Charles Ryan: Hello from PCF 2019. I'm joined today by Dr. Justin Drake from the University of Minnesota where he is an Assistant Professor in the Departments of Urology and Pharmacology. Justin is one of my colleagues and we have a mutual interest in neuroendocrine prostate cancer. And you have your own space that you're looking at in neuroendocrine prostate cancer and that's RET signaling. And tell us how this could be important.

Justin Drake: Yeah, well, you know, my lab focuses a lot on kinase signaling, which in the prostate world isn't as popular as it used to be, but I think in the neuroendocrine space it might have a unique niche. I think the unique niche around it is more around AR indifferent, AR negative type signaling in neuroendocrine disease, which has been discussed by other colleagues I'm sure you've discussed with. So where I think it comes in handy is we've found through our research that several clinical datasets show enhanced RET gene expression in patients that have this AR negative neuroendocrine positive phenotype, suggesting that something is driving RET expression. And then we've also used some animal models to then perturb RET with some different inhibitors to show that targeting RET may actually be efficacious in these models.

Charles Ryan: And there are other cancers where RET plays an important role, correct?

Justin Drake: Yeah, absolutely. One reason why we thought it may be important to neuroendocrine prostate cancer is it's usually fused or mutated in other tumors that have neuroendocrine phenotypes such as papillary thyroid carcinoma or MEN's disease. And in fact, there are some compounds out there now that are being tested clinically in lung cancers and papillary thyroid cancers that have RET fusions. So Blueprint Medicines has a compound out that they're testing and that's shown some efficacy in patients with these fusions.

Charles Ryan: Okay. So if we're thinking about neuroendocrine prostate cancer as this emerging entity, and I think a lot of us clinicians are worried that as we continue to develop more efficacious treatments, one of the concerns is that, when the disease progresses, it's going to be a more aggressive one. And you know the DREAM Team programs have shown that neuroendocrine prostate cancer is not rare, but it is hard to detect sometimes because it does require biopsies. But you have noninvasive ways of detecting RET signaling, or at least you're exploring that. And that's through CTCs.

Justin Drake: Right, exactly. So the traditional way is to biopsy, do IHC stains to assess the protein landscape of certain proteins or genes. So what we're trying to do is actually do liquid base so we can do serial-based biopsies to assess, you know, if a patient progresses on abiraterone or enzalutamide, the standard of care, that we may be able to detect early on if a patient may be progressing to neuroendocrine prostate cancer. Now it's early on, we don't know if RET is indeed going to be a predictive biomarker, even a prognostic biomarker for this disease, but it's a promising one. And so we're trying to assess using mass spec-based proteomics to take CTCs and assess the proteins of those in those CTCs.

Charles Ryan: Are you able to detect RET at all in localized tumors and high grade localized tumors? I mean, could the detection of RET in a localized tumor be a predictor of eventual resistance to treatment? Does it track with Gleason grade, things like that?

Justin Drake: Yeah, you can detect it. What we don't know is the second part to that question, is whether or not it can be tractable to whether or not a patient will develop an aggressive form of the disease. I think it's still early on to know if that's the case.

Charles Ryan: And should there a space for RET inhibitors in the clinic? Can you think about what mechanistically, how they would sort of fit into our treatment paradigms? Could they be monotherapy, should they be combined with other things? How do you think we should be developing or thinking about RET inhibitors?

Justin Drake: Yeah, I mean the logical approach would be to do monotherapy initially to correct a standard of care, so which is platinum-based chemotherapy for patients with neuroendocrine disease. But it would also make sense to even try combinations with a platinum-based chemo, plus a RET inhibitor, or even potentially combine it with some type of antiandrogen earlier on, see if you can even prevent the progression of the disease in the first place. I think that second part is going to require a little more basic science to understand can RET inhibitors actually reverse the phenotype of AR indifferent signaling, and potentially turn that AR signaling back on, and if so, then a combination therapy with hormonal therapy may make sense.

Charles Ryan: Let's circle back to that point you made because you said that RET appears to be active in the AR negative or the AR null neuroendocrine. Are those mutually exclusive events where you do not see the co-activation of AR and RET? Or do they sometimes exist together?

Justin Drake: They do exist together, at least based on transcriptome analyses, that's the case. So what could be happening there is, you know, you could be capturing a tumor in its transition from an adenocarcinoma to a neuroendocrine or AR indifferent state. So remember it's a progression, right? So it could just be that we're capturing that in the middle of that progression.

Charles Ryan: But RET is a kinase, right? And help me understand the mechanism a little bit better. Is there phosphorylation going on through RET kinase that leads to alterations in the androgen receptor phosphorylation pattern? Is there a mechanistic link between these two molecules?

Justin Drake: Yeah, so right now we don't have a mechanistic link. what we'd like to do is assess RET activity as a measure of whether or not drug efficacy may be important. So you know, trying to assess RET phosphorylation would be critical, or looking at downstream pathways that RET turns on, you know, the MAPK pathway, the AKT pathway, some of your standard pathways that a lot of RTKs turn on.

Charles Ryan: Right, right.

Justin Drake: But those could be some potential biomarkers that you could look at also to assess.

Charles Ryan: And two questions. One is, do you think RET kinase inhibition would be more likely to be efficacious in PTEN-null or PI3 kinase mutated prostate cancers, or are those mechanisms not linked either?

Justin Drake: Yeah, so I mean a lot of neuroendocrine tumors have PTEN loss and P53 RB mutations. So genomically that would be the type of tumor that may benefit the most from a RET inhibitor therapy, but we haven't really stratified them enough to know which subpopulations would benefit the most at this stage.

Charles Ryan: Yeah. I mean there are AKT inhibitors being developed and in the early clinical trials it looks like they only work in PTEN loss patients, which makes a lot of sense. And so one wonders is as we get into the clinic with the RET inhibitor, is that an approach we would want to think about as well? And the other question I was going to ask is, and I may be way off here, but are the tyrosine kinase inhibitors that we see so frequently used in kidney cancer and other diseases, do they have any crossover inhibition on RET? Because oftentimes those are very promiscuous inhibitors.

Justin Drake: Yep, absolutely. So cabozantinib has been tested clinically in prostate, and up to Phase III, it was promising. And then it didn't really meet the endpoints in Phase III. So that's thought to be a RET inhibitor to some extent, but obviously it has other targets that it inhibits as well. So these newer compounds are thought to be more RET-specific. And maybe that will also help to eliminate some of the ambiguity that maybe you're observing clinically as well.

Charles Ryan: Well cabozantinib may be making a comeback, and in specific areas like maybe this and other areas where people think that there's a window for it to be efficacious, probably based on some sort of molecular biomarker.

Justin Drake: Right. Absolutely.

Charles Ryan: So that's great. So tell us, what's the next step for your lab in terms of moving this science to the next level?

Justin Drake: Yeah, so right now we're trying to just kind of firm up our basic science and our preclinical work. So we're getting some of the clinical compounds to see if we can phenocopy what we've done with some of the RET inhibitors that we were able to find commercially available. And if that's the case, then I think the next phase would really start to think about can we really target RET in any PC or neuroendocrine prostate cancer setting? And if so how to set that up. So, you know, I think right now that's where we want to go with it, and then start to get samples from those patients. Start to ask, can we identify the biomarkers that may be predictive of whether a patient responds?

Charles Ryan: Great. Well, it's always a pleasure to talk to you about your science and your work, and it's great to be working with you in Minneapolis.

Justin Drake: Yeah, absolutely.

Charles Ryan: And here at the PCF in sunny San Diego to talk a little bit about where you're going. So thank you for joining us.

Justin Drake: Yeah, thanks, Chuck.