Abstract P5-08-08: C/EBPβ antagonist peptide, ST101, as a novel therapeutic for breast cancer

Abstract

Abstract CCAAT/Enhancer Binding Protein Beta (C/EBPβ) is an oncogenic transcription factor that is active in many cancers, where it drives the expression of factors that promote tumor survival and proliferation. In breast cancer, increased C/EBPβ expression is associated with a metastatic phenotype, high tumor grade and an overall poor prognosis (Zahnow, 2009). C/EBPβ forms dimers via leucine zipper domain interactions that are required for its transcriptional activity . 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 binds to the C/EBPβ leucine zipper domain and antagonizes it’s dimerization, resulting in increased C/EBPβ proteosomal degredation and significantly decreased target gene transactivation. Here, we describe the non-clinical anti-tumor activity of ST101 against breast cancer. In vitro studies in 4T1-luc triple-negative (TNBC) and MCF7 HRPOS BC cells demonstrate ST101 dose-dependent cytotoxicity (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 HR-negative BC and TNBC tumoroids in vitro, ST101 exposure resulted in a dose-dependent reduction in proliferation and viability, with EC50 values of 18.56 and 15.32 µM, respectively. In vivo experiments indicate significant anti-tumor activity. In a MCF7 subcutaneous xenograft model, 25 mg/kg ST101 resulted in tumor growth delay and a significant decrease in tumor volume (p<0.001 vs. controls). In a 4T1-luc orthotopic model, ST101 resulted in dose-dependent tumor growth inhibition, and tumor regression following 25 mg/kg ST101 (p<0.001 vs. controls). These data emphasize the potential of ST101 as a potent peptide therapeutic for HRPOS and triple-negative BC. Citation Format: Jim Rotolo, Mark Koester, Rick Ramirez, Siok Leong, Lila Ghamsari, Erin Gallagher, Emad Darvishi, Gene Merutka, Barry Kappel. C/EBPβ antagonist peptide, ST101, as a novel therapeutic for breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-08.