Life activities involved in folic acid

Folic acid is an essential vitamin for one-carbon metabolism and DNA biosynthesis, repair, and methylation of rapidly proliferating cells ^[1]. Folate is transported across membranes in three ways. The main way of uptake is distributing reducing folate carriers to promote folate uptake in food. The second way is transported folate to cells by the proton-coupled folate transporter using the membrane proton gradient to mediate . The third way is transported through the folate receptor, and there are four glycopolypeptide molecules (FRα, FRβ, FRγ and FRδ) with a molecular weight of about 38-45kD. Folate receptor alpha, FR-α, also known as FOLR1 or folate-binding protein, is a glycoprotein anchored on the cell membrane by glycosylated phosphatidylinositol (GPI), and has a high affinity for folic acid , can transport folic acid by receptor-mediated endocytosis.

Function of folate receptor alpha (FR-α) 

FRα acts as a signaling molecule to promote malignant tumor growth. Similar to other glycosylated phosphatidylinositol family proteins, FRα initiates an intracellular regulatory signaling network upon binding to folic acid. Boshnjaku et al. reported that after absorbing and internalizing folic acid, FRα can localize to the nucleus and act as a transcription factor binding cis-regulatory element. FRα directly regulates the expression of key developmental genes in tumor cells through this mechanism.

After ovarian cancer cells were transfected with FRα-targeting single-chain intracellular antibodies, the expression of FRα on the cell surface was reduced, which repairs tumor cell proliferation, reduces colony formation and adhesion , and reverses the transformed phenotype of tumor cells.

FRα is known to be expressed on the entire surface of tumor cells in various cancer types including ovarian cancer, TNBC, endometrial cancer, mesothelioma and lung cancer. The role of FRα in cancer is perhaps best studied in ovarian cancer. Up to 90% of ovarian cancers constitutively express FRα, while FRα is barely expressed in non-malignant ovarian tissue. Different levels of FRα expression were observed in different histological subtypes of ovarian cancer.

▲The expression level of FRa in different types of tumors^[2]

FRα and Ovarian Cancer

Folate receptor alpha (FRα) is a potent anticancer drug target. It includes limited expression in non-malignant tissues, combined with overexpression in malignant tissues in some cancers, making FRα a potential target using multiple platforms such as antibodies, antibody-drug conjugates (ADCs), bispecific antibodies or chimeric antigen receptor (CAR) T cells.

▲FRα as a therapeutic target for cancer patients

In the 2023 V1 version of the NCCN Guidelines for Ovarian Cancer, the ADC drug Mirvetuximab soravtansine-gynx is listed as a recommended drug for the relapse treatment of platinum-resistant diseases, and it is a tumor target for FRα expression.

▲ NCCN Guidelines for Ovarian Cancer 2023 V1^[3]

For the treatment of gynecological malignant tumors, comprehensive treatment measures such as surgery, chemotherapy, and radiotherapy are currently used clinically and with postoperative adjuvant chemotherapy, it can effectively control the subclinical small tumor lesions of the tumor, thereby improving the clinical cure rate. From traditional small molecule chemotherapy drugs to antibody drugs, and then to the newly developed antibody-drug conjugates (ADC), the development of chemotherapy tends to be more targeted, with higher cytotoxicity and less adverse reactions.

At the end of 2022, the FDA granted accelerated approval to Mirvetuximab soravtansine-gynx for FRα-positive, platinum-resistant ovarian, fallopian tube or peritoneal epithelial cancer.

▲FDA official website^[4]

The drug's approval was based on the evaluation of efficacy in Study 0417 (NCT04296890), a single-arm trial of 106 patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Among patients (104 patients) with platinum-resistant measurable disease who received at least one dose of therapy, the confirmed ORR was 31.7% (95% CI: 22.9, 41.6), and the median DOR was 6.9 months (95% CI: 5.6, 9.7).

▲ NCT04296890 research data ^[5]

Future research prospects of folate receptor α in the direction of gynecological tumors

FRα is a highly relevant and potentially exploitable target in cancer therapy. In selected tumors, differential expression of FRα on the surface of malignant cells enables the development of antibody-based therapeutic strategies, including ADCs, BiTEs, and CAR-T cells. In addition, compared to natural folate in the diet, FRα's affinity for nonphysiological substrates, such as higher folate, enables the generation of folate conjugates associated with chemotherapeutic payloads, radioisotopes, and/or fluorescent molecules, thereby further Facilitate the development of anticancer drugs and imaging agents.

At present, there is generally a lack of efficient biological markers for the diagnosis, treatment and prognosis of gynecological tumors ^[6]. Further in-depth research on the expression and distribution of FRα on the surface of tumor cells can promote the research on gynecological tumor-associated antigens, and perhaps FRα can be used as a new tumor biomarker for gynecological tumors.

References

[1].doi.org/10.1038/s41571-020-0339-5

[2]. Application of folate receptor α in targeted diagnosis and treatment of ovarian cancer

[3].NCCN Guidelines Version 1.2023 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

[4].FDA official website

[5]. Elahere Drug Instructions

[6]. The current status of clinical application of folate receptor α in gynecological tumors

——This article is only used to provide scientific information to medical professionals