Abstract 1500: Inhibition of tumor hypoxia response with synthetic transcriptional repressors

Abstract Hypoxia, a hallmark of aggressive solid tumors, promotes metastasis and therapy resistance by activating factors such as hypoxia-inducible factors (HIFs) that support cellular adaptation and tumorigenesis. Under hypoxic stress, transcription factors like HIFs and X-box-binding protein 1 (XBP1) are activated and bind to unfolded protein response element (UPRE) and hypoxia response element (HRE) motifs, regulating oncogenic gene expression. We identified that the core HRE motif (5’-ACGTG-3’) is embedded within the canonical UPRE motif (5’-TGACGTGG-3’), and prior research shows overlap in the binding patterns of HIF1α/ARNT and XBP1. We propose a novel strategy to target the tumor hypoxia response by using fully synthetic transcriptional repressor (STR) peptides that mimic the basic leucine zipper DNA-binding domain of XBP1. These peptides effectively bind to UPRE and HRE DNA elements. Our lead peptide, STR22, inhibits the DNA binding of both XBP1 and HIF1A, resulting in global suppression of the hypoxia response transcriptional program in vitro and in triple-negative breast cancer (TNBC) tumor models. STR22 has shown no observable toxicity with either intratumoral or intravenous administration and significantly inhibits tumor growth and metastasis in TNBC-bearing mice. Our findings validate STRs as a safe and promising approach for targeting DNA motifs, including tumor hypoxia response elements, through direct DNA binding competition with oncogenic transcription factors. This strategy offers potential to outperform single-factor therapies, presenting a novel option for clinical applications. Citation Format: Long Chi Nguyen, Zeyu Qiao, Dongbo Yang, Christopher Dann, Deborah Thomas, Madeline Henn, Andrea Valdespino, Colin Swenson, Scott Oakes, Marsha Rich Rosner, Raymond Moellering. Inhibition of tumor hypoxia response with synthetic transcriptional repressors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1500.