DKK1 and Prostate Cancer - David Wise

David Wise discusses his work studying the role of DKK1 as a driver of some forms of CRPC with Charles Ryan.  He describes that the role of immune checkpoint inhibitors in prostate cancer has been largely disappointing.  Dr. Wise shares his previous findings that DKK1 is upregulated in a subset of metastatic CRPC with low or no expression of AR and that do not have features of neuroendocrine or small cell prostate cancer. DKK1 is a secreted protein that is known to inhibit the WNT signaling pathway and can also inhibit the development of anti-tumor immune responses.  Dr. Wise will determine the role of the secreted protein DKK1 in driving the development of CRPC and in preventing anti-tumor immune responses and will determine the clinical efficacy of targeting DKK1 in advanced prostate cancer patients. This may lead to a new treatment for a subset of patients with CRPC and improve our understanding of immune tolerance in prostate cancer.

Biographies:

David R. Wise, MD, Ph.D., assistant professor, Department of Medicine, assistant professor, Department of Urology, NYU Langone's Perlmutter Cancer Center. The Prostate Cancer Foundation 2018 Young Investigator Award - John & Daria Barry Foundation–PCF VAlor Young Investigator Award.

Charles J. Ryan, MD, The B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology and Transplantation, Minneapolis, Minnesota, United States
 
Read the Full Video Transcript

Charles Ryan: Hello from ASCO 2019. I'm delighted to be joined by David Wise, who's an assistant professor at the NYU Langone Hospital at NYU Medical Center in New York, where you're a GU medical oncologist and focusing on prostate cancer, and have some interesting work in development. I understand we share an interest in NK cell therapies, having both worked on some projects. Tell us about what you're doing.

David Wise: Great. So, first of all, it's great to be here. Thank you so much for the invitation. So, we need better therapies for prostate cancer, and we need to figure out why the immune system is not there to treat prostate cancer. Unfortunately, as everybody knows, checkpoint inhibitors have been largely disappointing in prostate cancer patients.

Furthermore, the other really important issue is that most of our therapies still focus on the androgen receptor, and we know that as prostate cancers progress recent data has really suggested that a significant subset of these patients who are progressing, their cancers are getting worse. They're growing despite these therapies. What's happening is that they're losing expression of AR. They're losing expression of PSA.

So, that was really something that I really wanted to focus in on. Those two questions, the immune system and how we can activate it, and how we can treat cancers that lose AR, I think this project that I'm working on is really trying to attack that question.

Charles Ryan: So, how are you going to augment the immune system?

David Wise: So, what we did is we actually looked at a significant subset of metastatic biopsies to try to identify what are some new targets in this space. We specifically looked at cancers that lost PSA expression. We wanted to focus on that because those cancers are so aggressive. What we found in looking at the genes that are differentially expressed in those cancers is upregulation of this gene called DKK1.

Obviously, there were many genes that we could've focused on, but as a clinician, as an oncologist, I really wanted to focus on something that was the low-hanging fruit in my opinion, and which were genes for which we already had a drug that could be active, for which we have relatively well-understood biology and potentially could be linked to the immune system.

So, DKK1 was one of those genes, and it's a really interesting gene because it's actually a target of Wnt signaling. So, Wnt mutations turn it on, and we know that Wnt signaling is one of those pathways that might really predict immune escape, immune evasion, and DKK1 has actually been linked in some good basic science work to actually shutting off natural killer cells. It's a secreted protein, so the cancers really spit it out into the microenvironment.

Charles Ryan: So, Wnt signaling is going on, DKK is being spit out by the tumor. DKK1 goes and is basically regulating or suppressing NK cells in the microenvironment?

David Wise: That's our model.

Charles Ryan: Okay.

David Wise: That's our model, and so there's actually a neutralizing antibody that's already gone through phase one studies, been shown to be very well-tolerated, which is being developed by a biotech company. I went to them, and said, "Let's try this in prostate." And they never thought of that, and they were very excited about it, and we have a phase one, two trial now. It's already open. We put some patients on already, and we're very excited about it.

Actually, because it's a secreted protein, we can measure it in blood, and so part of the trial is also going to be testing that question, "Can we use this as a blood base biomarker for this type of biology?" We're measuring it in tissue as well, and so it's actually for patients who have expression of DKK1, and we give them this IV infusion of a neutralizing antibody to lower levels of DKK1, and we're really asking the important question to the patient, which is, "Is this going to shrink the tumor?"

But we're also, what I think is truly important in these early-stage studies, which are really based on new mechanisms and new biology, are we doing what we think we're doing to the biology of the cancer? So, we're really heavily invested together with the Prostate Cancer Foundation in studying the immune system of those patients, and what are we doing in the short term immediately after giving the infusion and over the course of the study?

Charles Ryan: So, are you able to look at NK cells and their activity levels or exhaustion levels over time? That's a big question right now.

David Wise: Yes.

Charles Ryan: Which is are NK cells and CRPC exhausted and unable to do their effective work, so to speak?

David Wise: Exactly. I think that the low-hanging fruit there is to look in the peripheral blood, which we're doing with conventional multicolor flow cytometry. We are, as well, applying for other funding to do single-cell sequencing to see if we can learn more about the transcriptional activity in the NK cells specifically.

Then, obviously, getting as many on-treatment biopsies as we can, but that's always been such a difficult endeavor. I think it's going to continue to be a problem because it's not always safe. It's not always feasible, and really the point is to help patients get better, and sometimes that does not go towards your endpoint.

Charles Ryan: So, do you think ideally you would identify a group of patients who have exhausted NK cells, you'd give them the DKK1 inhibitor, essentially wake up their NK cells hoping for an anti-tumor response, right?

David Wise: Ideally, and those kinds of questions are critical. What can we look at in the tumor before the treatment to give us that signal, and is it exhausted NK cells? Do we just have to look for a Wnt mutation? And maybe Wnt mutation is itself a marker of that. Or, could we look in the periphery? That would be the holy grail. Could we find the peripheral marker? I'm not sure, but that's what we really-

Charles Ryan: What's the prevalence of the Wnt mutation?

David Wise: It's interesting. APC biallelic loss, beta-catenin hotspot mutations, R-spondin amplifications, if you put them all together, it's probably about 20% of cancers. If you look at DKK1 upregulation, it's about 25, 30%. Is there always an overlap? Is it 100%? It's not. We don't exactly know why. We see, actually, loss of AR, loss of PSA itself also seems to independently predict higher DKK1 expression. Is that because there's APC gene methylation and it's an epigenetic mechanism that we're not detecting? We don't know, but we're also very interested in that.

Charles Ryan: Okay. Interesting.

David Wise: Yeah.

Charles Ryan: And we'll look forward to hearing results from your clinical trial, and hopefully hear about, someday, a future phase two or phase three trial.

David Wise: That's what we're hoping.

Charles Ryan: Really interesting angle on immunotherapy and prostate cancer, so thank you for joining us today. Great stuff.

David Wise: Thanks, Charles.

Charles Ryan: Congratulations.

David Wise: Appreciate it. Thank you.
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