Anti-Folate Receptor alpha-directed Antibody Therapies Restrict the Growth of Triple Negative Breast Cancer
| Autor: | Anthony Cheung, Diana Dominguez Rodriguez, Mariangela Figini, James Spicer, Anita Grigoriadis, Cheryl Gillett, Nirmesh Patel, James W. Opzoomer, Angela Clifford, Matthew Fittall, Giulia Pellizzari, Patrycja Gazinska, Hasan Mirza, Luned M. Badder, Andrew Tutt, Frank O. Nestle, Daniel Larcombe-Young, Silvia Mele, Debra H. Josephs, Rebecca Marlow, Sophia N. Karagiannis, Silvia Crescioli, Sarah E Pinder, Heather J. Bax, Gyula M. Petranyi, Erika Francesch-Domenech, Silvana Canevari, Ricarda M. Hoffmann, Kristina M. Ilieva |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Folate Receptor Alpha Cancer Research Cell Survival Cell Gene Expression Triple Negative Breast Neoplasms Models Biological Article 03 medical and health sciences Mice 0302 clinical medicine Breast cancer Immune system Antineoplastic Agents Immunological Cell Line Tumor medicine Animals Humans Folate Receptor 1 Molecular Targeted Therapy Triple-negative breast cancer Cell Proliferation Neoplasms Basal Cell biology Cell growth business.industry medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays Tumor Burden Disease Models Animal 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research biology.protein Female RNA Interference Antibody business Signal Transduction |
| Zdroj: | Cheung, A, Opzoomer, J W, Ilieva, K M, Gazinska, P, Hoffmann, R M, Mirza, H, Marlow, R, Francesch-Domenech, E, Fittall, M W, Dominguez Rodriguez, D, Clifford, A, Badder, L, Patel, N, Mele, S, Pellizzari, G, Bax, H J, Crescioli, S, Petranyi, G, Larcombe-Young, D, Josephs, D H, Canevari, S, Figini, M, Pinder, S E, Nestle, F O, Gillett, C, Spicer, J, Grigoriadis, A, Tutt, A & Karagiannis, S N 2018, ' Anti-Folate Receptor alpha-directed Antibody Therapies Restrict the Growth of Triple Negative Breast Cancer ', Clinical Cancer Research, vol. 24, no. 20, pp. 5098-5111 . https://doi.org/10.1158/1078-0432.CCR-18-0652 |
| DOI: | 10.1158/1078-0432.CCR-18-0652 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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