Review article
The prostate-specific membrane antigen: Lessons and current clinical implications from 20 years of research

https://doi.org/10.1016/j.urolonc.2013.09.003Get rights and content

Abstract

Objective

Despite a multitude of detection and treatment advances in the past 2 decades, prostate cancer remains the second leading cause of deaths due to cancer among men in the United States. Technological evolution and expanding knowledge of tumor biomarkers have invigorated exploration in prostate cancer therapeutics. Prostate-specific membrane antigen (PSMA) was one of the first prostate cancer biomarkers successfully cloned. Since then, it has been characterized as the prototypical cell-surface marker for prostate cancer and has been the subject of intense clinical inquiry. In this article, we review the relevant research in PSMA on the 20th anniversary of its cloning.

Methods and materials

A PubMed search using the keywords ā€œprostate-specific membrane antigenā€ or ā€œglutamate carboxypeptidase IIā€ provided 1019 results. An additional 3 abstracts were included from scientific meetings. Articles were vetted by title and abstract with emphasis placed on those with clinically relevant findings.

Results

Sixty articles were selected for inclusion. PSMA was discovered and cloned in 1993. Its structure and function were further delineated in the ensuing decade. Consensus sites of expression in normal physiology are prostate, kidney, nervous system, and small intestine. PSMA has been implicated in the neovasculature of several tumors including urothelial and renal cell carcinomas. In prostate cancer, expression of PSMA is directly related to the Gleason grade. PSMA has been tested both in imaging and therapeutics in a number of prostate cancer clinical trials. Several recent approaches to target PSMA include the use of small molecule inhibitors, PSMA-based immunotherapy, RNA aptamer conjugates, and PSMA-targeted prodrug therapy. Future study of PSMA in prostate cancer might focus on its intracellular functions and possible role in tumor neurogenesis.

Conclusions

Twenty years from its discovery, PSMA represents a viable biomarker and treatment target in prostate cancer. Research to delineate its precise role in prostate carcinogenesis and within the therapeutic armamentarium for patients with prostate cancer remains encouraging.

Section snippets

Objectives

Prostate cancer is the most prevalent noncutaneous malignancy in men in the United States and remains the second leading cause of deaths due to cancer in this population [1]. Recently, as a result of well-publicized large randomized controlled trials [2], [3], the use of prostate-specific antigen (PSA) as a screening tool has come under fire. This has culminated in the publication of guidelines aimed at reducing or in some cases eliminating the use of PSA as a screening tool for prostate cancer

Materials and methods

A PubMed search using the keyword ā€œprostate-specific membrane antigenā€ or ā€œglutamate carboxypeptidase type IIā€ yielded 1019 results. An additional 3 abstracts were included from scientific meetings. Articles were vetted by title and abstract with emphasis placed on those with clinically relevant findings. Articles not written in English were excluded. A total of 85 articles were selected based on abstract and the full text was read in entirety. From this, 60 articles were selected for inclusion

Discovery, structure, and physiology of PSMA

PSMA was first cloned in 1993 [7]. Since then, it has been shown to be identical to both folate hydrolase 1 found at the jejunal brush border and N-acetyl-alphaā€“linked acidic dipeptidase (NAALADase) in the nervous system [8]. The multiple names have led some to argue for standardization of nomenclature based on function (e.g., glutamate carboxypeptidase type II), however, this has not been widely accepted. Regardless of name, PSMA is a type II transmembrane protein with an N-terminal

Conclusions

PSMA remains an attractive target for the detection, diagnosis, and treatment of prostate cancer 20 years from the date of its cloning. Therapeutics based on it biological role in the nervous system where it functions as an NAALADase are promising in preclinical models. There has yet to be a clinically important effect on survival in patients as a result of PSMA-based therapeutics in prostate cancer. However, several recent new approaches to target PSMA including the use of small molecule

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