Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer

SIMPLE SUMMARY: New therapies are urgently needed for ovarian cancer, the most lethal malignancy in women. To identify new approaches for targeting ovarian cancer, metabolic vulnerabilities must be discovered and strategies for the selective delivery of therapeutic agents must be established. New approaches that are tumor-selective and that facilitate the internalization of novel drugs or provide targets for therapy are being developed for treating ovarian cancer involving folate receptors and the proton-coupled folate transporter. New drugs are being discovered that target key metabolic processes in tumors and neighboring immune cells which contribute to tumor progression. In this review, we describe the remarkable advances in this rapidly evolving area and their extraordinary potential to improve the lives of women diagnosed with this devastating disease. ABSTRACT: New therapies are urgently needed for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy. To identify new approaches for targeting EOC, metabolic vulnerabilities must be discovered and strategies for the selective delivery of therapeutic agents must be established. Folate receptor (FR) α and the proton-coupled folate transporter (PCFT) are expressed in the majority of EOCs. FRβ is expressed on tumor-associated macrophages, a major infiltrating immune population in EOC. One-carbon (C1) metabolism is partitioned between the cytosol and mitochondria and is important for the synthesis of nucleotides, amino acids, glutathione, and other critical metabolites. Novel inhibitors are being developed with the potential for therapeutic targeting of tumors via FRs and the PCFT, as well as for inhibiting C1 metabolism. In this review, we summarize these exciting new developments in targeted therapies for both tumors and the tumor microenvironment in EOC.