Ovarian cancer is a challenging gynecological malignancy, often diagnosed in advanced stages, which contributes to its high mortality rate. New therapeutic approaches focus on identifying unique molecular targets present on the surface of cancer cells but largely absent from healthy cells. One such target that has generated considerable interest is Folate Receptor Alpha, or FR\(\alpha\). This protein is a cell-surface receptor that is overexpressed on the membranes of a significant percentage of ovarian cancer cells. The high and selective expression of FR\(\alpha\) makes it a promising docking site for therapies designed to deliver a potent anticancer payload directly to the tumor.
Why Ovarian Cancer Cells Overexpress Folate Receptor Alpha
Folate, also known as Vitamin B9, is an essential water-soluble nutrient required for fundamental biological processes like DNA synthesis, repair, and cell division. Since cancer is characterized by rapid and uncontrolled cell proliferation, malignant cells have a drastically increased demand for folate compared to normal, quiescent tissues. Folate Receptor Alpha is a protein that serves to transport folate into cells with high efficiency, especially when folate concentrations outside the cell are low.
The overexpression of FR\(\alpha\) in ovarian cancer, particularly in high-grade serous carcinoma, is a biological adaptation to meet this accelerated growth demand. This elevated expression is often driven by genetic changes, such as gene amplification of the FOLR1 gene, which provides the blueprint for the FR\(\alpha\) protein. Epigenetic mechanisms, including a decrease in DNA methylation, also contribute to the heightened production of this receptor on the cell surface. This constitutive overexpression is maintained even after chemotherapy, which is why FR\(\alpha\) remains a persistent target in recurrent disease.
Normal tissues generally express FR\(\alpha\) at very low levels, primarily confined to the apical surfaces of certain epithelial cells in organs like the kidney, lung, and choroid plexus. The stark contrast between this minimal expression and the prevalent expression on up to 80% of epithelial ovarian cancer cells makes FR\(\alpha\) a tumor-selective target. This differential expression profile allows for the development of treatments that can specifically recognize and attack cancer cells while sparing most healthy tissue.
Utilizing FR\(\alpha\) for Early Detection and Prognosis
Measuring FR\(\alpha\) status through a tissue biopsy, using immunohistochemistry (IHC), is a standard practice for selecting appropriate patients for targeted therapies. The VENTANA FOLR1 RxDx Assay, for example, is a clinically validated test used to confirm FR\(\alpha\) positivity in tumor samples.
FR\(\alpha\) expression levels also provide important information about the likely course of the disease, acting as a prognostic biomarker. Higher levels of FR\(\alpha\) are often associated with more advanced stages and higher grades of ovarian cancer. Studies suggest that this elevated expression correlates with an increased likelihood of chemotherapy resistance and a generally less favorable patient outcome.
A shed, soluble form of the receptor, known as sFR\(\alpha\), can be detected in the patient’s bloodstream, offering a non-invasive way to monitor the disease. Measuring sFR\(\alpha\) levels correlates with the tumor burden and serves as an indicator of disease recurrence. sFR\(\alpha\) may be more accurate than the traditional ovarian cancer marker, CA-125, in tracking disease status, particularly during recurrence. Furthermore, imaging agents linked to folate are being investigated to help visualize FR\(\alpha\)-expressing tumors throughout the body, improving the precision of diagnosis and surgical planning.
Therapeutic Strategies Targeting FR\(\alpha\)
The selective nature of FR\(\alpha\) expression has led to the development of several innovative therapeutic strategies. The most clinically advanced approach involves the use of Antibody-Drug Conjugates (ADCs). ADCs are sophisticated molecules that combine the specificity of an antibody with the cell-killing power of a chemotherapy drug.
In this context, the antibody component is engineered to specifically bind to the FR\(\alpha\) protein on the cancer cell surface. Once bound, the ADC is internalized into the cell through a process called endocytosis, effectively using FR\(\alpha\) as a “Trojan Horse.” Inside the cancer cell, the highly potent chemotherapy payload, which would be too toxic to administer systemically, is released to destroy the cell. This mechanism allows for the targeted delivery of the cytotoxic agent, minimizing damage to normal, healthy cells that express little to no FR\(\alpha\).
Another strategy involves using the receptor to deliver radioactive isotopes, known as folate-targeted radiopharmaceuticals. These agents use a folate molecule to guide the radioactive material directly to the FR\(\alpha\)-expressing tumor cells. The localized radiation damages the cancer cell’s DNA, leading to its death while limiting systemic exposure. Immunotherapy approaches are also under investigation, including vaccines and specialized Chimeric Antigen Receptor (CAR) T-cell therapies, which aim to activate the patient’s immune system to recognize and attack FR\(\alpha\)-expressing cancer cells.
Current Status of FR\(\alpha\)-Targeted Treatments
The most significant clinical breakthrough in FR\(\alpha\) targeting is the development of the Antibody-Drug Conjugate, mirvetuximab soravtansine (Elahere). This drug represents the first approved targeted therapy for FR\(\alpha\)-positive ovarian cancer. It is specifically indicated for patients with platinum-resistant disease who have received one to three prior systemic treatments. It received accelerated approval from the U.S. Food and Drug Administration (FDA) in late 2022 based on data from the SORAYA trial.
The drug’s full FDA approval was later granted in early 2024 following the positive results from the confirmatory Phase 3 MIRASOL trial. In this study, mirvetuximab soravtansine demonstrated a statistically significant improvement in overall survival compared to standard-of-care chemotherapy. Patients treated with the ADC achieved a median overall survival of 16.5 months, an improvement over the 12.7 months seen with chemotherapy alone.
The MIRASOL trial also showed a significantly higher objective response rate of 42% for the ADC group, compared to 16% for the chemotherapy group. While highly effective, the drug is associated with side effects, most notably ocular toxicities like blurred vision and corneal disorders, which are managed through careful monitoring and dose adjustments. The success of mirvetuximab soravtansine has validated FR\(\alpha\) as a target and paved the way for future research into combination therapies, such as pairing the ADC with other agents like bevacizumab or immune checkpoint inhibitors.