New Therapeutic Targets for Metastatic Castration-Resistant Prostate Cancer - Aaron LeBeau
November 8, 2019
Aaron LeBeau, Ph.D., Assistant Professor in the Department of Pharmacology at the University of Minnesota Masonic Cancer Center
Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.
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Charles Ryan: Hello from PCF 2019. I'm delighted to be joined with my colleague Aaron Le Beau from the University of Minnesota. Aaron is an Assistant Professor in the Department of Pharmacology. And you're doing some very interesting work. You know, there's a lot of talk in our field now about PSMA as a cellular therapy target, a radioligand target, and a disease marker. And you're working on something that might be an alternative to PSMA tell us about it.
Aaron LeBeau: Correct, correct. So my lab specializes in the developments of targeted imaging agents and therapeutics for prostate cancer using novel antibody constructs. And in our laboratory, we use a technique called antibody phage display, and this allows us to identify high-affinity antibodies for targets of interest. That could be anything basically. And we have used our antibody libraries to identify antibodies for two very compelling targets that are associated with prostate cancer, very aggressive prostate cancer. One is Trop-2, which is expressed in castration-resistant prostate cancer. And the other is CD133, which is expressed in neuroendocrine differentiated prostate cancer.
Charles Ryan: So this is different from PSMA, in that we think of PSMA as an androgen receptor driven target. And...
Aaron LeBeau: Yeah.
Charles Ryan: Maybe it is more expressed in lower-grade or better differentiated, more well-differentiated tumors. So is it possible that you're going to see Trop-2 at a higher expression level when PSMA levels are down? In other words, they're kind of mutually exclusive?
Aaron LeBeau: Yeah. The data suggests that over the course of treatment with abiraterone, other second-generation antiandrogens, you see PSMA levels fluctuate. And we know from trials from Mayo Clinic, that Trop-2 levels do not change at all. They stay fairly level during the course of treatment. So it's potential, it's possible that Trop-2 levels will not be modulated by therapies will always consistently be there and more available than PSMA, which the levels we know can change.
Charles Ryan: If you look at the density of Trop-2 on a cell surface versus the density of PSMA, which is more prevalent? Which is more dense?
Aaron LeBeau: From what we've seen in our studies thus far, they're fairly similar. I would say that Trop-2 maybe express a bit more than PSMA.
Charles Ryan: Okay. And does Trop-2 have a function? Is it an enzyme or...?
Aaron LeBeau: Trop-2, we don't really know what it does. It's thought to play a role. It's an extracellular protein but does have this domain and the cytosol of the cell and it's thought that domain might be cleaved off and lead to signaling. But we have not thoroughly ascribed a role for it in cancer progression.
Charles Ryan: So what are we going to do with Trop-2? Is it going to be a radioligand target? Is it going to be a cellular therapy target? How, do we take Trop-2 the next level?
Aaron LeBeau: Yeah, Trop-2, its specificity looks fairly cancer-specific. So it could be a safe target for radiotherapy, radioimmunotherapy, or for CAR T cells or CAR NK cells. And my personal interests are largely more in radiotherapy and also imaging.
Charles Ryan: Radioligand therapy?
Aaron LeBeau: Radioimmunotherapy.
Charles Ryan: Okay. Radiotherapy. So very interesting in that you have, we have a potential alternate target to PSMA. One of the things we're interested in learning about PSMA is are there toxicities associated with it based on where PSMA is expressed in the nonmalignant tissue. Do you think Trop-2 is malignancy specific or are there normal tissues like the salivary glands in the case of PSMA, that express Trop-2?
Aaron LeBeau: Yeah. We think that is more specific than PSMA is. But, you have to do studies to find out.
Charles Ryan: Well, this is ongoing...
Aaron LeBeau: And we don't really know until you actually inject the first patient with the therapeutic imaging probe.
Charles Ryan: Right. Very true. Well, it's exciting and I'm looking forward to working with you and watching your work develop in this area. You have another target, which is CD133.
Aaron LeBeau: Yes.
Charles Ryan: This is something that's really important at our institution, which is natural killer cells and the development of NK cells as a therapy. What's the story with the CD133?
Aaron LeBeau: Yeah. So, CD133 is an interesting molecule in that it has been associated with stem cells for the longest time. It's said that if a cell is CD133 positive, it has stemness. And we now know that it's not really a marker of stem cells. Not all stem cells express CD133, and not all CD133 expression cells show stemness. And I first got interested in CD133 many years ago as a grad student at Johns Hopkins. When the lab next to ours, John Isaacs' lab, he was trying to investigate what CD133 does in prostate cancer. And its role in the stem cell, cancer stem cell morphology and evolution. And I came to the University of Minnesota, decided to develop a high-affinity antibody for CD133, just because we could and we were trying to find projects and we identify this antibody and we started to screen by immunohistochemistry, different tissue microarrays of prostate cancer. And we did not see any immunoreactivity at all for the most part.
Charles Ryan: Okay.
Aaron LeBeau: In primary prostate cancer as well as in metastatic prostate cancer. So, that was quite depressing. And then we screened a TM, a tissue microarray made up of the LuCaP series of patient derived xenografts. And of the 30 or so LuCaP xenografts only three were positive for CD133. And those three positive xenografts, all were androgen receptor-negative and had neuroendocrine differentiation.
Charles Ryan: Okay.
Aaron LeBeau: Which was quite...
Charles Ryan: Obvious simplification there that we can think about CD133 in a neuroendocrine or a small cell, a phenotype or a treatment emergent, small cell, whatever we're going to call it. Or wherever we're going to see it.
Aaron LeBeau: Yeah.
Charles Ryan: So what's the next step?
Aaron LeBeau: Chronologically, we then found out we didn't, we then screened biopsies from patients who failed abiraterone therapy, enzalutamide, other therapies. And found that if they were AR negative and positive for neuroendocrine differentiation, they were positive for CD133. So this suggests that CD133 targeted antibodies could potentially be a therapeutic option or imaging option for men with this type of aggressive disease.
Charles Ryan: Okay, great. Well, it's really exciting. And now you've won a challenge award from the Prostate Cancer Foundation this year.
Aaron LeBeau: Correct.
Charles Ryan: For your work. Congratulations. And you've been getting a lot of other funding and notice of your work. And it's great and delightful and wonderful to see it developing at the University of Minnesota. So, thanks for talking with us today and congratulations again.
Aaron LeBeau: Thank you.