New Theranostic Targets in Prostate Cancer: What Do We Do to Keep Up? - Hans David Ulmert
February 15, 2024
In a conversation with Phillip Koo, David Ulmert discusses the limitations and future directions of theranostics in prostate cancer, focusing on Lutetium-177 PSMA. Dr. Ulmert identifies the off-target effects and variable expression of PSMA as key challenges. He suggests broadening the theranostic approach beyond radioligands to include options like ADCs, CAR-T, or bispecifics. Highlighting PSMA's non-specificity, Dr. Ulmert notes the need to separate diagnostic and therapeutic pathways. He points to promising targets like STEAP1 and DLL3 for neuroendocrine prostate cancer, alongside others like CD276 and Trop2. The discussion also covers the importance of understanding the regulation of these targets and the biological responses to radiation. Additionally, Dr. Ulmert addresses the challenges posed by cumulative radiation doses in earlier theranostic interventions, especially with antibody-based therapies, emphasizing the need for continuous research and innovation.
Biographies:
Hans David Ulmert, MD, PhD, Assistant Professor and Director, Preclinical Theranostics Program, University of California Los Angeles (UCLA), Los Angeles, CA
Phillip J. Koo, MD, FACS, Division Chief of Diagnostic Imaging, Banner Health MD Anderson Cancer Center, AZ
Biographies:
Hans David Ulmert, MD, PhD, Assistant Professor and Director, Preclinical Theranostics Program, University of California Los Angeles (UCLA), Los Angeles, CA
Phillip J. Koo, MD, FACS, Division Chief of Diagnostic Imaging, Banner Health MD Anderson Cancer Center, AZ
Related Content:
EAU 2023: Burning Questions in Oncological Urology: The Current and Future Role of PSMA-Based Theranostics in Men with Advanced Prostate Cancer
PSMA-Targeted Radionuclide Therapy in the Pre- and Post-Chemotherapy Settings in Prostate Cancer - Louise Emmett
Navigating Salvage Radiotherapy with Insights from PSMA PET - Jeremie Calais
EAU 2023: Burning Questions in Oncological Urology: The Current and Future Role of PSMA-Based Theranostics in Men with Advanced Prostate Cancer
PSMA-Targeted Radionuclide Therapy in the Pre- and Post-Chemotherapy Settings in Prostate Cancer - Louise Emmett
Navigating Salvage Radiotherapy with Insights from PSMA PET - Jeremie Calais
Read the Full Video Transcript
Phillip Koo: Hi, this is Phillip Koo. Welcome back to UroToday. Today, we have with us Dr. David Ulmert, who's the director of Preclinical Theranostics at UCLA. Welcome, David.
Hans David Ulmert: Thank you so much for having me.
Phillip Koo: So you've done a lot of work with different targets in prostate cancer when it comes to theranostics, but before we get into that, can you talk a little bit about the limitations with what we are currently doing today with Lutetium-177 PSMA?
Hans David Ulmert: Well, if you look at the PSMA target and articles, it's obvious that the biggest limitation is the off-target sites. Not only do we have heterogeneity in expression in prostate tumors, but also that we have expression in other organs such as the salivary glands, for example. Another limitation is the regulation of PSMA; it's still not been completely mapped.
We know that if we decrease the AR pathway activity early on in disease development, we see that PSMA is decreasing. However, in later stages, we see that PSMA actually increases when we decrease the AR pathway activity. So that's one of the limitations that we have.
The other I will also see as a conceptual problem is that if we talk to the hardliners in radio theranostics, I see very much that you have a particle that is then aiming for a specific target and you are then changing it out. So you have the imaging capacity in one go and then you're changing it to a toxic radionuclide.
I think we should broaden that field and look at it more as a way for us to image and select patients and then you have an opportunity either to go in with an ADC or a CAR-T or bispecific so that you're not limited to utilizing the radiotherapy part of it, but you can exchange that for another type of toxin.
Phillip Koo: I think you bring up some really great points. I think I want to repeat just so we make sure our listeners get that. PSMA stands for Prostate Specific Membrane Antigen, but you've clearly highlighted the fact that it's not so specific. That's something for us to remember.
And then I love that, sort of separating the diagnostic from the therapeutic. We talk so much about theranostics and it being one molecule for both, but once we identify a target, it doesn't mean we have to target that with one specific pathway.
So from that perspective, where do you think we're headed? So I guess we could separate the targets from the payloads. What are some of your thoughts on what the future targets are? What are the exciting targets that we're seeing today?
Hans David Ulmert: There are tons of really exciting targets. Some of them, just like PSMA, things move back and forth. One day it's very interesting and then people get a little bit bored of it and they see limitations and then it falls in disfavor for something else. I think one interesting aspect to bring up, just like PSMA, which is one that was the hottest thing ever 20 years ago and then it decreased in interest and now then it came back up again.
I think one of the targets that has been overlooked that is actually working really well is STEAP1. There have been some really nice zirconium images or PET imaging of STEAP1, and we see that actually we have a higher overall expression in tumors compared to PSMA, for example. Then we also keep in mind that I don't think there's going to be a golden bullet or target that is going to cure all of the disease treatments that we need to do.
There are always going to be a number of targets either that we can utilize in combination or in sequential fashion. I think the big problem is that we have not yet, outside the preclinical stage, found a target that is really good for neuroendocrine prostate cancer. I think that DLL3 could be a really interesting target when it comes to that part.
I also think CD276 or B7-H3 is very interesting. CD46, another one, and then also Trop2. And of course, I'm a little bit biased, but I think that KLK2, KLK3 targeting or HK2 and PSA targeting is something that is very interesting as well. But of course, I'm biased since those are my two babies when it comes to radioimmunotheranostics.
Phillip Koo: Great. So it's interesting. A lot of targets, but I agree with you. Probably no magic bullet that's going to always just work a hundred percent. I guess if that were the case, it'd be a little too easy. So we've talked about the targets. There's also a lot of discussions about how we then deliver the payload, and we've heard a lot about alpha emitters. Right now we're using beta particles, alpha emitters, bispecifics.
Talk to us a little bit about that because clearly when it comes to theranostics, it's really a combination of both of those factors.
Hans David Ulmert: Yeah, I think that here what's important to bring up is that alphas are, even though it's been debated that there are some bystander effects with alphas, however, nothing compared to if you look at lutetium-177 and beta. But in order to make it really effective, you need to have an internalizing particle, either an antibody or a small molecule when it comes to utilizing alphas effectively.
The other thing that we should keep in mind that is really... That we need to do our homework in, it's definitely looking at the radiology. How is the radiology and the radio pathology, how is that reacting towards the... What happens in the tumor and what happens to the biology when we're attacking these tumors with either betas or alphas? And there we have so far only touched upon what is happening and we need to do our mapping and the effect of this much more thoroughly.
Here again, it plays in with the AR pathway. Again, if you look at, for example, PSMA, which is then at more advanced stages is then reversely connected to AR. So again, PSMA expression goes down as a reaction to AR going up, and that happens when we're going with a beta or an alpha. The DNA repair mechanism is then increasing the AR activity. So the problem with PSMA is then that if AR goes up as an effect of DNA repair, PSMA expression will go down.
So in order to fully utilize the targets that we're looking at right now, we need to know we map the regulation of these targets. For example, when it comes to KLK2, KLK3, we know that those are directly regulated by AR. Meaning that AR goes up, KLK2 and KLK3 go up. So there we can utilize what's called a feedforward activation, meaning that the cells are dying, they're trying to repair themselves.
AR goes up, that's a reaction to that. The cells are surviving, they have a higher, or we have increased AR, so the target expression goes up. So the tumor gets smaller, but the target is increased, which increases the chance of us targeting that tumor with a radio theranostic particle.
Phillip Koo: So that's really interesting. I think you bring up a lot of great points about identifying the target, understanding the biology, and obviously that'll help us not just identify what we're hitting, but also I imagine this will have a huge impact on using imaging to evaluate treatment response, which is sometimes a challenge with PSMA.
The next question I want to ask about is radiation exposure. Right now we're seeing a trend towards earlier use of the PSMA targeted therapies. With that comes concerns about cumulative doses of radiation. So how does that factor into a lot of the preclinical work that you're doing in the future of theranostics?
Hans David Ulmert: It's a great question. Since I'm mainly focusing my preclinical research on antibodies, that is a problem because there you have a longer circulation time if you have full-sized antibodies, and what happens is that you then need to do sequential treatments. So you need to monitor the patient carefully, the mice in this case, so you're not ablating the bone marrow.
So you need to elegantly shown by Bander when they utilize the [inaudible 00:10:01] antibody that you are monitoring the effect on the bone marrow. You see that blood particles are then decreasing and when they're going up again, you can give a second dose and meet the reaction of the patient as well. So that's something that we are carefully looking into. Obviously, if you're using alphas, you have less of this effect with the bone marrow problem.
Phillip Koo: Great. Well, this is really exciting. I think it's really exciting to know that we have really smart people continuing to push the envelope when it comes to theranostics, and I think this will help obviously stimulate more innovation and provide our patients with many more options. So thank you so much for joining us today.
Hans David Ulmert: Thank you for having me.
Phillip Koo: Hi, this is Phillip Koo. Welcome back to UroToday. Today, we have with us Dr. David Ulmert, who's the director of Preclinical Theranostics at UCLA. Welcome, David.
Hans David Ulmert: Thank you so much for having me.
Phillip Koo: So you've done a lot of work with different targets in prostate cancer when it comes to theranostics, but before we get into that, can you talk a little bit about the limitations with what we are currently doing today with Lutetium-177 PSMA?
Hans David Ulmert: Well, if you look at the PSMA target and articles, it's obvious that the biggest limitation is the off-target sites. Not only do we have heterogeneity in expression in prostate tumors, but also that we have expression in other organs such as the salivary glands, for example. Another limitation is the regulation of PSMA; it's still not been completely mapped.
We know that if we decrease the AR pathway activity early on in disease development, we see that PSMA is decreasing. However, in later stages, we see that PSMA actually increases when we decrease the AR pathway activity. So that's one of the limitations that we have.
The other I will also see as a conceptual problem is that if we talk to the hardliners in radio theranostics, I see very much that you have a particle that is then aiming for a specific target and you are then changing it out. So you have the imaging capacity in one go and then you're changing it to a toxic radionuclide.
I think we should broaden that field and look at it more as a way for us to image and select patients and then you have an opportunity either to go in with an ADC or a CAR-T or bispecific so that you're not limited to utilizing the radiotherapy part of it, but you can exchange that for another type of toxin.
Phillip Koo: I think you bring up some really great points. I think I want to repeat just so we make sure our listeners get that. PSMA stands for Prostate Specific Membrane Antigen, but you've clearly highlighted the fact that it's not so specific. That's something for us to remember.
And then I love that, sort of separating the diagnostic from the therapeutic. We talk so much about theranostics and it being one molecule for both, but once we identify a target, it doesn't mean we have to target that with one specific pathway.
So from that perspective, where do you think we're headed? So I guess we could separate the targets from the payloads. What are some of your thoughts on what the future targets are? What are the exciting targets that we're seeing today?
Hans David Ulmert: There are tons of really exciting targets. Some of them, just like PSMA, things move back and forth. One day it's very interesting and then people get a little bit bored of it and they see limitations and then it falls in disfavor for something else. I think one interesting aspect to bring up, just like PSMA, which is one that was the hottest thing ever 20 years ago and then it decreased in interest and now then it came back up again.
I think one of the targets that has been overlooked that is actually working really well is STEAP1. There have been some really nice zirconium images or PET imaging of STEAP1, and we see that actually we have a higher overall expression in tumors compared to PSMA, for example. Then we also keep in mind that I don't think there's going to be a golden bullet or target that is going to cure all of the disease treatments that we need to do.
There are always going to be a number of targets either that we can utilize in combination or in sequential fashion. I think the big problem is that we have not yet, outside the preclinical stage, found a target that is really good for neuroendocrine prostate cancer. I think that DLL3 could be a really interesting target when it comes to that part.
I also think CD276 or B7-H3 is very interesting. CD46, another one, and then also Trop2. And of course, I'm a little bit biased, but I think that KLK2, KLK3 targeting or HK2 and PSA targeting is something that is very interesting as well. But of course, I'm biased since those are my two babies when it comes to radioimmunotheranostics.
Phillip Koo: Great. So it's interesting. A lot of targets, but I agree with you. Probably no magic bullet that's going to always just work a hundred percent. I guess if that were the case, it'd be a little too easy. So we've talked about the targets. There's also a lot of discussions about how we then deliver the payload, and we've heard a lot about alpha emitters. Right now we're using beta particles, alpha emitters, bispecifics.
Talk to us a little bit about that because clearly when it comes to theranostics, it's really a combination of both of those factors.
Hans David Ulmert: Yeah, I think that here what's important to bring up is that alphas are, even though it's been debated that there are some bystander effects with alphas, however, nothing compared to if you look at lutetium-177 and beta. But in order to make it really effective, you need to have an internalizing particle, either an antibody or a small molecule when it comes to utilizing alphas effectively.
The other thing that we should keep in mind that is really... That we need to do our homework in, it's definitely looking at the radiology. How is the radiology and the radio pathology, how is that reacting towards the... What happens in the tumor and what happens to the biology when we're attacking these tumors with either betas or alphas? And there we have so far only touched upon what is happening and we need to do our mapping and the effect of this much more thoroughly.
Here again, it plays in with the AR pathway. Again, if you look at, for example, PSMA, which is then at more advanced stages is then reversely connected to AR. So again, PSMA expression goes down as a reaction to AR going up, and that happens when we're going with a beta or an alpha. The DNA repair mechanism is then increasing the AR activity. So the problem with PSMA is then that if AR goes up as an effect of DNA repair, PSMA expression will go down.
So in order to fully utilize the targets that we're looking at right now, we need to know we map the regulation of these targets. For example, when it comes to KLK2, KLK3, we know that those are directly regulated by AR. Meaning that AR goes up, KLK2 and KLK3 go up. So there we can utilize what's called a feedforward activation, meaning that the cells are dying, they're trying to repair themselves.
AR goes up, that's a reaction to that. The cells are surviving, they have a higher, or we have increased AR, so the target expression goes up. So the tumor gets smaller, but the target is increased, which increases the chance of us targeting that tumor with a radio theranostic particle.
Phillip Koo: So that's really interesting. I think you bring up a lot of great points about identifying the target, understanding the biology, and obviously that'll help us not just identify what we're hitting, but also I imagine this will have a huge impact on using imaging to evaluate treatment response, which is sometimes a challenge with PSMA.
The next question I want to ask about is radiation exposure. Right now we're seeing a trend towards earlier use of the PSMA targeted therapies. With that comes concerns about cumulative doses of radiation. So how does that factor into a lot of the preclinical work that you're doing in the future of theranostics?
Hans David Ulmert: It's a great question. Since I'm mainly focusing my preclinical research on antibodies, that is a problem because there you have a longer circulation time if you have full-sized antibodies, and what happens is that you then need to do sequential treatments. So you need to monitor the patient carefully, the mice in this case, so you're not ablating the bone marrow.
So you need to elegantly shown by Bander when they utilize the [inaudible 00:10:01] antibody that you are monitoring the effect on the bone marrow. You see that blood particles are then decreasing and when they're going up again, you can give a second dose and meet the reaction of the patient as well. So that's something that we are carefully looking into. Obviously, if you're using alphas, you have less of this effect with the bone marrow problem.
Phillip Koo: Great. Well, this is really exciting. I think it's really exciting to know that we have really smart people continuing to push the envelope when it comes to theranostics, and I think this will help obviously stimulate more innovation and provide our patients with many more options. So thank you so much for joining us today.
Hans David Ulmert: Thank you for having me.