Anti-Folate Receptor Alpha-Directed Antibody Therapies Restrict the Growth of Triple-negative Breast Cancer

Anthony Cheung, James Opzoomer, Kristina M Ilieva, Patrycja Gazinska, Ricarda M Hoffmann, Hasan Mirza, Rebecca Marlow, Erika Francesch-Domenech, Matthew 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 JosephsSilvana Canevari, Mariangela Figini, Sarah Pinder, Frank O Nestle, Cheryl Gillett, James F Spicer, Anita Grigoriadis, Andrew N J Tutt, Sophia N Karagiannis

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)5098-5111
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number20
DOIs
Publication statusPublished - Oct 15 2018

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    Cheung, A., Opzoomer, J., Ilieva, K. M., Gazinska, P., Hoffmann, R. M., Mirza, H., Marlow, R., Francesch-Domenech, E., Fittall, M., Dominguez Rodriguez, D., Clifford, A., Badder, L., Patel, N., Mele, S., Pellizzari, G., Bax, H. J., Crescioli, S., Petranyi, G., Larcombe-Young, D., ... Karagiannis, S. N. (2018). Anti-Folate Receptor Alpha-Directed Antibody Therapies Restrict the Growth of Triple-negative Breast Cancer. Clinical Cancer Research, 24(20), 5098-5111. https://doi.org/10.1158/1078-0432.CCR-18-0652