Is Targeting the Folate Receptor in Ovarian Cancer Coming of Age?
Ontology highlight
ABSTRACT:
SUBMITTER: Birrer MJ
PROVIDER: S-EPMC6459241 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer, and presents a major clinical challenge due to limited treatment options. Folate receptor alpha (FRα), encoded by the FOLR1 gene, is an attractive therapeutically target due to its prevalent and high expression in EOC cells. Recent basic and translational studies have explored several modalities, such as antibody-drug conjugate (ADC), monoclonal antibodies, small molecules, and folate-drug conjugate, to exploit FRα for EOC treatment. In this review, we summarize the function of FRα, and clinical efficacies of various FRα-based therapeutics. We highlight mirvetuximab soravtansine (MIRV), or Elahere (ImmunoGen), the first FRα-targeting ADC approved by the FDA to treat platinum-resistant ovarian cancer. We discuss potential mechanisms and management of ocular adverse events associated with MIRV administration.
| S-EPMC10499382 | biostudies-literature
Project description:PurposeCancer cells are highly dependent on folate metabolism, making them susceptible to drugs that inhibit folate receptor activities. Targeting overexpressed folate receptor alpha (FRα) in cancer cells offers a therapeutic opportunity. We investigated the functional mechanisms of MORAB-003 (farletuzumab), a humanized mAb against FRα, in ovarian cancer models.Experimental designWe first examined FRα expression in an array of human ovarian cancer cell lines and then assessed the in vivo effect of MORAB-003 on tumor growth and progression in several orthotopic mouse models of ovarian cancer derived from these cell lines. Molecular mechanisms of tumor cell death induced by MORAB-003 were investigated by cDNA and protein expression profiling analysis. Mechanistic studies were performed to determine the role of autophagy in MORAB-003-induced cell death.ResultsMORAB-003 significantly decreased tumor growth in the high-FRα IGROV1 and SKOV3ip1 models but not in the low-FRα A2780 model. MORAB-003 reduced proliferation, but had no significant effect on apoptosis. Protein expression and cDNA microarray analyses showed that MORAB-003 regulated an array of autophagy-related genes. It also significantly increased expression of LC3 isoform II and enriched autophagic vacuolization. Blocking autophagy with hydroxychloroquine or bafilomycin A1 reversed the growth inhibition induced by MORAB-003. In addition, alteration of FOLR1 gene copy number significantly correlated with shorter disease-free survival in patients with ovarian serous cancer.ConclusionsMORAB-003 displays prominent antitumor activity in ovarian cancer models expressing FRα at high levels. Blockade of folate receptor by MORAB-003 induced sustained autophagy and suppressed cell proliferation.
| S-EPMC4297546 | biostudies-literature
Project description:Promising targeted treatments and immunotherapy strategies in oncology and advancements in our understanding of molecular pathways that underpin cancer development have reignited interest in the tumor-associated antigen Folate Receptor alpha (FR?). FR? is a glycosylphosphatidylinositol (GPI)-anchored membrane protein. Its overexpression in tumors such as ovarian, breast and lung cancers, low and restricted distribution in normal tissues, alongside emerging insights into tumor-promoting functions and association of expression with patient prognosis, together render FR? an attractive therapeutic target. In this review, we summarize the role of FR? in cancer development, we consider FR? as a potential diagnostic and prognostic tool, and we discuss different targeted treatment approaches with a specific focus on monoclonal antibodies. Renewed attention to FR? may point to novel individualized treatment approaches to improve the clinical management of patient groups that do not adequately benefit from current conventional therapies.
| S-EPMC5239573 | biostudies-literature
Project description:Cyclins and cyclin-dependent kinases (CDKs) play versatile roles in promoting the hallmarks of cancer. Therefore, cyclins and CDKs have been widely studied and targeted in cancer treatment, with four CDK4/6 inhibitors being approved by the FDA and many other inhibitors being examined in clinical trials. The specific purpose of this review is to delineate the role and therapeutic potential of Cyclin K in cancers. Studies have shown that Cyclin K regulates many essential biological processes, including the DNA damage response, mitosis, and pre-replicative complex assembly, and is critical in both cancer cell growth and therapeutic resistance. Importantly, the druggability of Cyclin K has been demonstrated in an increasing number of studies that identify novel opportunities for its use in cancer treatment. This review first introduces the basic features and translational value of human cyclins and CDKs. Next, the discovery, phosphorylation targets, and related functional significance of Cyclin K-CDK12/13 complexes in cancer are detailed. This review then provides a summary of current Cyclin K-associated cancer studies, with an emphasis on the available Cyclin K-targeting drugs. Finally, the current knowledge gaps regarding the potential of Cyclin K in cancers are discussed, along with interesting directions for future investigation.
| S-EPMC10453554 | biostudies-literature
Project description: Not available
| S-EPMC10326788 | biostudies-literature
Project description:Novelty and Impact Statement: Our findings suggest that soluble folate receptor (sFR) could be used in both the initial diagnosis and surveillance of patients with ovarian cancer. Our cohort constitutes one of the largest comparison groups for sFR analyzed so far. We have defined the background level of sFR using healthy volunteers. This is also the first study to prospectively follow patients in the surveillance setting to concurrently identify differential changes in tumor markers CA-125 and sFR.
| S-EPMC6434204 | biostudies-literature
Project description:The development of specialized nanoparticles for use in the detection and treatment of cancer is increasing. Methods are being proposed and tested that could target treatments more directly to cancer cells, which could lead to higher efficacy and reduced toxicity, possibly even eliminating the adverse effects of damage to the immune system and the loss of quick replicating cells. In this mini-review we focus on recent studies that employ folate nanoconjugates to target the folate receptor. Folate receptors are highly overexpressed on the surface of many tumor types. This expression can be exploited to target imaging molecules and therapeutic compounds directly to cancerous tissues.
| S-EPMC3521101 | biostudies-literature
Project description:Folate uptake in epithelial ovarian cancer (EOC) involves the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), both facilitative transporters and folate receptor (FR) α. Although in primary EOC specimens, FRα is widely expressed and increases with tumor stage, PCFT was expressed independent of tumor stage (by real-time RT-PCR and IHC). EOC cell line models, including cisplatin sensitive (IGROV1 and A2780) and resistant (SKOV3 and TOV112D) cells, expressed a 17-fold range of FRα and similar amounts (within ∼2-fold) of PCFT. Novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates AGF94 and AGF154 exhibited potent antiproliferative activities toward all of the EOC cell lines, reflecting selective cellular uptake by FRα and/or PCFT over RFC. When IGROV1 cells were pretreated with AGF94 at pH 6.8, clonogenicity was potently inhibited, confirming cell killing. FRα was knocked down in IGROV1 cells with lentiviral shRNAs. Two FRα knockdown clones (KD-4 and KD-10) showed markedly reduced binding and uptake of [3H]folic acid and [3H]AGF154 by FRα, but maintained high levels of [3H]AGF154 uptake by PCFT compared to nontargeted control cells. In proliferation assays, KD-4 and KD-10 cells preserved in vitro inhibition by AGF94 and AGF154, compared to a nontargeted control, attributable to residual FRα- and substantial PCFT-mediated uptake. KD-10 tumor xenografts in severe-compromised immune-deficient mice were likewise sensitive to AGF94 Collectively, our results demonstrate the substantial therapeutic potential of novel 6-substituted pyrrolo[2,3-d]pyrimidine antifolates with dual targeting of PCFT and FRα toward EOCs that express a range of FRα, along with PCFT, as well as cisplatin resistance. Mol Cancer Ther; 16(5); 819-30. ©2017 AACR.
| S-EPMC5443351 | biostudies-literature
Project description:Tumor-associated macrophages (TAMs) facilitate cancer progression by promoting tumor invasion, angiogenesis, metastasis, inflammatory responses, and immunosuppression. Folate receptor β (FRβ) is overexpressed in TAMs. However, the clinical significance of FRβ-positive macrophages in lung cancer remains poorly understood. In this study, we verified that FRβ overexpression in lung cancer TAMs was associated with poor prognosis. We utilized a folate-modified lipoplex comprising a folate-modified liposome (F-PLP) delivering a BIM-S plasmid to target both lung cancer cells and FRβ-positive macrophages in the tumor microenvironment. Transfection of LL/2 cells and MH-S cells with F-PLP/pBIM induced cell apoptosis. Injection of F-PLP/pBIM into LL/2 and A549 lung cancer models significantly depleted FRβ-positive macrophages and reduced tumor growth. Treatment of tumor-bearing mice with F-PLP/pBIM significantly inhibited tumor growth in vivo by inducing tumor cell and macrophage apoptosis, reducing tumor proliferation, and inhibiting tumor angiogenesis. In addition, a preliminary safety evaluation demonstrated a good safety profile of F-PLP/pBIM as a gene therapy administered intravenously. This work describes a novel application of lipoplexes in lung cancer targeted therapy that influences the tumor microenvironment by targeting TAMs.
| S-EPMC6976681 | biostudies-literature
Project description:Purpose: Folate receptor alpha (FR) is overexpressed in several cancers. Endogenous immunity to the FR has been demonstrated in patients and suggests the feasibility of targeting FR with vaccine or other immune therapies. CD4 helper T cells are central to the development of coordinated immunity, and prior work shows their importance in protecting against relapse. Our previous identification of degenerate HLA-class II epitopes from human FR led to the development of a broad coverage epitope pool potentially useful in augmenting antigen-specific immune responses in most patients.Patients and Methods: We conducted a phase I clinical trial testing safety and immunogenicity of this vaccine, enrolling patients with ovarian cancer or breast cancer who completed conventional treatment and who showed no evidence of disease. Patients were initially treated with low-dose cyclophosphamide and then vaccinated 6 times, monthly. Immunity and safety were examined during the vaccine period and up to 1 year later.Results: Vaccination was well tolerated in all patients. Vaccine elicited or augmented immunity in more than 90% of patients examined. Unlike recall immunity to tetanus toxoid (TT), FR T-cell responses developed slowly over the course of vaccination with a median time to maximal immunity in 5 months. Despite slow development of immunity, responsiveness appeared to persist for at least 12 months.Conclusions: The results demonstrate that it is safe to augment immunity to the FR tumor antigen, and the developed vaccine is testable for therapeutic activity in most patients whose tumors express FR, regardless of HLA genotype. Clin Cancer Res; 24(13); 3014-25. ©2018 AACR.
| S-EPMC6030477 | biostudies-literature