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The transcription factor CCAAT/Enhancer Binding Protein β (C/EBPβ) is aberrantly activated in many cancers, where it drives a genetic profile that promotes survival and proliferation of tumor cells and inhibits differentiation. ST101 is a peptide antagonist of C/EBPβ that prevents its dimerization by binding the leucine zipper domain, ultimately targeting C/EBPβ for proteosomal degradation. Here we describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of ST101 in a non-clinical orthotopic breast cancer model. An integrated population PK/PD model was developed to describe the exposure−response relationship for ST101 anti-tumor activity in female Balb/c mice bearing 4T1-luc triple-negative breast cancer orthotopic tumors. Exposure−response predictions were made based on estimated potency in mice and mean plasma concentrations observed at the doses investigated. Approximately 100% tumor growth inhibition (TGI) was observed at the highest doses administered in this study. The AUC values required to achieve IC50 and IC90 were 80,500 and 99,600 ng/ml*hr, respectively, corresponding to cumulative doses of 97 mg/kg and 120 mg/kg per week in mice. The integrated model provides a useful tool to characterize and predict the ST101 dose-response relationship, provide a quantitative rationale for dose selection in a phase 2 clinical trial and supports the continued development of ST101 as a potent peptide therapeutic for patients with solid tumors. Citation Format: Jim Rotolo, Mark Koester, Rick Ramirez, Erin Gallagher, Lila Ghamsari, Siok Leong, Emad Darvishi, Jerel Gonzales, Timothy Taylor, Richard Upton, Gene Merutka, Barry Kappel. Characterizing the PK/PD relationship of C/EBPβ antagonist peptide ST101 in a mouse orthotopic breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB206. |
