Abstract C014: Overcoming chemoresistance in ovarian cancer through therapeutic targeting of Oxysterol-Binding Proteins (OSBP/ORP4)

Abstract Overcoming clinical chemoresistance in ovarian cancer is a significant unmet therapeutic need. Targeting adaptive ovarian cancer survival mechanisms, which drive chemoresistance, is a novel and promising route for new anticancer therapeutic development. Based on our work, oxysterol-binding protein (OSBP) and oxysterol-binding protein (OSBP)-related protein 4 (ORP4) are potential precision druggable targets in ovarian cancer with a unique mechanism of inducing cancer cell death. The OSBP/ORP-targeting compound OSW-1 shows potent anti-ovarian cancer activity in patient-isolated chemoresistant multicellular ovarian cancer spheroids, outperforming the standard of care chemotherapy drugs. Our research aims to elucidate the cellular mechanism(s) by which small-molecule targeting of the OSBP/ORP4 proteins induces ovarian cancer cell death, including the patient-derived chemoresistant spheroids. Our results demonstrate that altering cholesterol uptake and/or biosynthesis sensitizes cells to the anticancer activity of OSW-1. Based on these results, our hypothetical model suggests that the OSBP/ORP4 proteins are essential for cholesterol mobilization in ovarian cancer cells, particularly in multicellular spheroids and tumors. The lack of appropriate cholesterol mobilization, resulting from the inhibition of OSBP/ORP4, limits the adaptive stress response in cancer cells, leading to non-apoptotic pathways of cell death. Additionally, to aid in novel therapeutic development, we are also defining the structure-activity relationships (SAR) of the OSBP/ORP4-targeting OSW-1 compound. Our lab has also synthesized and isolated several OSW-1 analog compounds with different structural modifications, evaluating the anticancer activity and binding affinity of this library of OSW-1-derived compounds. This presents a SAR model of OSBP/ORP4 inhibition. Our findings further establish OSBP/ORP4 as novel, cancer-specific therapeutic targets for chemoresistant ovarian cancer, delivering a foundation for developing newer generations of OSBP/ORP4 inhibitors based on the OSW-1 natural product compound. Citation Format: Swati Choudhary, Richard Hoang. Bui, Jorge L. Berrios- Rivera, Susan L. Nimmo, Anthony W. G. Burgett. Overcoming chemoresistance in ovarian cancer through therapeutic targeting of Oxysterol-Binding Proteins (OSBP/ORP4) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C014.