Prostate-Specific Membrane Antigen, or PSMA, is a glycoprotein, a protein with sugar molecules attached to it. It is classified as a type II transmembrane glycoprotein, meaning it passes through the cell’s outer membrane once. This protein has a distinct structure with a short segment inside the cell, a single part that crosses the cell membrane, and a large external segment.
While its exact biological roles are still under investigation, PSMA functions as an enzyme, specifically a carboxypeptidase. This enzymatic function is believed to play a part in how cells take up nutrients and in cell signaling processes. The protein can also be taken into the cell from the surface, a process involving recycling through internal cellular compartments.
PSMA as a Prostate Cancer Biomarker
A biomarker is a measurable substance in the body that indicates the presence of a disease. PSMA serves this purpose in prostate cancer because its presence on cells changes dramatically. While PSMA is found on normal prostate tissue, its concentration can increase by 100 to 1,000 times on prostate cancer cells, making it a reliable indicator for the disease.
The level of PSMA expression often correlates with the cancer’s severity and stage. Higher amounts of this protein are found in more aggressive, high-grade tumors. Its presence is not confined to the prostate gland; it is also found on metastatic prostate cancer cells that have spread to other parts of the body, such as the lymph nodes and bones. This is valuable for identifying advanced, androgen-independent prostate cancer, a form of the disease that no longer responds to hormone therapy.
This overexpression makes PSMA a target for medical applications. Because the protein is so much more abundant on cancerous cells than on most normal body cells, it acts like a flag identifying the location of the cancer. This allows for the development of agents that can seek out and bind to the PSMA protein, forming the basis for advanced imaging and targeted treatments.
Diagnostic Imaging with PSMA
The high concentration of PSMA on prostate cancer cells allows for sensitive diagnostic imaging through Positron Emission Tomography (PET) scans. PSMA PET scans work by using a radioactive tracer designed to attach to the PSMA protein. This process begins with injecting a small amount of a radiotracer, which consists of a molecule that binds to PSMA linked to a radioactive isotope.
Two common radiotracers are Gallium-68 (⁶⁸Ga) PSMA-11 and Fluorine-18 (¹⁸F) DCFPyL. These molecules travel throughout the body, seeking out and attaching to PSMA proteins on the surface of prostate cancer cells. Once bound, the radioactive component emits positrons detected by the PET scanner. The scanner then generates detailed 3D images that illuminate the location and extent of the cancer.
This imaging technique has several clinical uses. It is employed for the initial staging of men with high-risk prostate cancer to determine if the cancer has spread. It is also effective in detecting the recurrence of cancer in men who have been treated, especially when their prostate-specific antigen (PSA) levels rise. The precision of PSMA PET scans is higher than traditional imaging methods like CT and bone scans, allowing doctors to find very small tumors. This detailed mapping helps in planning subsequent treatments.
Therapeutic Applications of PSMA
The same principle that makes PSMA a target for diagnostic imaging is also used for therapy. This dual-use approach is a concept called theranostics, which combines diagnosis and treatment. For therapeutic purposes, the PSMA-targeting molecule is attached to a therapeutic radioisotope that delivers radiation to kill cancer cells. This method is a form of radioligand therapy.
The process functions as a “seek and destroy” mission. A therapeutic agent is created by linking a PSMA-binding molecule to a radionuclide, such as Lutetium-177 (¹⁷⁷Lu). When this compound is injected, it circulates and binds to PSMA proteins on the cancer cells. Once attached, the Lutetium-177 delivers a localized dose of beta radiation to the tumor site. This targeted delivery destroys the cancer cells while largely sparing surrounding healthy tissues.
This treatment has led to the development of drugs like Lutetium-177 vipivotide tetraxetan, marketed as Pluvicto. It is approved for patients with metastatic castration-resistant prostate cancer (mCRPC). These are patients whose cancer has spread and no longer responds to treatments designed to lower testosterone levels. Patients become eligible for this therapy after they have undergone other treatments, such as chemotherapy and androgen receptor pathway inhibitors.