Abstract 5273: A novel immunogenic cell death that exploits the cancer-specific overexpression of Rad51

Abstract

Abstract Overexpression of the Homologous Recombination (HR) DNA repair pathway is often correlated with poor prognosis and metastatic disease. SyntheX developed STX100, a small, stabilized peptide that is able to disrupt the function of Rad51 - a crucial component of HR. STX100 exhibits low nanomolar affinity to the target, cell permeability, and proteolytic stability. STX100 has acute mono-agent activity that is selective towards HR-overexpressing cancer cells. Interestingly, STX100-mediated cell killing is independent of canonical cell death mechanisms (apoptosis, necroptosis, pyroptosis, ferroptosis, etc.). Rather, the elevated abundance of Rad51 in cancer cells relative to healthy tissues underlies the selective cytotoxicity resulting from an acute calcium surge upon STX100-mediated target engagement. The mechanism translates to in vivo models, where a single dose can achieve sustained survival when administered locally as a mono-therapy or in combination with an immune checkpoint blockade agent. Citation Format: Maria Soloveychik, Charly Chahwan. A novel immunogenic cell death that exploits the cancer-specific overexpression of Rad51 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5273.