A Perspective on the Evolving Story of PSMA Biology, PSMA-Based Imaging, and Endoradiotherapeutic Strategies

Abstract

In this review, we cover the evolution of knowledge on the biology of prostate-specific membrane antigen (PSMA) and its translation to therapy. The usual key to discovery is a realistic model for experimentation and for testing a hypothesis. A realistic model is especially needed in the case of the human prostate, which differs significantly from the prostate of species often used as research models. We will emphasize the genetic characterization of PSMA, the nature of the PSMA protein, and its role as a carboxypeptidase, with differing important substrates and products in different tissues. We give special prominence to the importance of PSMA as a target for imaging and therapy in prostate cancer and its underdeveloped role for imaging and targeting the neovasculature of tumors other than prostate cancer. Lastly, we bring attention to its importance in other nonprostatic tissues.

Keywords: angiogenesis; endoradiotherapy; folate; inflammatory bowel disease; prostate cancer; tumor neovasculature.

FIGURE 1.

Proposed mechanisms by which PSMA contributes to tumor growth and progression. Poly-γ-glutamated folates released from dead and dying tumor cells are hydrolyzed to folate by PSMA and can then be taken up by nearby healthy tumor cells via proton-coupled folate transporter (PCFT), folate receptor (FR), or reduced folate carrier (RFC). Once inside the cell, folate is again polyglutamated and used for polyamine synthesis, methylation reactions, and the nucleotide synthesis required for cell proliferation. Free glutamate released by this reaction may be taken up by glutamate receptor, stimulating proliferative growth pathways; however, the role of glutamate in this process, whether metabolic or signaling, is still being clarified.