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Anti-Folate Receptor alpha-directed Antibody Therapies Restrict the Growth of Triple Negative Breast Cancer

Research output: Contribution to journalArticle

Anthony Cheung, James W Opzoomer, Kristina M Ilieva, Patrycja Gazinska, Ricarda M Hoffmann, Hasan Mirza, Rebecca Marlow, Erika Francesch-Domenech, Matthew W Fittall, Diana Dominguez Rodriguez, Angela Clifford, Luned Badder, Nirmesh Patel, Silvia Mele, Giulia Pellizzari, Heather J Bax, Silvia Crescioli, Gyula Petranyi, Daniel Larcombe-Young, Debra H Josephs & 9 more Silvana Canevari, Mariangela Figini, Sarah E Pinder, Frank O Nestle, Cheryl Gillett, James Spicer, Anita Grigoriadis, Andrew Tutt, Sophia N Karagiannis

Original languageEnglish
Pages (from-to)5098-5111
JournalClinical Cancer Research
Volume24
Issue number20
Early online date1 Aug 2018
DOIs
Publication statusPublished - 15 Oct 2018

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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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