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Andrea Miyahira: Hi, I am Dr. Andrea Miyahira here at the Prostate Cancer Foundation. Thank you for joining us. Today with me is Dr. Nima Sharifi, who recently became the scientific director of the Desai Sethi Urology Institute at the University of Miami. Dr. Sharifi will share his group's latest paper, "Elevated Periprostatic Venous Testosterone Correlates with Prostate Cancer Progression After Radical Prostatectomy." It was published in the Journal of Clinical Investigation. Thank you for joining me today, Dr. Sharifi.

Nima Sharifi: Great. Thank you so much, Andrea. Thank you so much for your invitation to discuss this paper that's just come out from our group. I'll start out by saying that this is almost a 10-year-long story. It took quite some time to complete the story, as well as to get it published, for a variety of reasons.

But just to start out, the background here is that, as you know, there are a number of studies looking at consequences or associations of certain circulating androgens in prostate cancer, whether it's prostate cancer outcomes, prostate cancer risk. And by and large, there doesn't seem to be much of a consensus for the value of eugonadal testosterone levels in prostate cancer risk for outcomes.

We also have a number of studies looking at intraprostatic androgens and metabolism. That's an area that's sort of near and dear to our hearts as well. But what we don't have to my knowledge, are any studies looking at the vasculature that's associated with the prostate and prostate cancer.

So the study design here is that we assessed peripheral androgens in addition to tissue androgens, as well as the androgens in the dorsal vein of the prostate, which is part of the vasculature that actually drains the prostate. In other words, really, the periprostatic venous plexus. It is part of the same complex. And if you would've asked me in the very beginning of the study, what sort of testosterone levels would you expect here? I would've said, I would've hypothesized, that the testosterone levels will be either the same, or perhaps slightly lower than what you find in peripheral circulation. Because the prostate may utilize some of the androgens, and so, the levels may be a bit lower. So that was my expectation.

We, of course, looked at steroids a bit more broadly, and we did this in over 200 men undergoing radical prostatectomy, and you can see this time span here.

We also excluded men with presurgical hormonal treatment, and we included just over 200 men in the final analysis, along with clinical outcomes. And we looked at a variety of things. Steroid profiling in both blood compartments. We also did metabolomics on a subset, and we looked at clinical outcomes.

So this is the finding that was incredibly surprising to me, and I think, to others as well. So what we're looking at here, is the ratio of local or periprostatic venous testosterone, compared with peripheral testosterone. So each of these lines, each of these bars, is an individual patient. And my expectation would've been that, everybody would be down here around a ratio of one-to-one. But what I think is immediately obvious is, that there's a pretty sizable subset of these men who have really high local or periprostatic androgens or testosterone. Such that, about a quarter of these men have twofold higher periprostatic androgens compared with peripheral testosterone. And about 5% have a log higher local testosterone. So really surprising.

What we think is occurring here is that a subset of these men have collateral circulation that allows the gonadal drainage, the gonadal venous drainage, to connect with periprostatic veins. This may allow an enriched source of gonadal testosterone to be exposed to the prostatic tissue itself. And there are a variety of different potential plausible mechanisms of this collateral circulation, shown here is just one of those possibilities.

So you might ask, well, is this just an artifact of free versus bound testosterone? And for example, extraction of the androgens from blood. One of the steroids that we looked at is a steroid called 17-hydroxyprogesterone, which is a known intermediate metabolite for synthesis of testosterone in the Leydig cells of the testes. And what we find is that, when men have elevated local or periprostatic testosterone, they also have elevated periprostatic 17-hydroxyprogesterone.

So what this says to me is that, this is all really coming from a source of steroidogenesis, again, most likely of which is the testes. And this is not an artifact of simple steroid extraction. We also did unbiased metabolomics, looking at non-steroid metabolites as well. And to sort of make this part short, we also find that isocaproic acid is elevated when you have elevated periprostatic testosterone and the other steroid intermediate. Isocaproic acid is a byproduct of the first step of steroidogenesis. So these six carbons are cleaved, come off, and it's not used for the steroids themselves, but simply a marker. So all these things really fit together.

And finally, what I'll share with you is that, we looked at clinical outcomes in these men who underwent radical prostatectomy. And what we find, is that those men who have elevated periprostatic testosterone actually have worse outcomes, when you're looking at a composite outcome of PSA recurrence, or salvage radiation therapy, compared with those who have low periprostatic androgens.

And I should say, that this is not a cut point that we really cherry-picked. We looked at a variety of different cut points and the finding essentially holds true for a variety of different cut points and will be correct for known clinical factors. This association with worse clinical outcomes actually becomes stronger. It doesn't become weaker. So it seems to be an independent marker of clinical outcomes.

So just to conclude here, a subset of men undergoing prostatectomy have high periprostatic or local testosterone. There are additional biochemical markers that really corroborate. This is from an enriched source of androgen biosynthesis, again, most likely the gonadal source.

And we call this sneaky testosterone. This physiology really appears to have a distinct clinical biology and worse clinical outcomes. And then the final point here is that, peripheral testosterone measurements may not accurately reflect local prostatic exposure. Because again, the subset may have this sort of short circuit, or sneaky testosterone, where you're not going to appreciate it just by looking at peripheral testosterone.

So thank you. I'll stop there.

Andrea Miyahira: Thanks so much, Nima, for sharing that. So what do you think drives the association between the higher dorsal T and shorter progression-free survival? Do you think dorsal T is feeding straight to prostate cancer cells that are left behind after surgery? Or does that somehow change prosthetic biology? Perhaps, I don't know, encouraging early metastasis, for instance?

Nima Sharifi: Yeah. It's a great question. It's hard to answer that definitively. I think that the likelihood is that, the enriched androgen source is enabling the growth of prostate cancer. How much of that biology is important, or exposure is important, prior to prostatectomy versus after prostatectomy? It's really hard to say.

The other possibility is that, there may be other metabolites that are coming from the gonads, and that enriched prostatic exposure to those other metabolites could also be a contributing factor.

Andrea Miyahira: Thank you. Do you think high dorsal T levels could be used as a biomarker for risk of recurrence? And do you think this could be feasibly assessed using either prostatectomy samples, or estimated with the peripheral blood metabolite?

Nima Sharifi: Yeah. Again, wonderful question. So to use this as a biomarker directly, there would have to be some sort of intraoperative collection of the same circulation. In the absence of those intraoperative collections, there may be other ways of non-invasive means of assessing for the presence of this sneaky testosterone. One potential way is to identify a peripheral metabolomic signature of this physiology.

Another possibility for non-invasive assessment, is to come up with an imaging modality that tells us who has this collateral circulation. We also think that this collateral circulation, it actually has the common physiology of varicoceles, in effect, having incompetent gonadal veins and backup. So it may be that, identification of varicoceles on physical examination could be a biomarker or a physical exam biomarker of this physiology.

Andrea Miyahira: All right, thank you. And what are your team's next steps in this research?

Nima Sharifi: So this is part of what's so exciting about this for us, is that, there's a number of different directions that we can take with it, and that we intend to take with it, largely in collaboration as well. Some of it, as I mentioned is, looking for radiographic means of assessing this physiology. The other part is, looking at the other metabolites in an unbiased fashion, both locally, what other metabolites are enriched from gonadal circulation? And is there a way of identifying this physiology just by peripheral blood draw? And the other part is really figuring out whether these other metabolites that are enriched from the gonads actually have some sort of biologic function on the prostate. It's very early in those studies, but that's certainly a direction that we're highly interested in.

The other thing that I'll add is that, I think an area of exploration is to figure out whether this might lead to a different indication for varicocelectomy, right? What does varicocele repair do to this physiology, if indeed there is that common connection? I don't know the answer to that, but it's something I think we need to explore.

Andrea Miyahira: All right. Well, thank you again for coming on and sharing this with me today. And congratulations on this paper, and again, on your new appointment at the University of Miami.

Nima Sharifi: Thank you so much. Great to see you.