An interview with Ida Sonni, MD, a nuclear medicine physician trained in Italy at the University of Rome Sapienza, currently an academic researcher in the department of radiological sciences, integrated diagnostics (IDx), at UCLA.

Interviewed by Akhil Saji, MD, chief urology resident at New York Medical College/Westchester Medical Center.

This is the first of a 2-part conversation with Dr. Sonni. Watch part 2 here.

Dr. Akhil Saji: Welcome, everyone. This is GU Oncology Now. Today, we will be conducting an interview with Dr. Ida Sonni. Dr. Sonni is a nuclear medicine physician, trained in Italy at the University of Rome Sapienza. She’s currently an academic researcher at UCLA, working at the department of radiology, and focusing mostly on clinical research of prostate cancer.

Today, we’re going to be discussing PSMA PET, specifically to understand how we can utilize PSMA PET to inform therapeutic plans for patients with a high risk of recurrence. Welcome. Myself, I’m Akhil Saji. I’m the chief urology resident at New York Medical College, and I’ll be conducting this interview.

Dr. Ida Sonni: Hi, Akhil. Nice to meet you. It’s a pleasure to be here.

Dr. Saji: Pleasure to have you. We’ll jump right in. Our first question is, could you briefly explain to the audience what PSMA is? Then also just briefly review the biochemistry behind its application in prostate cancer.

Dr. Sonni: Sure. I’m sure that most of you know what PSMA stands for. The term itself, prostate specific membrane antigen, already tells us what it is. PSMA is a membrane antigen or a transmembrane protein that is expressed on certain types of cell, in the cell membrane of certain types of cells. It is different from what the name implies, it’s not specific for the prostate. It is also expressed on many other cells, many other tissues, like the salivary glands, the small bowel, the liver, for instance.

It’s also expressed in the endovascular tract of some solid tumors. It’s not specific for the prostate, but the reason why the term prostate specific really stood with us, and we’re using it currently to call this protein, it’s because it’s highly over expressed in prostate cancer cells. This is something that is really important for us as nuclear medicine physicians when we want to develop a PET radio pharmaceutical. We want to have a target that is highly over expressed in whatever we want to image. We want to have this high tumor to background contrast.

That allows these lesions that express the target to really stand out when we are looking at the PET images. This high over expression, we’re talking about hundreds to thousand times higher expression in prostate cancer cells compared to the normal tissues, the normal prostate, the normal background. This over expression allows us to have really good images, and makes the PSMA PET images relatively easy to interpret.

This is the reason behind the success of PSMA PET. It is highly over expressed in the majority of prostate cancers, and it is an ideal target for nuclear theranostics. We can use it for PET imaging, and we can also use it for radioligand therapy. We can label with different radio isotopes and do both imaging and therapy, so the whole concept of nuclear medicine theranostics.

Dr. Saji: Great. Thank you. Now that we have a basic understanding of how PSMA works, could you review the commonly utilized radio tracers that are found that are utilized by being attached to PMA-based compounds, and then perhaps explain the differences between the different ligands?

Dr. Sonni: Sure. There are different radio pharmaceuticals that target the PSMA. Some are used for PET imaging, some are used for radioligand therapy, some are used for both. I’ll talk a little more about the two radio pharmaceuticals that are approved in the United States, and the ones that we have more experience with as well internationally. Those are gallium 68, PSMA 11, and fluorine 18 DCFPyL. These are the only two that are currently approved by the FDA for using prostate cancer.

These two radio pharmaceuticals, they belong to the same family. They basically have a part of their chemical structure that is similar, that is identical. This is the part that targets the PSMA. It’s a uria motive, so it’s specifically binding and attaching to the PSMA. This is the part of both of these radio pharmaceuticals that gives them the specificity for PSMA. In terms of specificity, they’re absolutely identical, we can say. The specificity binding with the molecule, with the target on the prostate cancer cells, is the same.

If you’re asking me from a clinical point of view, what is the difference? I would say there’s not much of a difference. They should be considered almost identical. The studies that were used for the FDA approval for both PSMA 11 and DCFPyL, in both the clinical indications of initial staging and biochemical recurrence of disease, they basically obtained almost identical results, in terms of diagnostic accuracy. We’re talking about very similar sensitivity, specificity, positive, and negative predictive value.

Clinically, they’re almost identical. If you want to know a little more about the differences, I’ll be a little more technical. I’ll talk a little more about the radiopharmaceutical and the way they’re composed. The radiopharmaceuticals that we use in nuclear medicine, they have two components: the radioactive part, and the pharmaceutical part. Pharmaceutical part, in this case, it’s the part that targets the PSMA that gives the specificity to the molecule. Then we have the radioactive component, that is the radio I.

In this case, both PSMA 11 and DCFPyL, the radio label with the isotopes, that emits positrons, so we can use them in PET imaging. PSMA 11 is radio labeled with gallium 68. That is produced in a generator. The generator allows us to do the synthesis of only a small number of doses of gallium in a day, which basically means that we can image a small number of patients in a day. Fluoride 18 is produced in a cyclotron. The cyclotron allows us to produce much larger quantities of fluoride, and we can image many more patients.

Another important difference, physical difference of these two radio isotopes is that they have different half-lives. The half-life tells us how long the radioactivity remains in this radio isotope. Basically, gallium 68 has a shorter half-life, and fluoride 18 has a slightly longer half-life, which is an advantage. If you have a hospital that has a PET scanner, but does not have a cyclotron, you can have the fluoride 18 being produced in a different facility, and then delivered to the facility that needs to use it for imaging.

With gallium 68 having a relatively shorter half-life, this is not possible. We have some limitations with the gallium labeled radiopharmaceuticals, and I believe that it’s an important, practical reason that makes the fluorinated versions of these radio pharmaceuticals, more likely to be widespread in the future.

Another maybe small difference can be from the remaining part of the chemical structure. They have slight differences. The buying distribution can be slightly different, but from a clinical standpoint, which is what we care about, they are to be considered almost identical.

Dr. Saji: Okay, thank you so much. That’s really interesting to hear, especially about the half-lives, and how that can impact delivery of these compounds to different areas of the country. For the next question, we know that in the past couple of years, PSMA has been gaining mainstream traction, especially in the metastatic prostate cancer sphere.

However, it appears that its utility, whether in a diagnostic capacity or in a theranostic capacity, and the clinically localized or locally advanced patient population is less clear. Could you explain what the current thinking is behind utilizing this technology in these patient groups, and how that can inform treatment planning?

Dr. Sonni: Yeah. I can talk about my experience working directly with the radiation oncologists. They are the physicians that are in charge of treating the oligometastatic disease, or the clinically localized, or even the locally advanced disease. I know that there’s a high reliance from the radiation oncology community on PSMA PET. I believe that the use of PSMA PET has significantly changed the way they are treating their patients.

If you think about it, in the pre-PSMA era, the radiation oncologists were treating an area of the body where they thought there could be cancer. They were treating based on the probability of having disease in a specific part of the body. After the advent of PSMA PET, in a patient that has a biochemical recurrence after definitive treatment, we can image and with high specificity, even at low PSA levels. All of these diseases, we can evaluate the extent and the localization of this disease.

We can give the radiation oncologists a significant amount of confidence when they’re doing their treatment. Even though we don’t have at the moment any studies, any results of any solid evidence, basically, showing that what happens afterwards, after the treatments that is based on the results of the PSMA PET, is influencing overall survival or biochemical free survival, I know that in the clinical practice, the clinicians really rely on this. These studies are on the way. They’re going to come, but the changes already happen. The clinicians are already giving it a lot of trust in this imaging modality.