Follistatin mRNA-Loaded Lipid Nanoparticles Target Activin A-Expressing Metastatic Ovarian Cancer and Associated Cachexia [ID 1644]

INTRODUCTION: Metastatic ovarian cancer, often accompanied by cachexia, is a deadly gynecological malignancy. Activin A (ActA), overexpressed in ovarian, endometrial, and cervical cancers, promotes tumor growth, metastasis, and muscle atrophy. Follistatin (FST), an ActA inhibitor, is a promising therapeutic target. Lipid nanoparticles (LNPs), proven effective in COVID-19 vaccines, offer efficient mRNA delivery for transient protein expression. This study investigates LNP-based Fst mRNA therapy to inhibit ActA activity in ovarian cancer and cachexia. Given the scarcity of murine gynecological cancer models overexpressing ActA, we also evaluated efficacy in ActA-overexpressing head and neck and lung cancer models. METHODS: Fst mRNA LNPs were administered intraperitoneally in murine models of metastatic ovarian cancer, alone and combined with cisplatin. Outcomes included cancer progression, serum ActA levels, muscle mass, cachexia markers, and survival. RESULTS: Fst mRNA LNP therapy reduced serum ActA levels twofold. Combined with cisplatin, it extended survival to 33.8 ± 2.4 days versus 21.2 ± 1.66 days (cisplatin-only). It reversed 37% muscle loss in controls, increased muscle fiber cross-sectional area by 90%, and decreased malignant ascites fivefold, forming easily resectable nonadherent tumors. Similar reductions in cachexia and metastasis were observed in head and neck and lung cancer models overexpressing ActA. CONCLUSIONS/IMPLICATIONS: Fst mRNA LNP therapy offers a novel approach to treating metastatic ovarian cancer and associated cachexia by inhibiting ActA. It delays tumor progression, reduces muscle wasting, and significantly decreases malignant ascites. Leveraging LNPs, proven effective in COVID-19 vaccines, this therapy shows promise for improving outcomes in ovarian cancer patients, warranting further clinical investigation.