TROP2 as Alternative Target for Metastatic Prostate Cancer Imaging and Therapy "Presentation" - Tanya Stoyanova
April 29, 2025
At the 2025 UCSF-UCLA PSMA Conference, Tanya Stoyanova discusses TROP2 as a promising alternative target for prostate cancer imaging and radiotherapy. She highlights that 25% of metastatic castration-resistant patients have low PSMA expression. Dr. Stoyanova explains that TROP2, already targeted by FDA-approved Trodelvy for other cancers, is highly expressed across prostate cancer subtypes.
Biography:
Tanya Stoyanova, PhD, Associate Professor of Molecular and Medical Pharmacology, Associate Professor of Urology, University of California, Los Angeles (UCLA), Los Angeles, CA
Biography:
Tanya Stoyanova, PhD, Associate Professor of Molecular and Medical Pharmacology, Associate Professor of Urology, University of California, Los Angeles (UCLA), Los Angeles, CA
Read the Full Video Transcript
Tanya Stoyanova: So first of all, I would like to thank the organizers for having me here today with you, and giving me the opportunity to share some of our work, and the work of others, on other targets-- other attractive targets-- for imaging and radio therapies. So one challenge that we are facing now in metastatic castration-resistant prostate cancer is really a tumor heterogeneity. And this is intra-patient heterogeneity-- amongst patients and within the tumors.
And Misha Beltran, Peter Nelson, and others have really subgrouped these tumor subtypes into four major subtypes based on the status of their androgen receptors and neuroendocrine markers. And they can be AR positive and NE negative, which is a majority of the tumors and adenocarcinoma-- double positive, AR positive, and neuroendocrine markers positive-- neuroendocrine, which is usually characterized with low or negative AR and presence of neuroendocrine markers and double negative.
So Michael Haffner's group at Fred Hutch and what they have looked at-- it's the status of PSMA in patients from normal autopsy program at the University of Washington. And what they found is-- so they analyzed 52 patients, and each one of them had 20 different samples of metastatic lesions per patient. And what they found is that 25% of these patients actually had very low PSMA. As you can see, the first group here, and a lot of these patients were different-- belonging to different subgroups. But they were either neuroendocrine positive-- positive for neuroendocrine markers-- double negative, and others. The majority of patients also had heterogeneous PSMA. So they had some lesions with low or negative PSMA and some lesions with very high PSMA. And about 16% of the patients-- about 31% of the patients-- had high PSMA, and the majority of those were adenocarcinoma or double positive.
So what they also have done is to look at a couple of markers-- two of them more specific for neuroendocrine prostate cancer. And we heard about DLL3 being an attractive target for imaging and radiotherapies. And besides the two markers that you can see here-- more specific for neuroendocrine prostate cancer-- they also looked at the molecule TROP2, which is a cell surface receptor. It's an epithelial marker, which they found highly expressed in adenocarcinoma, consistent with other studies, and also highly expressed in double positive and double negative metastatic prostate cancer, as well as in some patients with neuroendocrine prostate cancer.
So what TROP2 is-- it's a single-pass transmembrane protein. It's known to be involved in regulating many pathways that regulate cancer initiation and progression in the context of prostate and many other cancers. So it's overexpressed not only in prostate cancer and metastatic prostate cancer, but also across nearly all carcinomas. So the molecule got a lot of attention when Trodelvy was FDA approved for breast cancer, as well as for urothelial cancer. This is an antibody-drug conjugate that targets TROP2-- it's conjugated with SN-38.
So in this study, again from Michael Haffner's group at Fred Hutch and University of Washington, they now looked at the status of TROP2 and PSMA in these patients from their warm autopsy program. And what was interesting that in this typical adenocarcinoma-- AR positive, NE negative-- there were these about 20% of patients that had high levels of TROP2 but were negative for PSMA. So this is really a window of patients where we can think of now combining-- potentially targeting-- TROP2 imaging agents and radiotherapeutics with existing PSMA agents.
So as I mentioned, TROP2 is overexpressed in many epithelial cancers. So this will be applicable across other epithelial cancers such as triple-negative breast cancer, bladder cancer, different subtypes of lung cancer, as you can see here. So in our group, we have also looked at prostate cancer, as many others. This is a cohort from Stanford University. And what we found is that TROP2 was very high in patients that will go on and develop biochemical recurrence.
We also found that high levels of TROP2 correlate with worse overall survival. And consistent from the Fred Hutch study, we also found TROP2 very highly expressed in metastatic castration resistant prostate cancer, especially adenocarcinoma. And it was even higher than what we see in localized prostate cancer.
So what we have done is-- we developed a series of antibodies. This is a collaborative project with Anna Wu and Owen Witte here at UCLA. So we use Phage Display Library, and we constructed 16 different human anti-TROP2 antibody fragments, complete antibody molecules, and minibodies. So this has been a work done by many people in my lab.
So here is one example of an antibody fragment-- Human Anti-TROP2 antibody fragment. So we found that it's stable in the blood for about seven days in circulation. So these cells are detecting our antibody, injected in animals. These different antibody fragments have different properties, if you will. Some of them rapidly internalize; others don't internalize.
So here are two examples of the antibodies that we developed that rapidly internalize. So you can see at zero hour, they nicely bind to the membrane of cells that are high for TROP2. And when we wash out these antibodies, you can see that they now internalize inside the cells. And 38 hours-- this is the maximum internalization.
So we tested these molecules first as naked agents, meaning no toxins or radioisotopes were attached to them. So we tested them first in the context of double negative prostate cancer model, DU145. This is endogenously expressing very high levels of TROP2. And indeed, what we can see is that when we treat these xenografts with these animals with the antibodies, we see significant delay in tumor growth over time. So we compared two of our antibodies head-to-head with Trodelvy. Our antibodies here are naked molecules. Trodelvy is an antibody-drug conjugate.
We were excited to see that two of our antibodies performed as well as an ADC at the same dose, with no loss in body weight. We found similar findings with our antibodies in inhibiting metastatic colonization. You can see here-- this is bioluminescence-- showing that when we treat these animals that carry non-small cell lung cancer metastatic colonization model, now we see significant decrease in metastatic colonization-- liver, lung, kidney, and bone.
We are not the only ones thinking about this. There are many groups that have developed many antibodies, which is exciting times for this molecule. So this is one example from group from China that made a human anti-TROP2 antibody and labeled it with lutetium. You can see that it performs much better than the naked antibody. And here is the first imaging agent with an anti-TROP2 nanobody-- this is an image of a patient with metastatic breast cancer.
So what we're currently doing-- we're exploring all these series of antibodies that we have made. We are very interested in radiolabeling them for imaging and for radiotherapies. So with that, I would like to thank my lab, who has done a tremendous amount of work to characterize these molecules, our collaborators, and our funding. This antibody construction project was funded by Worldwide Cancer Research in the UK. And with that, I would like to thank you also.
Tanya Stoyanova: So first of all, I would like to thank the organizers for having me here today with you, and giving me the opportunity to share some of our work, and the work of others, on other targets-- other attractive targets-- for imaging and radio therapies. So one challenge that we are facing now in metastatic castration-resistant prostate cancer is really a tumor heterogeneity. And this is intra-patient heterogeneity-- amongst patients and within the tumors.
And Misha Beltran, Peter Nelson, and others have really subgrouped these tumor subtypes into four major subtypes based on the status of their androgen receptors and neuroendocrine markers. And they can be AR positive and NE negative, which is a majority of the tumors and adenocarcinoma-- double positive, AR positive, and neuroendocrine markers positive-- neuroendocrine, which is usually characterized with low or negative AR and presence of neuroendocrine markers and double negative.
So Michael Haffner's group at Fred Hutch and what they have looked at-- it's the status of PSMA in patients from normal autopsy program at the University of Washington. And what they found is-- so they analyzed 52 patients, and each one of them had 20 different samples of metastatic lesions per patient. And what they found is that 25% of these patients actually had very low PSMA. As you can see, the first group here, and a lot of these patients were different-- belonging to different subgroups. But they were either neuroendocrine positive-- positive for neuroendocrine markers-- double negative, and others. The majority of patients also had heterogeneous PSMA. So they had some lesions with low or negative PSMA and some lesions with very high PSMA. And about 16% of the patients-- about 31% of the patients-- had high PSMA, and the majority of those were adenocarcinoma or double positive.
So what they also have done is to look at a couple of markers-- two of them more specific for neuroendocrine prostate cancer. And we heard about DLL3 being an attractive target for imaging and radiotherapies. And besides the two markers that you can see here-- more specific for neuroendocrine prostate cancer-- they also looked at the molecule TROP2, which is a cell surface receptor. It's an epithelial marker, which they found highly expressed in adenocarcinoma, consistent with other studies, and also highly expressed in double positive and double negative metastatic prostate cancer, as well as in some patients with neuroendocrine prostate cancer.
So what TROP2 is-- it's a single-pass transmembrane protein. It's known to be involved in regulating many pathways that regulate cancer initiation and progression in the context of prostate and many other cancers. So it's overexpressed not only in prostate cancer and metastatic prostate cancer, but also across nearly all carcinomas. So the molecule got a lot of attention when Trodelvy was FDA approved for breast cancer, as well as for urothelial cancer. This is an antibody-drug conjugate that targets TROP2-- it's conjugated with SN-38.
So in this study, again from Michael Haffner's group at Fred Hutch and University of Washington, they now looked at the status of TROP2 and PSMA in these patients from their warm autopsy program. And what was interesting that in this typical adenocarcinoma-- AR positive, NE negative-- there were these about 20% of patients that had high levels of TROP2 but were negative for PSMA. So this is really a window of patients where we can think of now combining-- potentially targeting-- TROP2 imaging agents and radiotherapeutics with existing PSMA agents.
So as I mentioned, TROP2 is overexpressed in many epithelial cancers. So this will be applicable across other epithelial cancers such as triple-negative breast cancer, bladder cancer, different subtypes of lung cancer, as you can see here. So in our group, we have also looked at prostate cancer, as many others. This is a cohort from Stanford University. And what we found is that TROP2 was very high in patients that will go on and develop biochemical recurrence.
We also found that high levels of TROP2 correlate with worse overall survival. And consistent from the Fred Hutch study, we also found TROP2 very highly expressed in metastatic castration resistant prostate cancer, especially adenocarcinoma. And it was even higher than what we see in localized prostate cancer.
So what we have done is-- we developed a series of antibodies. This is a collaborative project with Anna Wu and Owen Witte here at UCLA. So we use Phage Display Library, and we constructed 16 different human anti-TROP2 antibody fragments, complete antibody molecules, and minibodies. So this has been a work done by many people in my lab.
So here is one example of an antibody fragment-- Human Anti-TROP2 antibody fragment. So we found that it's stable in the blood for about seven days in circulation. So these cells are detecting our antibody, injected in animals. These different antibody fragments have different properties, if you will. Some of them rapidly internalize; others don't internalize.
So here are two examples of the antibodies that we developed that rapidly internalize. So you can see at zero hour, they nicely bind to the membrane of cells that are high for TROP2. And when we wash out these antibodies, you can see that they now internalize inside the cells. And 38 hours-- this is the maximum internalization.
So we tested these molecules first as naked agents, meaning no toxins or radioisotopes were attached to them. So we tested them first in the context of double negative prostate cancer model, DU145. This is endogenously expressing very high levels of TROP2. And indeed, what we can see is that when we treat these xenografts with these animals with the antibodies, we see significant delay in tumor growth over time. So we compared two of our antibodies head-to-head with Trodelvy. Our antibodies here are naked molecules. Trodelvy is an antibody-drug conjugate.
We were excited to see that two of our antibodies performed as well as an ADC at the same dose, with no loss in body weight. We found similar findings with our antibodies in inhibiting metastatic colonization. You can see here-- this is bioluminescence-- showing that when we treat these animals that carry non-small cell lung cancer metastatic colonization model, now we see significant decrease in metastatic colonization-- liver, lung, kidney, and bone.
We are not the only ones thinking about this. There are many groups that have developed many antibodies, which is exciting times for this molecule. So this is one example from group from China that made a human anti-TROP2 antibody and labeled it with lutetium. You can see that it performs much better than the naked antibody. And here is the first imaging agent with an anti-TROP2 nanobody-- this is an image of a patient with metastatic breast cancer.
So what we're currently doing-- we're exploring all these series of antibodies that we have made. We are very interested in radiolabeling them for imaging and for radiotherapies. So with that, I would like to thank my lab, who has done a tremendous amount of work to characterize these molecules, our collaborators, and our funding. This antibody construction project was funded by Worldwide Cancer Research in the UK. And with that, I would like to thank you also.