Abstract C079: Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new approach to treat pancreatic cancer

Abstract

Abstract Background and aims: Annual world-wide cancer-related fatalities remain high for pancreatic ductal adenocarcinoma (PDAC), largely due to the presence of “stem-like” tumor cells known as cancer stem cells (CSCs). Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic CSCs meet their energetic requirements; therefore, OXPHOS represents an Achille’s heel of these highly tumorigenic cells. Methods: The anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) was evaluated across primary PDAC cultures and 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action. Results: We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for PaCSCs that heavily depend on mitochondrial respiration. Conclusion Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover an unprecedented approach to fight PDAC based on targeting CSC OXPHOS. Citation Format: Bruno Jr Sainz, Sonia Alcalá, Lara Villarino, Laura Ruíz-Cañas, José Couceiro, Miguel Martínez-Calvo, Adrián Palencia-Campos, Diego Navarro, Pablo Cabezas-Sainz, Alfonso Cordero-Barreal, Juan A. Rubiolo, Cristina González-Páramos, Alfredo Carrato, Patrick C. Hermann, Laura Sánchez, Susana Torrente, Miguel Ángel Fernández-Moreno, José L. Mascareñas. Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new approach to treat pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C079.