Tag Archives: psma

December 18, 2021 · 4:18 pm

Molecule of the year: PSMA


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We made it around the sun another time, and in spite of Covid 19, are still here to thank you for your interest in this blog and most especially for your support of prostate cancer research via my annual efforts to grow a moustache and help Movember raise funds for prostate cancer research. A heartfelt thankyou!!

With all of the “Ten best” and “top songs” lists that appear this time of the year, I thought I would expand a bit on PSMA as a real game-changer that is coming on strong to change our management of prostate cancer. So what is Prostate Specific Membrane Antigen?? Well, first of all, I think you know what an antigen is, or if not, here’s a timely clue: Spike protein. When you received your vaccination with Moderna, Pfizer or J&J vaccine, you were exposed for the first time to a foreign protein that the SARS CoV2 virus (COVID-19 disease causing) uses for entering the cells that line your airways. Your body responded to this antigen (foreign protein) by developing antibodies – the levels (titers) of which prevented you from getting COVID, or at least prevented you from getting very sick. Antibodies are very specific proteins made by the B-cells of your immune system that bind to foreign antigens and are the first line of defense against invaders.

Now, if you inject a mouse with human prostate cells, the mouse will recognize all sorts of the proteins as “foreign” and make antibodies against them. In such an experiment, Wright and colleagues in the early 1990’s found that one such antibody could be useful in detecting prostate cancer. It turned out that the antibody was detecting a protein expressed on prostate cells, but also tumor blood vessels and the salivary gland that became known as PSMA. Unlike PSA, this protein is bound to the membrane of the cancer cells and doesn’t circulate in the blood stream. PSMA is actually an enzyme involved in the normal absorption of folate (a vitamin) from the intestine, but for unclear reasons, it is dramatically over expressed by prostate cancer cells. Over the next 25 years, numerous researchers worked on tagging radioactive isotopes to antibodies that would bind to PSMA and therefore could be used to detect prostate cancer or if the radioisotope was powerful enough, kill prostate cancer cells. One of the challenges, however, in using radio labeled antibodies is their size, resulting in a lot of non-specific “sticking” in the liver, spleen and elsewhere. A better approach evolved by finding small molecules that would stick to the PSMA enzyme activity site as illustrated in this figure:

As a result of this research, it became possible to develop highly sensitive PET scans that can detect much smaller metastases of prostate cancer than any previous bone or CT scans were able to do. Gallium and Fluorine isotopes hooked to the peptide (617) are rapidly becoming available in PET scan centers across the United States (and have been available for the past 3-5 years in Europe, Australia and elsewhere) and will likely become approved as the new standard for staging newly diagnosed and PSA recurrent metastatic prostate cancer. Moreover, the isotope Lu177, that emits strong beta radiation (electrons) can be attached to peptide 617 and kill cells that express PSMA.

In the VISION trial, published this year in NEJM, the use of Lu177 PSMA to treat advanced prostate cancer patients who had progressive disease after previous treatment with a second generation hormone agent (such as Zytiga or Xtandi) plus chemotherapy with a taxane (Taxotere or Jevtana) were scanned with Gallium labeled PSMA then treated with Lu177 PSMA. The treated men were compared to alternative “standard of care” which might have included other forms of chemotherapy for example. The results were extraordinary as shown in these curves.

So for this year, I’m nominating PSMA as the molecule of the year. PSMA PET scans will likely be the only scans needed to follow prostate cancer metastases, and are already being used in newly diagnosed patients with high risk disease to make sure we don’t miss something. Further, if there are only a few metastases, we can treat these at the same time we treat the prostate with hopes that some of the patients with metastatic disease can still be cured. And ongoing research is underway to evaluate the use of Lu177 PSMA in earlier patients without resistant disease. Great progress and I leave you with fond wishes to you and your family for a healthy (VACCINATED) 2022!

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June 16, 2021 · 2:01 pm

Lu-177-PSMA-617 and “what’s next?”


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The presentation that received the most attention from readers of this blog and the press at this year’s ASCO meeting was the one about Lu-177-PSMA-617 for patients with advanced, metastatic castrate resistant prostate cancer (mCRPC). I have previously posted about PSMA and this approach to treatment as you may want to review here. Briefly, Prostate Specific Membrane Antigen, is a protein expressed on the surface of prostate cancer cells. There are molecules (ligands) that bind to this protein and can be tagged with radioactive isotopes. Thus, the tagged ligand, once injected, carries the isotope to the tumor cells. If the isotope is a positron emitter, a CT-PET scanner (Positron Emission Tomography) will light up the tumor’s location. Examples include Ga-68 and F-18. If the isotope releases stronger radiation, (for example Lu-177 releases strong beta particles that can kill cancer cells, just as the approved agent, Radium 223 -aka Xofigo™ -is a bone seeking agent that seeks out bone metastases and kills cancer cells by releasing strong alpha particles) then prostate cancer cells expressing PSMA will be killed.

The data presented at ASCO 2021 on Lu-177-PSMA-617 was from a large phase III trial comparing Lu-177-PSMA-617 with “standard of care” in patients who had progressed on most other therapies. The results are shown in the following figure:

Slide from presentation on Cancer.net, 6/16/2021.

These data will be evaluated by the FDA and it seems likely this new therapy will be approved. The answer to the question of “what’s next?” for a new drug is usually to study its use in earlier stages of disease. What if patients who have metastases but have not yet been treated with hormonal manipulation were to receive the drug at the same time they start hormonal treatment? What if used before prostatectomy? There are 9 such ongoing trials you can read about here. The hope is, that by using the drug earlier, even more benefit will result, and this is often the case in cancer medicine – for example using early “adjuvant” chemotherapy in high risk breast cancer, or using apalutamide (Erleda™) at the outset when initiating prostate cancer ADT in high risk patients.

As we progress in our understanding of when and in whom to use more aggressive therapies, it will also be helpful to identify the patients at greatest risk for failing one treatment or another. In an article appearing this month in Annals of Oncology, investigators evaluated tumor DNA levels after a single cycle of abiraterone (Zytiga™) and found that patients who didn’t have circulating tumor DNA at the start or converted from positive to negative had significantly better overall survival than patients who did not convert to negative. This means that as soon as 30 days after starting abiraterone, you could already pick out patients in whom you might want to change therapy or add other agents to treatment. They also showed that patients with alterations in specific genes like TP53, RB1 or PTEN either at pretreatment or after one cycle had significantly shorter overall survival. This kind of individualizing risk analysis will further enhance the ability to introduce new drugs like Lu-177-PSMA-617 earlier in patients who need it and avoid toxicities in those who don’t.

For those who helped support my mustache during Movember, these findings are tangible evidence of real progress we can all be proud of. You can share in the great feelings and read about your accomplishment here: https://au.movember.com/story/new-treatment-for-men-with-advanced-prostate-cancer-more-effective-than-chemotherapy?tag=prostate-cancer. Our donations DO make a difference and thanks for your help!

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April 26, 2020 · 7:30 am

PSMA PET-CT scans for Prostate Cancer


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PSMA stands for Prostate Specific Membrane Antigen, which is a protein (enzyme) that is expressed on the surface of prostate cancer cells (and on a few other cell types). As with many cell surface proteins, you can find ligands that will bind to the protein, and then label these with radioactive isotopes that allow imaging. PET stands for Positron Emission Tomography, and of course, CT stands for Computerized Tomography. When you put these technologies together, you obtain a powerful way to look for prostate cancer that has spread outside the prostate gland. The physics of this (how a positron interacts with an electron, releasing gamma photons at 180 degrees) is very cool, but probably of interest only to the most nerdy. (I made a cloud chamber for my 7th grade science project and my hiking buddy is a nuclear medicine doc who wrote a definitive text on the math/science of his craft…so go figure).

Prior to developing PET agents for prostate cancer, we had standard CT scans and bone scans and we used these to determine whether someone with, for example, a very high PSA or high Gleason score had cancer deposits that had escaped (metastasized) from the prostate. If so, it was felt that putting them through surgery or radiation treatments in an attempt to cure was fruitless and exposed the patient to the unnecessary toxicity risks (impotence, incontinence, rectal damage, etc.) Especially if they had symptoms (e.g. bone pain), hormone treatment reducing testosterone was the best approach. If you had a rising PSA several years after local treatment, the question was always, “Where is the cancer?” but the sensitivity of routine bone and CT scans was quite limited not showing anything until the PSA reached 10 or so at which time ~1/2 of scans would be positive. Screen Shot 2020-04-26 at 7.26.14 AMThis figure illustrates the difference in sensitivity. A normal sized lymph node on CT scan (left) is revealed to  contain prostate cancer with the PET isotope technique (right). At present, the only approved PET scan in the U.S. is fluciclovine, the “Axumin” scan, which the FDA approved for detecting cancer in patients with rising PSA, but not in newly diagnosed patients. In several studies PSMA-PET CT scans are even more sensitive (about 3x) than Axumin. At the risk of calling up an overused phrase, “this changes everything”.

First, it is clear that many high risk patients we would previously have treated with surgery or radiation to the prostate hoping to cure them might now be found to have prostate cancer deposits outside of the treatment target (prostate or prostate + pelvic lymph nodes). A superb study in this month’s Lancet found that PSMA PET-CT scans provided higher sensitivity (85% vs 38%) and specificity (98% vs 91%) than routine bone and CT scans in high risk patients (PSA >20, Gleason 4+3 or worse). Does this mean we shouldn’t treat the prostate in high risk patients with positive scans? In the study, conventional imaging changed the management in 15% of men, while PSMA PET-CT imaging changed the plans in 28% (p=0.008). Should all high risk patients have a PSMA PET-CT before deciding on treatment? Should the FDA approve this scan quickly? (It is currently available only in research centers and not covered by insurance…read my blog on how to search for such studies or click here).

Second, what about treating a small number of prostate metastases (oligometastatic prostate cancer) in a patient who was treated years ago and now has a rising PSA? Ongoing investigations suggest this might delay the need for hormone therapy in such patients or potentially even cure some of them. But the PSMA PET-CT isn’t perfect. How high do you let the PSA go up before ordering such a scan? – the farther it rises, the more likely the scan will show something, but that gives the cancer more time to spread. A negative scan is no guarantee there aren’t many more foci of a few prostate cancer cells that will eventually show up elsewhere in the body. Is this some version of Whack-a-mole? And how do we define “cure” anyway?? (My personal definition is that you die from something else, regardless of your PSA or scan results).

Finally, since even at research centers the PSMA PET-CT scan may cost you $3,000 or so, is it worth it? It is “free” in the European health care systems, but we all know nothing is free – even if Medicare pays for something it costs society and ultimately must be accounted for in terms of value. Medicare covered PSMA PET-CT’s vs fixing pot holes and bridges? How about finding a treatment for SARS Co-V2 instead? No easy answers, but if you are like me, homebound as a “high risk” senior citizen, plenty to think about. Wash your hands, wear your mask, and enjoy your grandkids on Zoom!

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February 26, 2020 · 3:17 pm

New findings from clinical trials 2020


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There are a number of ongoing trials or completed trials that represent attempts to develop new approaches to prostate cancer. I am sometimes asked what I know or think about them (often not as much as I would like) from various investment consultants, so I thought rather than respond to a recent list, I would just use it to explain the trials for readers of this blog. Perhaps when your friends ask you whether there is “anything new out there”, you can point them to some of these.

The PROFOUND, TALAPRO-1, TRITON-2 studies are all designed to evaluate the efficacy of small molecule drugs that inhibit “PARP” which stands for an enzyme (Poly ADP-ribose polymerase) that is involved in DNA repair. It turns out that patients who inherit a damaged/mutated version of any of several enzymes that help cells maintain their DNA integrity (BRCA1/2 being an example you may have heard of – when mutated it leads to the development of breast and ovarian cancers as well) are more likely to get prostate cancer, and often it is of the more aggressive variety. It is also a frequent condition of prostate cancer metastases in patients who no longer respond to hormone therapies (leuprolide, abiraterone, enzalutamide, etc). These patients appear to be uniquely sensitive to PARP inhibitors and several pharmaceutical companies are developing them. Olaparib and rucaparib received breakthrough designation from the FDA for accelerated development. In the PROfound trial, patients who had progressed on either enzalutamide (Xtandi) or abiraterone (Zytiga) were randomized to receive the “other” new hormonal agent or the PARP targeted drug olaparib (Lynparza). As reported by my friend/colleague Maha Hussain, the olaparib treated patients fared significantly better than the patients who received the “other hormone”. The take-home message from these trials is that we now have ways to look at the molecular underpinnings of resistant prostate cancer. If you have metastatic prostate cancer, ask your physician about the genomic tests that can be done to see if you might benefit from one of these new drugs.

In a somewhat similar design, the CARD trial evaluated treating patients who had had been treated with docetaxel (Taxotere) and then progressed while on enzalutamide or abiraterone with cabazitaxel (Jevtana) rather than the alternate hormone targeted drug. Chemotherapy with cabazitaxel was the better approach. This was similar to a previous trial called FIRSTANA that looked at alternatives of mitoxantrone or cabazitaxel in progressing docetaxel treated patients. The take-home message here is that chemotherapy with cabazitaxel may be a good choice if you don’t fit the PARP profile above, and studies have shown that cabazitaxel is preferred in terms of side effects compared to docetaxel.

Finally, I will comment on the VISION trial. PSMA stands for prostate specific membrane antigen and it is expressed on prostate cancer cells. It can be used to direct pet-scanning agents to metastatic cancer deposits and these scans are currently the most sensitive ones we have for detecting prostate cancer. These scans are available at several centers in the U.S. and are now routinely used in Europe. By linking a more radioactive isotope, Lu177 to the PSMA, you can also treat prostate cancer and early results in patients with progressive hormone refractory disease have been encouraging with more than half of patients responding. The VISION trial compares this approach with cabazitaxel to see which might be the best, but in the long run, it may be possible to use both agents, and potentially to use them even earlier before resistant disease has developed.

We have entered an era when there are numerous promising options for treatment, and the key is to get as many men  as possible to participate so we can finish the trials and get these new agents approved. We also have drugs like cabazitaxel that have been approved for some time and a better idea of when to use them. Working with a team that has the expertise to guide a patient and offer the right choices at the right time is essential for the best outcomes.

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