The folate receptor: What does it promise in tissue-targeted therapeutics?

Abstract

For over a decade the folate receptor has been intensively investigated as a means for tumor-specific delivery of a broad range of experimental therapies including several conceptually new treatments. Despite a few set backs in clinical trials, the literature is replete with encouraging in vitro and pre-clinical studies of gynecological and other tumors and more therapeutic approaches are ready for clinical testing. Recent studies have added myelogenous leukemias to the list of candidate cancers for FR-targeted therapies. Each approach faces unique challenges in translation that could be addressed through a mechanistic understanding of the function and expression of the receptor in the appropriate experimental systems and by improvements in the technology. This review discusses FR in the context of positive recent developments in broad areas of FR-targeted therapy and attempts to highlight its potential and the anticipated challenges.

177Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy

“…In this respect, the folate receptor is an attractive target as it has been identified as specifically associated with a variety of cancer types, such as ovarian, endometrial, lung, brain, breast, and colorectal cancer (4,5). The vitamin folic acid has been used as a targeting ligand because it binds to the folate receptor with high affinity followed by endocytotic internalization of the therapeutic payload into cancer cells (6). While folic acid conjugates of highly toxic chemotherapeutics have been successfully used in clinical trials (7,8), application of therapeutic folic acid radioconjugates is currently being developed in preclinical studies.…”

Cellular folate status modulates the expression of BCRP and MRP multidrug transporters in cancer cell lines from different origins

“…Folate homeostasis is regulated by several enzymes in the folate metabolic pathway and also different transporters that mediate the uptake and efflux of folates from cells (8). Cellular uptake of folates may proceed via three different routes, including the reduced folate carrier (RFC) (9), folate receptors (10,11), and the recently cloned proton-coupled folate transporter (12). Folylpolyglutamate synthetase (FPGS) catalyzes folate polyglutamylation process, which is responsible for increasing the cellular retention of this vitamin.…”

Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition

“…FRα is generally displayed on the apical surface of polarized epithelial cells, particularly in the proximal tubule cells of the kidney and the choroid plexus (2,(33)(34)(35). hFRβ is expressed in latter stages of normal myelopoiesis and in the placenta, spleen, and thymus (36,37). In the normal development of the myelomonocytic lineage, hFRβ can be seen as a differentiation marker coexpressed with cluster of differentiation (CD) 14 at relatively low levels in monocytes but not in CD34 + normal hematopoietic progenitors (38,39).…”