Abstract B011: FSHR and AMHR-targeted gene delivery for potential high-grade serous ovarian cancer gene therapy

Abstract Objective High-grade serous ovarian cancer (HGSOC) is the most common prevalent ovarian cancer subtype, and treatment for HGSOC remains challenging due to limited effectiveness of targeted therapy. In our recent study, we developed a novel therapeutic strategy that integrates CRISPR-based gene editing with nanotechnology, utilizing a cationic synthetic polymer, poly(γ-propargyl L-glutamine (PPLQ). While this approach demonstrated promising initial results, the addition of an anionic polymer layer, necessary for systemic delivery, substantially reduced transfection efficiency in vitro. These findings highlight the need for further optimization of the delivery system to enhance transfection efficiency and improve therapeutic outcomes in HGSOC. Folic-stimulating hormone receptor (FSHR) is reported to be expressed in a significant proportion of ovarian cancers, while anti-Mullerian hormone receptor (AMHR) is found in various solid tumors including ovarian cancer. Given their tumor associated expression profiles, FSHR and AMHR represent promising targets for the selective gene delivery to ovarian cancer cells. Method In this study, FSHR and AMHR expressions on various ovarian cancer cell lines were examined by western blotting. FSH or AMH peptides were conjugated to PPLQ, and each peptide-conjugated PPLQ was complexed with the pGL3 luciferase reporter plasmid to form polyplexes. Particle size and zeta potential were measured by Zetasizer, and the transfection efficiency was evaluated by a luminescence assay. Result The western blot analysis demonstrated that ovarian cancer cell lines including Kuramochi, CAOV3, SKOV3 and OVCAR3 express both FSHR and AMHR. Compared to the positively charged PPLQ polyplexes (+55.8 mV), The FSH-PPLQ and AMH-PPLQ polyplexes exhibited highly negative surface charges of -72.06 mV and -80.86 mV, respectively. Particle size slightly increased from 25.1 nm for the PPLQ polyplexes to 40.9 nm and 32.3 nm for the FSH-PPLQ and AMH-PPLQ polyplexes, respectably. Conclusion Through the conjugation of FSH or AMH peptide to a cationic biopolymer, PPLQ, we successfully generated negative charged polyplexes without the need for an additional anionic polymer layer which is advantageous for in vivo delivery. The finding suggests that surface conjugation of FSH or AMH peptides has a great promise as an effective strategy for targeted gene therapy in HGSOC. Citation Format: Chaebin Lee, Kevin Elias. FSHR and AMHR-targeted gene delivery for potential high-grade serous ovarian cancer gene therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B011.