Targeting Folate Receptor Alpha for Ovarian Cancer Treatment Strategies
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Targeting Folate Receptor Alpha for Ovarian Cancer Treatment Strategies
Epithelial ovarian cancer (EOC) accounts for approximately 95% of ovarian cancer cases and remains a leading cause of gynecologic cancer-related mortality worldwide.
Currently, the standard treatment for newly diagnosed patients involves surgical removal of ovarian tumors followed by adjuvant or postoperative platinum-based chemotherapy. While most patients initially respond to chemotherapy, regrettably, up to 80% of them experience relapse, ultimately leading to fatalities.
Vascular endothelial growth factor inhibitors (e.g., bevacizumab) and poly(ADP-ribose) polymerase inhibitors (e.g., olaparib) have offered some clinical benefits to a subset of patients, albeit only slowing the recurrence of platinum-resistant EOC.
Large-scale clinical trials of immune checkpoint inhibitors (e.g., anti-PD1/L1 monoclonal antibodies) have failed to provide clinical benefits in EOC.
Over the past several decades, the 5-year relative survival rate for epithelial ovarian cancer has seen limited improvement, increasing from 43% in 1995 to 50% in 2018.
Consequently, treatment options for platinum-resistant EOC patients are extremely limited, representing a significant unmet clinical need.
Folate Receptor Alpha (FRα) as a Promising Therapeutic Target
Folate receptor alpha (FRα), encoded by the FOLR1 gene, has gained significant attention as a promising therapeutic target due to its widespread overexpression in EOC cells.
Recently, the first FRα-targeting antibody-drug conjugate (ADC) named mirvetuximab soravtansine (Elahere) received approval from the U.S. FDA for the treatment of platinum-resistant epithelial ovarian cancer. This approval has reignited interest in developing other FRα-targeting drugs for the treatment of EOC and other indications.
Folate Transport Proteins
The human body cannot synthesize folate, a vital vitamin required for the proliferation and differentiation of eukaryotic cells. Folate must be obtained from dietary sources.
The uptake of extracellular folate into cells is primarily facilitated by three types of folate transport proteins: Reduced Folate Carrier (RFC), Proton-Coupled Folate Transporter (PCFT), and Folate Receptor (FR).
The widely expressed RFC serves as the primary route for folate transport into systemic tissues, while PCFT, a proton-coupled transporter, is responsible for the absorption of dietary folate in the small intestine.
Both RFC and PCFT are low-affinity, high-capacity transport proteins. In contrast, FR is a high-affinity, low-capacity transport protein that mediates folate transfer through endocytosis in select tissues.
The FR family comprises four members: FRα, FRβ, FRγ, and FRδ, encoded by FOLR1, FOLR2, FORR3, and FOLR4, respectively.
FRα, FRβ, and FRδ are cell membrane proteins anchored by glycosylphosphatidylinositol (GPI), whereas FRγ is a secreted protein lacking a GPI-anchoring region.
FRα is the most extensively studied family member, predominantly expressed on the apical brush border membrane of epithelial cells in various tissues, including proximal renal tubular cells, retinal pigment epithelium, choroid plexus, lungs, ovaries, fallopian tubes, uterus, cervix, epididymis, submandibular salivary glands, bronchial glands, and the trophoblast layer of the placenta.
FRβ is primarily expressed in the placenta and myeloid cells, including activated macrophages, tumor-infiltrating macrophages, and acute and chronic myeloid leukemia cells.
FRγ is expressed in neutrophils and monocytes, while FRδ exhibits high expression in regulatory T cells and mammalian oocytes.
FRα in Physiology and Pathology
Folate (FA) is essential for embryonic development. Folate deficiency can lead to embryo mortality, including neural tube defects and orofacial abnormalities. Supplementation of folate by pregnant women before and during pregnancy significantly reduces embryo mortality rates. FRα is also necessary for the maintenance of several organ functions.
In the kidneys, FRα is the main transporter for folate reabsorption, and deletion of the Folr1 promoter results in impaired renal tubular folate reabsorption in spontaneous hypertensive rats (SHR), increasing the risk of diabetes and cardiovascular diseases.
In the brain, FRα is selectively expressed in the choroid plexus and promotes the vesicular transport of 5-methyltetrahydrofolate (5-mTHF) through the choroid plexus. Mutations in the FOLR1 gene lead to inadequate folate transport in the brain, causing neurodegenerative diseases in childhood.
In cancer, it has been proposed that FRα may promote tumorigenesis by facilitating the uptake of folate salts through increased one-carbon metabolism, although even with overexpressed FRα, the primary route for folate transport into cells is RFC.
Therefore, increasing folate levels is unlikely to be the main mechanism by which FRα promotes tumorigenesis.
Additionally, once inside the cell through endocytosis, FRα and associated FA can activate several cell pathways.
FRα can translocate to the cell nucleus and act as a transcription factor, promoting the expression of several genes, including Oct4, Sox2, Klf4, Hes1, and Fgfr4.
The FA-FRα complex can interact with gp130, initiating the JAK-STAT3 pathway, which is often associated with adverse patient outcomes.
The FRα-FA complex also interacts physically with the progesterone receptor, promoting ERK1/2 phosphorylation.
FRα can also promote cancer cell metastasis by downregulating the cell adhesion molecule E-cadherin.
Therapeutic Strategies Targeting FRα
The high expression of FRα in malignant tumors makes it an attractive target for anticancer drug development.
Various strategies have been explored, including monoclonal antibodies, ADCs, FRα-specific CAR-T cells, vaccines, small molecules, and folate-linked drugs. Some clinical trials involving FRα-targeting drugs are currently underway.
Monoclonal Antibodies
Several FRα-targeting monoclonal antibodies have been developed, including farletuzumab, MOv18 (IgG1), MOv18 (IgE), and MOv19 (IgG2A). Farletuzumab (MORab003) was the first anti-FRα monoclonal antibody, showing potential anticancer activity through inducing antibody-dependent cell cytotoxicity (ADCC), complement-dependent cell cytotoxicity (CDC), and sustained autophagy of tumor cells.
In a Phase I study, farletuzumab demonstrated good tolerability in EOC patients. In a Phase II study, farletuzumab, when combined with carboplatin and paclitaxel, increased response rates and duration of response in platinum-sensitive ovarian cancer patients. Unfortunately, it did not meet the clinical endpoint of PFS in a Phase III clinical trial for ovarian cancer patients. However, farletuzumab was incorporated as the anti-FRα component in the ADC drug MORAb-202.
MOv18 (IgG1) was not further developed. Two derivatives of MOv19 (IgG2A) have entered clinical trials, with one being M9346A, which is an anti-FRα antibody component of Elahere.
Anti-FRα ADCs
Mirvetuximab soravtansine, developed by ImmunoGen, is the first ADC targeting tumor cells expressing FRα. It consists of a humanized anti-FRα monoclonal antibody (M9346A), a cleavable linker, and the cytotoxic molecule DM4. DM4 exerts potent anti-mitotic effects by inhibiting microtubule dynamics. In 2022, Elahere received accelerated FDA approval for the treatment of adult patients with FRα-positive, platinum-resistant recurrent ovarian cancer (PROC), fallopian tube cancer, or primary peritoneal cancer.
The efficacy of Elahere in epithelial ovarian cancer has been studied in several clinical trials as monotherapy or in combination with other anticancer drugs. In an initial Phase I study (NCT01609556), preliminary data showed safety and efficacy. Out of 44 enrolled patients, two EOC patients had the most clinical benefit. The objective response rate (ORR) was 22%, and a superior response was observed in the subgroup with the highest FRα levels, with an ORR of 31% and a progression-free survival (PFS) of 5.4 months.
Building upon these results, a randomized, multicenter Phase III study, FORWARD I (NCT02631876), included platinum-FRα-positive PROC patients who had developed resistance to Elahere or chemotherapy. Elahere’s efficacy (ORR 47%, PFS 6.7 months) surpassed that of conventional single-agent chemotherapy.
Subsequent clinical trials explored combination approaches. In the FORWARD II trial, PROC patients positive for FRα received Elahere and bevacizumab. The ORR was 39%, including 5 complete responses (CR) and 21 partial responses (PR). The median PFS was 6.9 months. Consequently, the combination of Elahere and bevacizumab proved effective with durable responses and manageable safety for PROC patients.
The most common treatment-related adverse events for Elahere were diarrhea, blurred vision, nausea, and fatigue. These adverse events were mostly mild (Grade 1 or 2) and easily manageable with supportive care. Reversible ocular adverse events (AE) occurred frequently among patients, mainly involving corneal changes and blurred vision. The root cause of this ocular toxicity, which may be attributed to DM4, remains unclear.
MORAb-22 is an ADC that links a humanized anti-FRα antibody with the microtubule-targeting drug eribulin. Phase I clinical trial results demonstrated an ORR of 45.45% in 22 patients with late-stage solid tumors positive for FRα, with a CR of 4.5% and PR of 40.9%. Further exploration in a Phase II clinical trial is ongoing.
FRα-Specific CAR-T Cells
Preclinical studies indicated that FRα-specific CAR-T cell therapy had potent antitumor effects. However, a Phase I trial in ovarian cancer patients showed no reduction in tumor burden, primarily due to poor survival of these T cells. The addition of co-stimulatory signals, including CD27, CD28, CD134 (OX-40), and CD137 (4-1BB), to CARs has been shown to promote T cell survival. A CAR-T cell therapy, MOv19-BBZ, which fuses the 4-1BB and TCR zeta signaling domains, is currently undergoing evaluation in a Phase I clinical trial for recurrent high-grade serous ovarian cancer.
Vaccines
Peptide vaccines represent another strategy to stimulate anticancer immunity. FRα-derived peptides E39 (amino acids 191-199) and E41 (amino acids 245-253) have shown immunogenicity. In a Phase I/IIa trial involving 51 patients, E39 in combination with GM-CSF demonstrated good tolerability and potential benefit in preventing recurrence in high-risk ovarian cancer and endometrial cancer. In another Phase I trial, the safety and immunogenicity of five FRα-derived peptides were tested in breast and ovarian cancer patients. These studies suggest that FRα-derived peptides are safe, but their clinical efficacy requires further investigation.
Other Therapeutic Approaches
BGC 945 (ONX-0801 or CT900) is an inhibitor of thymidylate synthase internalized by FRα. In a recent Phase I clinical trial, it showed clinical benefits in patients with high-level serous cancer expressing medium to high levels of FRα. The most common treatment-related adverse events included fatigue, nausea, diarrhea, cough, anemia, and pneumonia.
EC131 is the first folate-linked compound comprising a potent microtubule inhibitor, DM1, linked to FA via a disulfide bond. EC131 has not been clinically tested yet. EC2629 is a folate-linked compound of the DNA crosslinker pyrrolobenzodiazepine (PBD). Preclinical studies have shown the antitumor activity of EC2629 in solid tumors, including ovarian cancer, endometrial cancer, and triple-negative breast cancer. BMS753493 is a folate-linked compound of an epothilone analog, with limited efficacy observed in solid tumors, including ovarian cancer, leading to its discontinuation.
EC145 (vinorelbine) is a water-soluble derivative of FA linked to the drug DAVLBH. In a Phase I trial, partial responses were observed in one patient with metastatic cancer. In a randomized Phase II trial for platinum-resistant ovarian cancer patients, the combination of EC145 and pegylated liposomal doxorubicin (PLD) showed superior efficacy compared to standard therapy. Unfortunately, in a Phase III clinical trial (NCT01170650), PFS was not met in ovarian cancer patients.
Conclusion
In the past decade, significant progress has been made in understanding the molecular characteristics of EOC. However, platinum resistance remains a major clinical challenge, making EOC the deadliest gynecologic malignancy.
Anti-angiogenic agents and PARP inhibitors have not significantly improved overall survival in most patients, highlighting the urgent need for innovative and effective treatment strategies.
In this regard, FRα has become an attractive and clinically validated candidate for targeted therapies.
The relative high expression of FRα on the surface of cancer cells and its ability to deliver cytotoxic payloads to cancer cells have spurred the development of various treatment modalities, including antibodies, ADCs, CAR-T cells, vaccines, small molecules, and folate-linked drugs.
Currently, Elahere, an FRα-targeting ADC, has been approved by the FDA for the treatment of adults with PROC, fallopian tube cancer, or primary peritoneal cancer. Several promising FRα-targeted therapies are also undergoing clinical evaluation.
Undoubtedly, the milestone approval of Elahere will inspire further enthusiasm for the development of new FRα-targeted diagnostic and therapeutic approaches to tackle epithelial ovarian cancer.
Targeting Folate Receptor Alpha for Ovarian Cancer Treatment Strategies
Reference
- Therapeutic strategies targeting folate receptor alpha for ovarian cancer. Front Immunol. 2023; 14: 1254532.
(source:internet, reference only)
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