FOLR1 is a gene that provides instructions for producing a protein called folate receptor alpha. This protein regulates the movement of folate, a B-vitamin, into cells. Folate receptor alpha helps cells acquire this important nutrient, which is involved in many biological processes.
Understanding FOLR1
The FOLR1 gene, located on human chromosome 11 at position 11q13.4, encodes the protein known as folate receptor alpha (FRĪ±). This protein is a member of the folate receptor family and is also known as folate-binding protein (FBP) or ovarian tumor-associated antigen Mov18. Folate receptor alpha is found on the surface of cells, anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) linkage.
The protein can also exist in a soluble form. Folate receptor alpha is abundant in tissues like the brain, especially in an area called the choroid plexus, and in epithelial cells of the kidney, lung, placenta, and thymus. Its structure includes a deep binding pocket that allows it to bind to folate with high affinity.
FOLR1’s Role in Folate Transport
Folate receptor alpha’s primary function is the binding and transport of folate, also known as vitamin B9, into cells. Folate is an essential nutrient that cells require for various metabolic processes. These processes include the production and repair of DNA, the regulation of gene activity, and the synthesis of proteins.
Folate receptor alpha works by attaching to 5-methyl-tetrahydrofolate (5-MTHF), a form of folate circulating in the bloodstream. This binding triggers a process called receptor-mediated endocytosis, where the cell surface membrane, with the folate-bound receptor, internalizes to form a vesicle. Once inside the cell, the vesicle’s slightly acidic environment changes the receptor’s shape, reducing its affinity for folate and leading to the vitamin’s release into the cell’s cytoplasm. The receptor is then recycled back to the cell surface to facilitate further folate uptake. This mechanism ensures a controlled delivery of folate into cells.
Implications of FOLR1 in Disease
Dysregulation or altered expression of FOLR1 is associated with various health conditions. In certain cancers, such as ovarian, lung, and triple-negative breast cancers, FOLR1 is overexpressed. This overexpression can fuel cancer growth by providing rapidly dividing cancer cells with an increased supply of folate, which is necessary for their proliferation and DNA synthesis. In ovarian cancer, specifically epithelial ovarian cancer (EOC), FOLR1 is highly expressed in approximately 80-90% of cases. Elevated FOLR1 expression in these tumors has been linked to a more aggressive disease phenotype.
FOLR1 also plays a role in neurological disorders. Mutations in the FOLR1 gene can cause cerebral folate transport deficiency, a rare autosomal recessive disorder. This deficiency results from a loss of function of the folate receptor alpha protein, which impairs the transport of folate into the cerebrospinal fluid (CSF). Consequently, the brain experiences a shortage of folate, even if systemic folate levels are normal, leading to neurological problems and impacting brain cell functions like DNA, protein, and neurotransmitter production. The deficiency also affects the stability of myelin, a fatty substance that insulates nerve fibers, leading to leukodystrophy.
Therapeutic Approaches Targeting FOLR1
The understanding of FOLR1’s role in various diseases has led to its exploration as a target for therapeutic interventions. Because FOLR1 is overexpressed in several cancer types, it has become a valuable diagnostic and prognostic biomarker. Detecting elevated levels of FOLR1, particularly in serum, can indicate the presence of certain cancers, such as ovarian carcinoma, and has shown correlation with established markers like CA125.
Therapeutic strategies targeting FOLR1 include developing drugs that specifically bind to the receptor. One such approach involves antibody-drug conjugates (ADCs), which deliver a potent chemotherapy agent directly to cancer cells that express FOLR1. For example, ELAHERE (mirvetuximab soravtansine-gynx) is an ADC approved by the FDA for treating FOLR1-positive platinum-resistant ovarian cancer. This therapy uses a companion diagnostic test to identify eligible patients. Other strategies include monoclonal antibodies that target FOLR1 and folate-targeted therapies, which leverage folate’s natural affinity for the receptor to deliver therapeutic agents. Research continues to explore combinations of FOLR1-targeting agents with other inhibitors, such as PI3K, mTOR, FGF(R), and VEGF inhibitors, to enhance therapeutic potential, particularly in ovarian cancer.