Prostate-Specific Membrane Antigen – The First Step Toward Controlling Prostate Cancer

INITIO is proud to present Dr. Philip Cohen’s paper on PSMA-PET and its use in controlling prostate cancer. Learn about booking a PSMA-PET scan for yourself on the INITIO booking page.

Philip Cohen MD FRCP (C)

Since it’s discovery in the 1980’s, prostate specific membrane antigen (PSMA), which is highly expressed on the membranes of most prostate cancer cells, has been an ideal target for both imaging and potentially – treating – prostate cancer. Thirty years of scientific efforts has led to the concept of utilizing PSMA becoming reality. PSMA PET and SPECT scans now can reveal soft-tissue spread of the cancer outside the prostate when CT scans or MRI scans or ultrasound scans are normal. The ability to target prostate cancer with diagnostic agents have led to development of therapeutic agents targeting prostate cancer with therapeutic radioactive compounds which can destroy the cancer. Initial studies, including the VISION phase 3 trial showed increased survival even in end-stage patients treated with standard care. More PSMA targeting agents are being developed, and novel radioactive compounds, which in a few individuals have led to remission of the disease, even in end stage prostate cancer. It is highly likely that as more experience with the scans and therapies – a new field called Theranostics – prostate cancer may become a disease which is controllable over the next decade.

Prostate-specific membrane antigen, theranostics, radionuclide therapy

One in 6 men will develop prostate cancer in their lifetimes. Currently, most men will be offered prostate ultrasounds, biopsy, and staging scans with CT and bone scan. Some men will be offered MRI scans of the prostate. Treatment will be offered: surgery to remove the primary tumour in the prostate, and if the disease has been found to have spread, or the blood PSA (Prostate Specific Antigen) rises, they will be placed on Androgen (Testosterone) deprivation therapy which will initially control the disease. However, after varying periods of time, many men will find the androgen deprivation no longer stops the disease from spreading. At this point there are limited choices – external radiation, chemotherapy, or novel anti-testosterones. None so far has led to major increases in survival once the men become androgen deprivation resistant.

This however is starting to change, and a new therapy using Prostate Specific Membrane Antigen (PSMA) is starting to make significant waves in the world of prostate cancer. Prostate Specific Membrane Antigen (PSMA) is completely different from PSA (Prostate Specific Antigen). PSA is an enzyme made by the normal prostate, which is also made in increasing amounts by prostate cancers. This enzyme can be measured in the blood, and the blood test for it has become the most sensitive way of early detection of prostate cancer, or if the man becomes symptomatic, a way of confirming likely presence of prostate cancer.

PSMA on the other hand is a protein which is expressed on the membrane of prostate cancer cells, and is highly specific to prostate cancer. There is no blood test for it, but because it is so highly expressed on prostate cancers, has become an attractive target for imaging prostate cancer. Once it was found that the PSMA could be imaged, it was only a short step to use the imaging compounds to target the PSMA on prostate cancers with radioactive destructive compounds to treat the cancers. This field of combining diagnostic imaging and therapy has been Christened “Theranostics” – where physicians can now see what they wish to treat, and can treat what they see. This new shift is being advanced primarily in prostate cancer.

Theranostics - An emerging tool in drug discovery and commercialisation

PSMA – like many medical discoveries, was actually discovered in a sense by accident. Researchers at Johns Hopkins were trying to find a target for glutamine, a neuroreceptor. Martin Pomper a neuroradiologist thought these compounds would be excellent for brain imaging, but it turned out they didn’t localize in the brain. However there was a very close agreement with the neuro-targeting agents, and PSMA in prostate cancer. A compound was synthesized using this substrate that not only bound to the surface of the prostate cancer cell, it was trapped and accumulated in the cell. By 2010 several imaging compounds, were starting to be used in prominent academic centers. In 2012, similar compounds were investigated in Heidelberg Germany, and the most common PSMA compound, PSMA-11 was synthesized. It was used with Gallium-68, a radioactive metal for detecting prostate cancer, and was found to be able to detect cancers that had spread outside the prostate when MRI, CT, and ultrasounds were normal. The Heidelberg Group also synthesized a similar compound PSMA-617 – for holding potentially cell-destroying radioactive compounds , either Lutetium-177 or Actinium-225. These radioactive compounds would turn out to be highly lethal to prostate cancer. Other groups have developed other imaging and therapeutic compounds, being able to be labeled with other radioactive agents, and which are even more avid for prostate cancers. These compounds, are now emerging from clinical trials and more will be available in the next 1-5 years. Most believe these compounds will prove life-saving, able to detect, and then possibly control the cancers. How well these new radioactive compounds will work, however, will require multiple clinical centers coordinating and collaborating on how best to use these new radioactive drugs.

A recent trial conducted in Australia showed that PSMA scans were able to detect more cancers than standard CT scans and bone scans. Of 300 men enrolled in the Australian trial, with high risk disease seen on microscope, half underwent CT and bone scan, and half had PSMA scans. The PSMA scans detected 27% more cancers, and was less likely to produce inconclusive results. The test was shown to be highly useful in men who had undergone prostate surgery to remove the prostate, but whose blood test (PSA-Prostate Specific Antigen) started to rise, with no evidence on any test where in the body the prostate cancer may be hiding. In other high risk patients, the PSMA imaging test was helpful to show that the disease had already spread, and then could be targeted with early radiation treatment, additional surgery, or earlier chemotherapy. Furthermore, the use of PSMA scans can be used to evaluate just how effective the therapy has succeeded, and along with serum PSA, may predict just how much radioactivity needs to be given for a given patient. The scans will determine if a given prostate cancer patient has the necessary PSMA targets, radioactivity targeting the PSMA can be given to the patient, and follow-up scans can see how successful each radioactive cycle has been.

Despite the now conclusive studies showing that PSMA scans are more sensitive and specific than any other imaging test or sets of imaging tests for prostate cancers outside the prostate, the real excitement occurred when the Heidelberg group, and the Australian groups, showed significant improvements in patients undergoing treatment for advanced prostate cancers. In both Germany and Australia, the regulations around new therapies are significantly more open than in Canada or the USA. Patients were given PSMA targeted radioactive compounds, and most (but not all) showed significant drops in their blood PSA markers. A few even had complete remissions of their cancers, although the remissions did not necessarily last. However most patients treated had very advanced prostate cancers, as this group would show the most dramatic responses if the therapy worked. Unfortunately many of the prostate cancer patients with advanced prostate cancer have tumours which become very “anaplastic” – or primitive, so primitive that they lose the PSMA receptors on the surface of the prostate cancers. This means that these patients will no longer respond to PSMA treatments. Those that do respond had very few side-effects, unlike chemotherapies which can often be quite hard on prostate cancer patients, with nausea, vomiting, skin changes, and other side effects.

For patients having treatments with PSMA, the main side effect has been dry mouth and dry eyes, as it turns out that normal saliva glands and tear glands also contain PSMA receptors as well. The radioactive compound Lu-177 PSMA showed only transient dry mouth and dry eyes, but the latest and more destructive radioactive compound Ac-225 PSMA, which emits an alpha particle, is very harmful to the salivary glands and tear ducts. This has led many laboratories worldwide to attempt to minimize this side effect, as doing so will not only make patients tolerate the treatment more willingly, but may also allow higher doses of radioactivity to be given to really destroy the prostate cancers.

This image was presented at the main scientific meeting of the Society of Nuclear Medicine in 2018, showing 8 patients with advanced prostate cancer (colored red) before and after treatment with the therapy, Lu-177 PSMA-617. Many of these patients had nearly complete elimination of their prostate cancers, although in most of these patients the cancers later recurred.

Image of the year: PSMA-PET before and after Lutetium-177  PSMA617

The dramatic examples, although in less than 2% of patients treated, showed just how potentially useful this new method of treatment could become. Researchers still need to work out which patients will do best with this treatment, which patients can expect to have their disease stabilized, and which patients won’t respond. Additionally other factors, such as how to minimize side effects, will need to be worked out.

Nevertheless, it is clear that this is a dramatic new therapy in the fight against cancer, and one which hopefully will be shortly available in Canada in the next 12-18 months.

In addition to PSMA, a new agent called FAPI (Fibroblast Activating Protein Inhibitor) has been used in several centers, again starting in Heidelberg, to image prostate and other cancers. The initial studies indicate that it images many other cancers, besides prostate cancer, and does so by binding to the fibrous capsules which occur around many cancers. This agent can also be labeled with Lu-177 or Ac-225, for therapy, so that if the PSMA target is no longer expressed, then this agent may be useful for radiotherapy. To date no preliminary reports have been released about the effectiveness of this agent, but it is likely another tool in the radioactive arsenal to fight prostate cancer. Other compounds likely will be released over the next decade, so it is highly probable that just as with chemotherapy, multiple radioactive compounds will be available for diagnosis and treatment, offering new hope to prostate cancer patients in the diagnosis, and even eventual control of their disease.

PSA, prostate-specific antigen
PSMA, prostate-specific membrane antigen
Ga-68 Gallium-68
Lu-177 Lutetium-177
Ac-225 Actinium-225
Author contributions
Philip Cohen MD FRCP(C)

Conflict of interest
The author declares no conflict of interest


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