Exploiting the folate receptor [alpha] in oncology

Folate receptor [alpha] (FR[alpha]) 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 FR[alpha] 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 FR[alpha] in a range of solid tumours, including ovarian, lung and breast cancers. Furthermore, using FR[alpha] 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 FR[alpha]-overexpressing cancers. FR[alpha] can also be harnessed for predictive biomarker research. Moreover, imaging FR[alpha] 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 FR[alpha] in cancer, including data from several late-phase clinical trials involving FR[alpha]-targeted therapies, and the use of new technologies to develop FR[alpha]-targeted agents with improved therapeutic indices. Cancer cells, like non-malignant cells, are dependent on folate uptake for growth. However, cancer cells are much more reliant on folate receptors (FRs) and particularly FR[alpha] for folate uptake than non-malignant cells. In this Review, the authors describe the available data on the role of FR[alpha] as a biomarker and as a target of imaging probes, and of targeted therapies in patients with solid tumours. Key points Non-malignant tissues have limited folate receptor [alpha] (FR[alpha]) 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. FR[alpha] has a high affinity for folates not present in a normal balanced diet, such as folic acid, compared with other folate transporters, making FR[alpha] a target for folic acid conjugates. Fluorescent folate conjugates can improve the surgical resection of FR[alpha]-expressing cancers when used intraoperatively and are currently being tested in late-phase clinical trials. Following the disappointing single-agent activity of FR[alpha]-targeted antibodies and early folate-