PSMA Theranostics and Personalized Prostate Cancer Care- Frankis Almaguel
July 16, 2019
Frankis Almaguel, MD, Ph.D., Director, Molecular Imaging and Therapeutics, Loma Linda University Cancer Center, Center for Health Disparities and Molecular Medicine
Phillip J. Koo, MD, Division Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center in Arizona.
Phillip Koo: Hello, this is Phillip Koo from UroToday. We're very fortunate to have with us today, Dr. Frankis Almaguel, who's Assistant Professor and Director of Molecular Imaging and Therapeutics at the Loma Linda University Cancer Center.
He's here today to continue our lecture series that is sponsored by the Society of Nuclear Medicine and Molecular Imaging, focusing on the latest and greatest technologies with regards to imaging and prostate cancer. Today he'll be tackling the very hot topic of PSMA theranostics, so thank you very much Dr. Almaguel for joining.
Frankis Almaguel: Thank you for the invitation. Very happy to come here to share something that is very sweet to my heart. I think it's going to be excellent for patients and for us physicians in treating prostate cancer. PSMA theranostics and the care of prostate cancer. What's going to happen in a few years?
I want to give a brief introduction to how prostate cancer and molecular imaging are going to help us take care of patients with prostate cancer. The role of PSMA in prostate cancer in the future of the care of prostate cancer and how PSMA will impact the care of prostate cancer.
We do have a problem in our hands. We have about three million men living in the US with prostate cancer. As we know, this is a very common disease. It's the second leading cause of death for American men, so this is not an insignificant problem. Despite very good therapies in the past, patients with metastatic prostate cancer have very poor outcomes, so new strategies are needed.
The idea is how can we move on to the next step, in terms of helping these patients, and we have an old age question. We need to find those cancers within the normal tissues. Finding problems within good things have been a problem for centuries and in this case, making sure the tares are not affecting the wheat when they're growing. The idea is how we can find those cancers within the normal tissues.
I think molecular imaging can help us to take a look at molecular processes in living cells. Those insights into the cellular and tissue physiology will help us significantly in the identification of these cancer cells, versus normal cells, normal tissue.
Molecular imaging is dependent on biomarkers. These biomarkers are the key to facilitate seeing those cancer cells within the normal tissue, so precise delivery of diagnostic and therapeutic payloads are unique. They're done because of these biomarkers. These biomarkers are the flags that show, hey, cancer is here, normal tissue doesn't have this. Precision medicine will be driven by this technology with these biomarkers.
I am daring to say and share that PSMA will be a game-changing modality for prostate cancer. These biomarkers will help us with many problems that we have right now in the care of these patients. Let me tell you a little bit more about PSMA. Prostate Specific Membrane Antigen is a 750 amino acid transmembrane protein that has glutamate carboxypeptidase, folate hydrolase. It's basically helping the cancer cells to survive. By imaging or by detecting PSMA, we are able to see prostate cancer at a level that we were not able to see before. This biomarker is overexpressed in metastatic disease, in castration-resistant cells, essentially in very high-grade tumors, poorly differentiated tumors. It's also expressed in the neovasculature of many other tumors and low-level expression in different normal tissues is also seen, but the expression is a thousand-fold lower than in cancer. It has promised to help us with the problem of finding that cancer cell within the normal tissue.
In addition, these biomarkers will help us with precision medicine. In the future, cancers will be classified by molecular phenotypes. These phenotypes will be defined by these biomarkers and molecular imaging will allow us to see them and to get insights into where are they in the tissues. It basically will allow us to select the right therapy for the right patient, at the right time, eliminating trial and error in medicine.
As you can see in the cartoon on the right-hand side here, you have one new image for this biomarker, the patients that are positive for PSMA will be offered a specific therapy based on these biomarkers. The prostate cancer patients that don't express these biomarkers will be treated in a different, more effective or efficient way for these specific populations. You don't have PSMA expression, we cannot treat you with something that is not going to work. Being able to treat the right patient at the right time, with the right therapy is priceless.
Let me tell you a little bit more about a specific membrane antigen. We have here low-grade tumor, has a low-grade expression of PSMA. High-grade tumor, high-level expression. This is very important if we are looking for the biomarker that has a correlation with this disease.
More studies are showing that you see this high-grade expression of PSMA, well it correlates directly with the recurrence-free survival of these patients. Low-level expression of PSMA, you can see here that the recurrence-free survival is much higher than when you have a high expression of PSMA, basically telling us that this biomarker is indeed telling us that high-grade prostate cancer is able to raise a flag saying, hey I'm right here. I'm a cancer cell.
The breakthrough of being able to image these biomarkers. Molecular imaging is taking us to the next step, saying we can have a technology that we can tell you where these prostate cancer cells are and if you can see this osteolytic lesion, will be a little bit hard to see in a normal CT, but when you see it on the PSMA-PET, is very clear. It's allowing us to detect cancer cells sooner than ever before and more specific.
It's basically helping us to detect that wolf dressing like a sheep. Let me stop here and give you a couple of cases. A 68 year old patient with prostate cancer underwent this bone scan and as you can see, it's very hard to tell him that he has metastatic disease. Just as it would be very hard for us with a flashlight to look into the dark and try to look for a wolf. But if we use the right technology, we know, we can see that the wolf is there. The same thing with this technology, it's going to allow us to see disease. This is a PSMA-PET of the same patient, showing us that if we had this technology we would be able to help patients sooner than we were able to help them before. Technically, we are raising up our game to make sure that when we say that a patient is not with metastatic disease, we're saying the truth. Right now, as you can see, this patient did have a lot of metastatic diseases, we just couldn't see it with the technology available at that time.
Another patient, Gleason score of 5. He had a radical prostatectomy in the past, salvage lymphadenectomy, salvage radiation. Presented with a PSA rise. He had a CT. It's very hard to see if there's any disease in this scan, but when you look at the PSMA-PET those areas of disease basically jump at you. This patient will be able to undergo the right therapy at the right moment in his disease process. What we're trying to say is that this technology is going to allow us to detect that prostate cancer much earlier than before and I think this is very valuable for our field and for our patients.
How can I illustrate this further? This patient, Gleason 9, radical prostatectomy, rising PSA. With the current guidelines, this patient will be a candidate for salvage radiation. With this scan, we know now that this patient has an intra‐abdominal disease, a disease in the chest. This patient will not benefit from salvage radiation. We have to think what would be the best therapy for this patient? Before, even if we wanted to help these patients, we just couldn't. Now we have more insight and I think this is going to change the way that we treat these patients, just because we have more information.
Another case, radical prostatectomy five years ago, negative PSA until recently and now increasing. This technology has the ability to detect soft tissue mets and bone mets. I think it will be very valuable if we can utilize this and take it to our patients right now.
But let's see what multi-center prospective studies are saying. This study from Fendler et al at JAMA Oncology is showing us, basically, the conclusion is it's highly accurate, it's reproducible and it's safe. With a positive predictive value from 84 to 92%. Detect rates, 75%, good inter-reader reproducibility. If I see a test that has this capacity, these qualities, I want to see if this test is actually changing the management for patients.
Of course, there is another multi-center prospective trial performed last year and it's basically showing that this technology is having a high impact on the management for these patients. That means that doctors treating prostate cancer have another tool to help them decide what will be the best management for these patients.
This technology is going to help us decide at what level this patient is and what should we do next? For example, if we have a patient that has a local recurrence, with this technology we can exclude distant disease, we can find if there's a disease in unsuspecting sites, so we can perform that therapy that is right for him. If this patient had only local disease, we could do salvage radiation. If this patient had, let's say a lot of patients who come in with polymetastatic disease, metastasis everywhere, then he wouldn't benefit from radiation or from other treatments. In this case, we could randomize this patient to go to theranostic therapy.
For example, this patient came in with one site of disease. It was only one place but easily seen, that area of metastasis was resected and the PSA going back to undetectable levels. Of course, one question that I had, it was what about the pathology for that resection. The pathology showed that it was prostate cancer.
When we merge a great diagnostic study with targeted therapy, we come up with something that is called theranostics. Theranostics is going to help us advance precision medicine. That means that the same biomarker that I'm using for diagnosis, now I could use for therapy.
How does this work? Let me go slow here, saying basically we have a target, that's our biomarker. Then we have a specific ligand that is designed to bind to this target and at the end of that structure here we have an isotope that can be put in there, that could give us a picture, in this case, it will be the gallium 68, F 18. We could see what the biomarker is, where those cancer cells are and now that we know where these cancer cells are we can just switch the isotope for let's say, in this case, it could be alpha radiation. We can go straight to help those patients by eliminating that disease. If you could tell me that this is something that will be happening right now, if I'm one of those patients, I'll be very excited to see how much help could a therapy so specific be.
I think it is basically a match made in heaven. It has a lot of potential and I think it will take us to the level where these targeted therapies are going to be able to be very effective, without having so many side effects, because we don't have to burn a forest anymore, we have therapies that will go to the areas that have the cancer cells and will leave alone the normal cells. This is the ideal way of treating disease.
This is the first part of this presentation and it is brought to you by the Society of Nuclear Medicine.