FOLR1

Official Full Name

folate receptor alpha

Organism

Homo sapiens

GeneID

2348

Background

The protein encoded by this gene is a member of the folate receptor family. Members of this gene family bind folic acid and its reduced derivatives, and transport 5-methyltetrahydrofolate into cells. This gene product is a secreted protein that either anchors to membranes via a glycosyl-phosphatidylinositol linkage or exists in a soluble form. Mutations in this gene have been associated with neurodegeneration due to cerebral folate transport deficiency. Due to the presence of two promoters, multiple transcription start sites, and alternative splicing, multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2009]

Synonyms

FBP; FOLR; NCFTD; FRalpha;

Bio Chemical Class

Folate receptor

Protein Sequence

MAQRMTTQLLLLLVWVAVVGEAQTRIAWARTELLNVCMNAKHHKEKPGPEDKLHEQCRPWRKNACCSTNTSQEAHKDVSYLYRFNWNHCGEMAPACKRHFIQDTCLYECSPNLGPWIQQVDQSWRKERVLNVPLCKEDCEQWWEDCRTSYTCKSNWHKGWNWTSGFNKCAVGAACQPFHFYFPTPTVLCNEIWTHSYKVSNYSRGSGRCIQMWFDPAQGNPNEEVARFYAAAMSGAGPWAAWPFLLSLALMLLWLLS

Open

Disease

Endometrial cancer, Lung cancer, Malaria, Ovarian cancer, Renal cell carcinoma, Solid tumour/cancer

Approved Drug

2 +

Clinical Trial Drug

10 +

Discontinued Drug

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Detailed Information

Folate receptor alpha (FRα) is considered to be an ideal drug-forming target due to its differential expression in multiple tumors or cancerous and normal tissues. Previously, some pharmaceutical companies have carried out the development of FRα-targeted small molecule coupling drugs or monoclonal antibody drugs, such as Eisai's humanized monoclonal antibody farletuzumab and Endocyte's small molecule coupling drug Vintafolide, but unfortunately, all of these drugs were declared clinical failures. It wasn't until antibody-coupled drugs (ADCs) began to explode on the global pharmaceutical scene that targeted FOLR1 or FRα therapeutics unexpectedly came out of the ring on the ADC track, with the fastest progress being made with ImmunoGen's ADC drug, ELAHERE(mirvetuximab soravtansine-gynx), which received FDA accelerated approval for the treatment of patients with FRα+ platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior therapies. With the confirmation of FRα's efficacy in ADC, drug companies are now laying out other tracks for targeting FRα, such as bispecific antibodies and CAR-T.

This figure illustrates the role of FRα in cell growth and its therapeutic applications. Figure 1. How FRα leads to cell growth. (Gonzalez T, et al., 2024)

1. Structure and distribution of FRα

FRα, together with FRβ, FRγ, and FRδ, all belong to the folate receptor (FR) family, encoded by the FOLR1, FOLR2, FOLR3, and FOLR4 genes, respectively. Except for FRγ, all other members of the FR family are single-chain glycoproteins anchored to the cell membrane via glycosylphosphatidylinositol (GPI), which can bind folate and transport folate into the cell via endocytosis, and are a type of folate transporter protein. Humans are unable to synthesize folic acid and must obtain it from their diet. Extracellular folate uptake occurs mainly through three types of folate transporter proteins, the reduced folate carrier RFC (encoded by the SLC19A1 gene), the proton-coupled folate transporter protein PCFT (encoded by the SLC46A1 gene), and FR. Of these, the ubiquitously expressed RFC, the main pathway for folate transport into systemic tissues, is an anionic reverse transporter protein that utilizes the higher intracellular gradient of higher organophosphates to transport folate into the cell and organophosphates out of the cell; PCFT couples folate with protons (H + ) along a pH gradient from the lower pH environment of the intestinal lumen to the higher pH environment within the intestinal cell; and FR is a high-affinity, low-flux transporter protein that transfers folate by endocytosis in selected tissues.

As mentioned earlier, FRɑ is encoded by the gene FOLR1, which is located on chromosome 11 and consists of seven exons and six introns. The FRɑ protein consists of 257 amino acids and has a molecular weight of 30 kDa. Normally, tissue expression of FRα is limited, and it is usually confined to the luminal (apical) surfaces of polarized epithelia, including the proximal renal tubules, lung type 1 and type 2 pneumocytes, choroid plexus, ovaries, fallopian tubes, uterus, cervix, epididymis, submandibular salivary glands, bronchial glands, and trophoblast cells in the placenta, which also makes the receptor less accessible to folate. In contrast, since FRα is overexpressed in cancers of epithelial origin, this also allows tumor cells to have direct access to folate.

2. Mechanism of action of FRα in tumors

FRα has now been shown to be barely expressed in normal cells, with widespread high expression in solid tumors, such as mesothelioma (72-100%), triple-negative breast cancer (35-68%), ovarian cancer (76-89%), and non-small-cell lung cancer (14-74%); whereas in non-malignant tissues, only the epithelial cells of the apical bronchus of the lungs, a certain percentage of the cells are expressed. In tumor cells, FRα can not only function as a folate transporter protein but also as a transcription factor in the process of cancer cell proliferation and metastasis. As shown in the figure below, FRα binds to folate and initiates a series of intracellular signaling cascade reactions through phosphorylation, thereby activating the ERK and STAT3 signaling pathways, which in turn activates important regulatory mechanisms of cell growth. In addition, FRα assists tumor invasion and spreading by down-regulating the intercellular adhesion molecule E-calmodulin.

3. Progress of clinical research on FRα-targeting drugs

According to incomplete statistics, a total of 43 FRα-targeting drugs or therapies have been documented worldwide, of which 13 are in the preclinical stage, one is already on the market, and 12 are currently in the clinical stage, involving a variety of drug types, including ADCs, monoclonal antibodies, CAR-T, bispecific antibodies, and fusion proteins.

A total of 21 ADC drugs targeting FRα have been documented, with 9 in preclinical stage, 7 in the clinical stage, and 1 marketed. It is the drug type with the highest number of clinical-stage drugs.

In addition to ADCs, among, the fastest clinical progress is in two vaccine products, with both monoclonal antibody and CAR-T therapies in clinical phase I. In addition, several bispecific antibodies are in the preclinical stage, such as Affmed; Roivant Sciences' AFM32 (CD16a/FRa), Phanes Therapeutics' PT790 (FRa/CD3), and PT796 (FRa/CD47) bis-antibodies and TeneoBio-developed TNB-928b, among others.

References:

Gonzalez T, Muminovic M, Nano O, et al. Folate Receptor Alpha-A Novel Approach to Cancer Therapy. Int J Mol Sci. 2024;25(2):1046.
Mai J, Wu L, Yang L, et al. Therapeutic strategies targeting folate receptor α for ovarian cancer. Front Immunol. 2024 Apr 17;15:1403324.
Elnakat H, Ratnam M. Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev. 2004;56(8):1067-1084.

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