Cheung, A;
Opzoomer, JW;
Ilieva, KM;
Gazinska, P;
Hoffmann, RM;
Mirza, H;
Marlow, R;
... Karagiannis, SN; + view all
(2018)
Anti-Folate Receptor alpha-directed Antibody Therapies Restrict the Growth of Triple Negative Breast Cancer.
Clinical Cancer Research
, 24
(20)
10.1158/1078-0432.CCR-18-0652.
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Abstract
PURPOSE: Highly-aggressive triple negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate Receptor alpha (FRα) is a central mediator of cell growth regulation that could serve as an important target for cancer therapy. EXPERIMENTAL DESIGN: We evaluated FRα expression in breast cancers by genomic (N = 3414) and immunohistochemical (N = 323) analyses and its association with clinical parameters and outcomes. We measured the functional contributions of FRα in TNBC biology by RNA interference and the anti-tumor functions of an antibody recognizing FRα (MOv18-IgG1), in vitro and in human TNBC xenograft models. RESULTS: FRα is overexpressed in significant proportions of aggressive basal like/TNBC tumors, and in post-neoadjuvant chemotherapy-residual disease associated with a high risk of relapse. Expression is associated with worse overall survival. TNBCs show dysregulated expression of thymidylate synthase, folate hydrolase 1 and methylenetetrahydrofolate reductase, involved in folate metabolism. RNA interference to deplete FRα decreased Src and ERK signaling and resulted in reduction of cell growth. An anti-FRα antibody (MOv18-IgG1) conjugated with a Src inhibitor significantly restricted TNBC xenograft growth. Moreover, MOv18-IgG1 triggered immune-dependent cancer cell death in vitro by human volunteer and breast cancer patient immune cells, and significantly restricted orthotopic and patient-derived xenograft growth. CONCLUSIONS: FRα is overexpressed in high-grade TNBC and post-chemotherapy residual tumors. It participates in cancer cell signaling and presents a promising target for therapeutic strategies such as antibody-drug conjugates, or passive immunotherapy priming Fc-mediated anti-tumor immune cell responses.
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