1. Anti-Folate Receptor Alpha-Directed Antibody Therapies Restrict the Growth of Triple-negative Breast Cancer.
- Author
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Cheung A, Opzoomer J, Ilieva KM, Gazinska P, Hoffmann RM, Mirza H, Marlow R, Francesch-Domenech E, Fittall M, Dominguez Rodriguez D, Clifford A, Badder L, Patel N, Mele S, Pellizzari G, Bax HJ, Crescioli S, Petranyi G, Larcombe-Young D, Josephs DH, Canevari S, Figini M, Pinder S, Nestle FO, Gillett C, Spicer JF, Grigoriadis A, Tutt ANJ, and Karagiannis SN
- Subjects
- Animals, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Agents, Immunological adverse effects, Cell Line, Tumor, Cell Proliferation, Cell Survival genetics, Disease Models, Animal, Female, Folate Receptor 1 genetics, Folate Receptor 1 metabolism, Gene Expression, Humans, Immunohistochemistry, Mice, Models, Biological, Molecular Targeted Therapy, Neoplasms, Basal Cell, RNA Interference, Signal Transduction, Triple Negative Breast Neoplasms pathology, Tumor Burden, Xenograft Model Antitumor Assays, Antineoplastic Agents, Immunological therapeutic use, Folate Receptor 1 antagonists & inhibitors, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms metabolism
- 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 = 3,414) and IHC ( 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 antitumor 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 postneoadjuvant 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 postchemotherapy residual tumors. It participates in cancer cell signaling and presents a promising target for therapeutic strategies such as ADCs, or passive immunotherapy priming Fc-mediated antitumor immune cell responses. Clin Cancer Res; 24(20); 5098-111. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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