The Potential of Novel Lipid Agents for the Treatment of Chemotherapy-Resistant Human Epithelial Ovarian Cancer

SIMPLE SUMMARY: Disease recurrence and chemotherapy resistance are the major causes of mortality for the majority of epithelial ovarian cancer (EOC) patients. Standard of care relies on cytotoxic drugs that induce a form of cell death called apoptosis. EOC cells can evolve to resist apoptosis. We developed drugs called glycosylated antitumor ether lipids (GAELs) that kill EOC cells by a mechanism that does not involve apoptosis. GAELs most likely induce cell death through a process called methuosis. Importantly, we showed that GAELs are effective at killing chemotherapy-resistant EOC cells in vitro and in vivo. Our work shows that the EOC community should begin to investigate methuosis-inducing agents as a novel therapeutic platform to treat chemotherapy-resistant EOC. ABSTRACT: Recurrent epithelial ovarian cancer (EOC) coincident with chemotherapy resistance remains the main contributor to patient mortality. There is an ongoing investigation to enhance patient progression-free and overall survival with novel chemotherapeutic delivery, such as the utilization of antiangiogenic medications, PARP inhibitors, or immune modulators. Our preclinical studies highlight a novel tool to combat chemotherapy-resistant human EOC. Glycosylated antitumor ether lipids (GAELs) are synthetic glycerolipids capable of killing established human epithelial cell lines from a wide variety of human cancers, including EOC cell lines representative of different EOC histotypes. Importantly, GAELs kill high-grade serous ovarian cancer (HGSOC) cells isolated from the ascites of chemotherapy-sensitive and chemotherapy-resistant patients grown as monolayers of spheroid cultures. In addition, GAELs were well tolerated by experimental animals (mice) and were capable of reducing tumor burden and blocking ascites formation in an OVCAR-3 xenograft model. Overall, GAELs show great promise as adjuvant therapy for EOC patients with or without chemotherapy resistance.