UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

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. Green open access

[thumbnail of 1078-0432.CCR-18-0652.full.pdf]
Preview
Text
1078-0432.CCR-18-0652.full.pdf - Accepted Version

Download (2MB) | Preview

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.

Type: Article
Title: Anti-Folate Receptor alpha-directed Antibody Therapies Restrict the Growth of Triple Negative Breast Cancer
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/1078-0432.CCR-18-0652
Publisher version: http://dx.doi.org/10.1158/1078-0432.CCR-18-0652
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
URI: https://discovery.ucl.ac.uk/id/eprint/10055634
Downloads since deposit
96Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item