Abstract P211: The investigational chemoprotection drug ALRN-6924, a dual inhibitor of MDMX and MDM2, shows potential for radioprotection

Abstract

Abstract Aim: We investigated whether p53 activation with ALRN-6924 can prevent toxicity in mouse models of acute radiation injury. Materials and methods: ALRN-6924 is a clinical-stage, first-in-class, stabilized cell-permeating alpha-helical peptide that disrupts the interaction of the p53 tumor suppressor protein with its endogenous inhibitors, MDMX and MDM2. In previous experiments it was shown that ALRN-6924 can induce transient, dose-dependent cell cycle arrest in the bone marrow to protect those cells from chemotherapy while not protecting p53-mutant cancer cells. Because radiation (like chemotherapy) preferentially affects proliferating cells, we hypothesized that ALRN-6924 may also protect proliferating cells in normal tissues from radiation-induced cellular toxicity. Cell cycle arrest was measured in the bone marrow of ALRN-6924-treated C57BL/6 mice by flow cytometry using EdU incorporation. Serum levels of macrophage inhibitory cytokine-1 (MIC-1), a biomarker of p53 activation, were measured by ELISA. Cell proliferation and apoptosis were measured in formalin-fixed mouse bone marrow by immunohistochemistry analysis of Ki67 and cleaved PARP, respectively. C57BL/6 mice (n=7/group) were treated with one or more intravenous 2.4 mg/kg doses of ALRN-6924 at 24, 16, 8, or 1 hour (or combinations thereof) or placebo prior to an abdominally targeted (shielded body) 15 Gy radiation dose and then monitored for body weight (BW). Results: MIC-1 was elevated in the serum of ALRN-6924-treated mice in a dose-dependent fashion. Repeated doses of ALRN-6924 every 8 hrs yielded sustained MIC-1 elevation, which correlated with reduced Ki67 positivity in the bone marrow. Treatment-dependent changes in cPARP expression were evident, but minimal in magnitude. In a nonlethal radiation exposure model, ALRN-6924 yielded significant protection from radiation-induced BW loss in a schedule-dependent manner. Placebo-treated mice showed 10% to 15% BW loss five days after irradiation, while mice receiving one or more ALRN-6924 doses 8 hrs prior to irradiation had an average of 4% BW loss (p=0.008, two-sided t test). Conclusions: ALRN-6924 mitigates toxicity in a mouse model of acute radiation injury. The observed radioprotection effect correlates with pharmacodynamic markers of cell proliferation and cell cycle arrest after one or more doses of ALRN-6924, and further supports previous demonstrations of chemoprotection with ALRN-6924. These results provide a rationale to investigate ALRN-6924 as a radioprotective agent. Citation Format: Allen Annis, David Sutton, Manuel Aivado, Vojislav Vukovic. The investigational chemoprotection drug ALRN-6924, a dual inhibitor of MDMX and MDM2, shows potential for radioprotection [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P211.