Abstract
Simple SummaryNew 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.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.
Highlights
Introduction iationsEpithelial ovarian cancer (EOC) is the leading cause of death in women diagnosed with gynecological cancers in the USA and accounts for ~90% of ovarian cancers [1]
We provide an overview of C1 metabolism, including the recent major discoveries in this area
As FRβ expression on tumor-associated macrophages (TAMs) was induced by malignant ascites and conditioned media from fibroblasts, it was suggested that the presence of FRβ on the surface of macrophages could offer an opportunity for depleting TAMs with cytotoxic folate-conjugates or antifolates as a component of therapy [16]
Summary
Folates are members of the vitamin B9 family and are composed of a bicyclic pteridine ring which in cells can be reversibly reduced by dihydrofolate reductase with one (dihydrofolate) or two (tetrahydrofolate (THF)) reducing equivalents, a p-aminobenzoate, and an. Extracellular folates use PCFT (SLC46A1) and RFC (SLC19A1), which are facilitive transporters, as well as FRs, for cellular uptake [6,9,28,29] (Figure 1). RFC is ubiquitously expressed in tissues and tumors and is the major tissue transporter of folate cofactors (e.g., 5-methyl THF) from the systemic circulation [9,28,29]. FRα is unique in its tissue specificity in that it is expressed on apical membranes in a small number of healthy epithelial tissues, including those of the female reproductive tract, as well as the kidney, lung, choroid plexus, and placenta [6,12,13,48,49]. Compared to facilitated (anti)folate transport by RFC and PCFT, cellular uptake through endocytosis by the GPI-linked FRs is inefficient [6,29]. In normal (polarized) tissues, with the exception of the placenta, FRα localizes to luminal membranes without exposure to systemic circulation [6,11,13] These features provide a compelling rationale for developing selective FR-targeted therapeutics for solid tumors. FRα may [36] or may not [62] be associated with FOLR1 gene amplification (chromosome 11q13.3)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
