Prostate-Specific Membrane Antigen (PSMA) is a protein found on the surface of cells that has become a major focus in the diagnosis and treatment of prostate cancer. The protein is encoded by the FOLH1 gene, formally named Folate Hydrolase 1, reflecting its original biological role. While PSMA’s name suggests it is exclusive to the prostate, it is present in small amounts in several other organs. Its medical significance stems from its dramatic overexpression on the surface of prostate cancer cells, which transforms it into a highly effective molecular beacon for identifying and targeting the disease. This unique characteristic allows clinicians to use PSMA in a novel “theranostic” approach, combining specific diagnostic imaging with precision-guided therapy.
The PSMA Protein’s Normal Function
PSMA is a type II transmembrane glycoprotein that acts as an enzyme, specifically a glutamate carboxypeptidase. This enzymatic function is responsible for two primary roles in the body outside of disease. In the digestive system, PSMA is highly expressed on the brush border membranes of the small intestine, where it functions as a folate hydrolase. It cleaves poly-gamma-glutamated folates into a form the body can absorb for nutrition. Its other main non-disease role is in the central nervous system, where it is known as N-acetylated-alpha-linked-acidic dipeptidase (NAALADase). In this capacity, the enzyme modulates neurotransmission by hydrolyzing the neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to release glutamate. PSMA is also found in the vasculature of certain tissues, including the kidneys and the capillary endothelium of various tumors. This normal tissue expression is low compared to malignant cells, but it must be accounted for during therapeutic applications.
PSMA Overexpression in Prostate Cancer
The reason PSMA has become a primary target in oncology is the massive, selective increase in its density on the surface of prostate cancer cells. This overexpression is observed in nearly all stages of prostate cancer, but it becomes particularly pronounced in advanced and metastatic forms of the disease. Studies have documented that PSMA levels can be elevated by as much as 100 to 1,000 times higher in malignant prostate cells compared to benign prostate tissue. The expression of the PSMA protein is inversely related to androgen signaling. As the cancer becomes resistant to hormonal therapies (androgen deprivation), PSMA expression often increases. This makes it an especially useful target in metastatic castration-resistant prostate cancer (mCRPC), which represents the most aggressive form of the disease. High PSMA expression is also strongly associated with a higher Gleason grade, advanced tumor stage, and a greater likelihood of early recurrence. This dramatic upregulation provides a clear molecular signature that can be exploited for both diagnosis and intervention.
PSMA Imaging for Diagnosis and Staging
The high concentration of PSMA on cancer cells allows for highly precise diagnostic imaging using Positron Emission Tomography (PET) scanning. This technique involves injecting a molecular probe, known as a PSMA-targeting ligand, that has been tagged with a diagnostic radioisotope. The ligand travels through the bloodstream, binds specifically to the PSMA on the surface of the cancer cells, and the radioisotope emits positrons that are detected by the PET scanner to create a detailed map of the disease.
Two common diagnostic radioisotopes used for PSMA PET scans are Gallium-68 (\(\text{}^{68}\text{Ga}\)) and Fluorine-18 (\(\text{}^{18}\text{F}\)), which are chemically bound to PSMA-targeting molecules like PSMA-11 or DCFPyL (Pylarify). The half-life of \(\text{}^{68}\text{Ga}\) is approximately 68 minutes, while \(\text{}^{18}\text{F}\) has a longer half-life of about 110 minutes, offering logistical advantages for production and distribution.
PSMA PET imaging is superior to conventional imaging methods like CT and bone scans, particularly for initial staging and detecting metastases or biochemical recurrence. This method is highly sensitive, capable of detecting cancer lesions even at very low levels of prostate-specific antigen (PSA) in the blood. By accurately mapping all sites of disease throughout the body, PSMA PET helps clinicians determine the true extent of the cancer, which is crucial for planning personalized and effective treatment strategies.
Targeted PSMA Therapy
The same principle used for PSMA imaging—a ligand binding to the PSMA protein—is adapted for therapeutic intervention in a process called Radioligand Therapy (RLT). In this approach, the PSMA-targeting ligand is chemically linked to a powerful therapeutic radioisotope instead of a diagnostic one. Once injected, the therapeutic agent, such as Lutetium-177 (\(\text{}^{177}\text{Lu}\))-PSMA-617, binds to the overexpressed PSMA on the cancer cell surface and is often internalized. The radioisotope then releases localized radiation, delivering a high dose directly to the tumor while minimizing exposure to surrounding healthy tissues.
Lutetium-177 is a beta-particle emitter, meaning it releases medium-energy electrons that penetrate tissue only a short distance, typically a few millimeters. This limited range ensures that the radiation is concentrated within the tumor and nearby cancer cells. This form of RLT is approved for patients with PSMA-positive metastatic castration-resistant prostate cancer who have progressed despite other treatments.
An even more potent form of RLT utilizes Actinium-225 (\(\text{}^{225}\text{Ac}\)), which is an alpha-particle emitter. Alpha particles are significantly heavier and more energetic than beta particles, but their path length in tissue is much shorter, typically less than 0.1 millimeters, or only a few cell diameters. This extreme precision allows for a highly cytotoxic effect on the tumor cells with less opportunity for off-target radiation damage to adjacent organs. However, some healthy tissues with PSMA expression, such as the salivary glands, can be affected by the treatment, leading to side effects like dry mouth (xerostomia). The use of \(\text{}^{225}\text{Ac}\) is often reserved for patients whose disease has proven resistant to \(\text{}^{177}\text{Lu}\) therapy, demonstrating the evolving, targeted nature of PSMA-based treatment.