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Exploiting the folate receptor α in oncology

Abstract

Folate receptor α (FRα) came into focus as an anticancer target many decades after the successful development of drugs targeting intracellular folate metabolism, such as methotrexate and pemetrexed. Binding to FRα is one of several methods by which folate is taken up by cells; however, this receptor is an attractive anticancer drug target owing to the overexpression of FRα in a range of solid tumours, including ovarian, lung and breast cancers. Furthermore, using FRα to better localize effective anticancer therapies to their target tumours using platforms such as antibody–drug conjugates, small-molecule drug conjugates, radioimmunoconjugates and, more recently, chimeric antigen receptor T cells could further improve the outcomes of patients with FRα-overexpressing cancers. FRα can also be harnessed for predictive biomarker research. Moreover, imaging FRα radiologically or in real time during surgery can lead to improved functional imaging and surgical outcomes, respectively. In this Review, we describe the current status of research into FRα in cancer, including data from several late-phase clinical trials involving FRα-targeted therapies, and the use of new technologies to develop FRα-targeted agents with improved therapeutic indices.

Key points

  • Non-malignant tissues have limited folate receptor α (FRα) expression; however, this receptor is overexpressed in a number of solid tumours, such as ovarian, triple-negative breast and lung cancers, making it a promising target for anticancer drug development.

  • FRα has a high affinity for folates not present in a normal balanced diet, such as folic acid, compared with other folate transporters, making FRα a target for folic acid conjugates.

  • Fluorescent folate conjugates can improve the surgical resection of FRα-expressing cancers when used intraoperatively and are currently being tested in late-phase clinical trials.

  • Following the disappointing single-agent activity of FRα-targeted antibodies and early folate–drug conjugates, reproducible single-agent activity has been seen with FRα-targeted antibody–drug conjugates and small molecules; clinical trials exploring the efficacy of these agents are currently ongoing.

  • FRα can potentially be targeted using chimeric antigen receptor T cell therapy platforms, and early phase clinical trials in this area have been initiated.

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Fig. 1: Cancers that overexpress FRα and concordant expression of FRα in non-malignant tissues.
Fig. 2: FRα as a treatment target in patients with cancer.
Fig. 3: Clinical applications of FRα-targeting agents in the diagnosis and treatment of cancer.

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Acknowledgements

All authors acknowledge funding from Cancer Research UK, The Experimental Cancer Medicine Centre, and Biomedical Research Centre Initiatives awarded to the (UK) Institute of Cancer Research and the Royal Marsden Hospital NHS Foundation Trust. U.B. is a recipient of a (UK) National Institute of Health Research Professorship award (ref RP-2016-07-028).

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Nature Reviews Clinical Oncology thanks S. Canevari, L. Teng and X. Shi for their contribution to the peer review of this work.

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All authors researched data for this article and made a substantial contribution to discussions of content. M.S., E.C. and U.B. wrote the manuscript, and M.S., S.B. and U.B. edited and/or reviewed the manuscript prior to submission.

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Correspondence to Udai Banerji.

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Competing interests

S.B. has received institutional research grants from AstraZeneca. She has received honoraria for advisory board membership, lectures and/or reimbursement from AstraZeneca, Clovis, Gamamabs, Immunogen, Merck Serono, Nucana, Roche, Seattle Genetics, and Tesaro. She has acted as an unpaid Trial Steering Committee Member for the FORWARD I trial (Immunogen) and the Local Principal Investigator for the phase I ONX-0801/CT900 trial. U.B. has received institutional research funding for the investigator-initiated trial of ONX-0801 (discussed in the article) from BTG International and ONYX Pharmaceuticals and institutional funding for other investigator-initiated trials from AstraZeneca, Chugai and Verastem. He is a full-time employee of the (UK) Institute of Cancer Research, which is involved in the development of inhibitors of PI3K, HSP90, AKT, HDAC, ROCK, RAF, CHK1, MPS-1, HSF1 and FRα-targeted drugs including CT900. He has received honoraria from Astellas, Astex, Boehringer–Ingelheim, Eli Lilly, Janssen, Karus Therapeutics, Novartis, Phoenix Solutions and Vernalis. He has acted as an unpaid adviser to Sierra Oncology. E.C. and M.S. declare no competing interests.

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Scaranti, M., Cojocaru, E., Banerjee, S. et al. Exploiting the folate receptor α in oncology. Nat Rev Clin Oncol 17, 349–359 (2020). https://doi.org/10.1038/s41571-020-0339-5

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