the presence and absence of metformin. Serial MRI was conducted to monitor for tumor development. To understand the effect of metformin on the mutant p53 radiation response in vivo, a similar murine workflow was established and irradiated skin was collected longitudinally from untreated and metformin-treated cohorts for whole transcriptome sequencing. Sequencing data were functionally validated in a separate cohort of mice using flow cytometry. In parallel, we performed RNA sequencing on LFS patient fibroblasts to characterize the effect of metformin on the human radiation response. RESULTS: We demonstrate that IR decreases tumor latency in TP53R172H/+ mice, and that metformin significantly delays tumor onset within the radiation field. Moreover, transcriptomic data revealed that metformin upregulates apoptosis following IR in TP53R172H/+ mice. Flow cytometry analysis of the radiation response validated these findings, demonstrating that metformin promotes the apoptosis-driven clearance of damaged, potentially tumorigenic cells following IR. Transcriptomic data from patient cell lines will be presented. CONCLUSIONS: Overall, we show that metformin may delay RIM in LFS mice, and have begun to characterize the biology underpinning this reprogrammed response to IR. This study is the first to highlight metformin as a radioprotective agent in the context of germline mutant p53, with the potential to broaden RT treatment options for LFS patients. Citation Format: Pamela Psarianos, Nicholas Fischer, David Malkin. Prevention of radiation-induced malignancies in Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1124.