Abstract 959: C/EBPβ antagonist peptide, ST101, as a therapeutic approach in breast cancer

Abstract

Abstract Breast cancer (BC) is the most common invasive cancer in women, with more than 2.1 million cases and over 626,000 deaths occurring worldwide annually. Although age-adjusted mortality from BC has been declining since 1990, the median survival for patients with metastatic disease remains at 2-3 years, and 5-year survival approximates 25%. Thus, the medical need for more effective agents in this clinical setting remains very high. CCAAT/Enhancer Binding Protein Beta (C/EBPβ) is a transcription factor overexpressed in many cancers that regulates expression of factors that promote tumor survival, proliferation and inhibit differentiation. C/EBPβ dimers, such as with Jun/Fos and CREB/ATF family members, form via basic leucine zipper (bZIP)-driven coiled-coil interactions and are necessary for its association with DNA and transcriptional activity. Due in part to the difficulty in therapeutically targeting transcription factors, no effective C/EBPβ inhibitors are clinically available. ST101 is a novel peptide antagonist of C/EBPβ currently being evaluated in a Phase 1/2 clinical study in patients with advanced unresectable and metastatic solid tumors. ST101 was designed to bind the C/EBPβ bZIP domain, thereby preventing dimer formation and inhibiting its transcriptional activity. Here we describe ST101 non-clinical anti-tumor activity to support further development as a therapeutic approach in BC. In vitro studies in 4T1-luc triple-negative breast cancer (TNBC) and MCF7 HRPOS breast adenocarcinoma cells demonstrate ST101 dose-dependent impact of cell viability (EC50 of 4.8 and 2.1 µM, respectively), accompanied by significant impact on C/EBPβ-mediated gene expression as determined by qPCR analysis. In contrast, normal human mammary epithelial cells were not sensitive to ST101 (EC50 >100 µM). In vivo experiments indicate dose-dependent tumor growth inhibition in an orthotopic 4T1-luc model following ST101 exposure, with significant tumor growth delays observed following 25 mg/kg ST101 (p<0.05 vs. controls). Mice treated with 25 mg/kg ST101 via subcutaneous injection demonstrated significant tumor growth delay and decrease in tumor volume vs. controls. These data emphasize the potential of ST101 as a potent peptide therapeutic for HRPOS and TN BC. Citation Format: Jim A. Rotolo, Mark Koester, Ricardo Ramirez, Lila Ghamsari, Siok Leong, Erin Gallagher, Gene Merutka, Barry J. Kappel. C/EBPβ antagonist peptide, ST101, as a therapeutic approach in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 959.