Exploiting the folate receptor α 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.