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Alicia Morgans: Hi, I'm so excited to be here today with Professor Nima Sharifi, who is a professor of Urology and the scientific director of the Desai Sethi Urology Institute at the University of Miami. Thank you so much for being here with me today, Nima.

Nima Sharifi: Thank you, Dr. Morgans, for having me. I'm very excited to be here and to discuss some of our work and background.

Alicia Morgans: Wonderful. Well, let's get started.

Nima Sharifi: Okay. Well, I'm absolutely delighted to be here, and thank you for asking me to talk about some of the background and the work on HSD3B1 and prostate cancer. I'm Nima Sharifi. I'm the scientific director of the Desai Sethi Urology Institute of the University of Miami, and part of the Sylvester Comprehensive Cancer Center. The background that I think most of us are aware of is that in addition to gonadal sex steroids, meaning testicular testosterone, adrenal androgens, or adrenal androgen precursors are a major part of the physiology of prostate cancer, particularly when it comes to castration-resistant prostate cancer. You can see that DHEA and DHEA sulfate are the most abundant adrenal androgens present in circulation, in fact, the most abundant steroids present in blood just in normal physiology.

So we know that both the gonadal and adrenal axes and their androgens are regulated originally from the pituitary here and so for about 80 years or so, from the time of Huggins and Hodges, we've used gonadal testosterone synthesis inhibition or gonadal testosterone blockade for the treatment of metastatic prostate cancer. But when we do that, what we're left with is an intact adrenal androgen pathway and these adrenal androgens, again, DHEA can be utilized by the prostate cancer here as substrates to make potent androgens like DHT or dihydrotestosterone, and this can feed into resistance mechanisms by stimulating the androgen receptor and androgen receptor-dependent transcription. So the discovery really starts well over a decade ago when we identified two different ways in which cells behave or prostate cancer cells behave with regard to handling adrenal androgens. And just to touch a little bit about the terminology here, I'm going to talk about an enzyme or protein called 3-beta HSD1, and that protein is made by a gene that's named HSD3B1.

Over a decade ago, we basically looked at how different prostate cancers or prostate cancer models handle adrenal androgens. Again, DHEA on its own doesn't do very much at all in the absence of metabolism. When we take DHEA and we put them on some prostate cancer models or some prostate cancers, you can see that there's very little conversion over basically a two-day period. The DHEA stays as DHEA, and there's very little enzymatic activity by 3-beta HSD1 and consequently very little downstream synthesis of DHT. So we've come to call this the adrenal restrictive phenotype because it limits the conversion from adrenal precursor steroids to downstream potent androgens. In other words, if this is the enzyme and this is the DHEA, there's very little forward flow. And in stark contrast to this model and this phenotype, when we look at other models, we see that over the course of the same experiment, that essentially all of the DHEA is consumed, and that's because the same enzyme, three beta HSD, in this context, with this model, is comparatively fast, and this enables the conversion from adrenal precursor steroids to downstream DHT.

And we've come to call this the adrenal permissive form because it enables conversion from the precursors to downstream potent androgens. What's important here is that what drives these different phenotypes is actually a single change in a nucleotide that encodes for an amino acid change, effectively stabilizing this protein, which allows for greater levels and greater metabolism to potent androgens. Another feature that's exquisitely important is that this missense mutation is in the germline or inherited, and it's there at a very high allele frequency. And so that's what I'll talk about next. This adrenal permissive allele, or the fast enzyme just to be simplistic about it, is actually very common in people of European genetic ancestry. In Europe, it's most common in Mediterranean populations, in Spain and Italy. It tends to be a bit less common in people from most East Asian countries, 5%, for example, from Korea. And in Sub-Saharan African populations, it's comparatively low as well. Altogether in Sub-Saharan Africa, the allele frequency is about five to 10%, about five to 10% in East Asia. But in Europe, it's much higher such that about one in two people of European genetic ancestry have at least one copy of the adrenal permissive allele.

The next question that we had after identifying that cellular metabolic phenotype is whether that actually means something for clinical outcomes. We know that men with advanced prostate cancer, treated with testosterone suppression, respond for quite variable periods of time. And we reason that if these tumors have an intrinsic capability of making their own intratumoral androgens from adrenal precursors more rapidly with the adrenal permissive allele, then perhaps they'll progress more quickly. This is the first cohort that we looked at, men who had biochemical recurrence after prostatectomy. When they were treated with androgen deprivation therapy, you can see progression-free survival here. For men who do not inherit the adrenal permissive allele, in the green curve here, they have the best outcomes, while those who inherit one copy of the adrenal permissive allele progress more rapidly, and those with two copies progress even more rapidly. So this really fits with the hypothesis.

And when we looked at a second cohort and several additional cohorts, we see effectively a very comparable or similar thing. And now there's data from at least 12 cohorts worldwide from Cleveland, Mayo, Utah, the Farber, Japan, Hopkins, Royal Marsden, and other places, which effectively show the same thing, particularly in men treated with hormonal therapy who have biochemical relapse or non-metastatic disease, as well as those who have low-volume metastatic disease. This appears to be a biomarker of progression. Then the question at this point becomes, are there any clear effects on overall survival or prostate cancer-specific survival? And this is where the most recent data came out. I was not involved with the study. This study came from the Million Veterans Program, and you can see that Dr. Rana McKay is the first author here.

This is probably the largest study worldwide that puts together genetics with clinical outcomes from the National VA system. Here they looked at over 5,200 men with prostate cancer and the incidence of prostate cancer-specific mortality. So men who are homozygous, the orange curve, for the adrenal permissive allele, have about twice the prostate cancer-specific mortality compared with those who don't inherit this allele as well as those who are heterozygous. They also looked at men who, and I should say that this includes men with non-metastatic or localized disease as well. So this is really all comers. For men who didn't have metastasis initially, but later developed metastasis, you can see that the effect or the association with prostate cancer-specific mortality is even greater. The hazard ratio is about 2.5. And so I think it's really important to state here that homozygosity for HSD3B1 is not a rare occurrence. This is about seven to 10% of the population. So this is a pretty, I think, large proportion with prostate cancer.

What I'd like to do is just quickly summarize where I see this in comparison with other monogenic drivers of prostate cancer mortality. If we compare, for example, BRCA2 inheritance or pathogenic BRCA2 inheritance, depending on the study, the frequency here is about 2% to 4%. BRCA2, when it's pathogenic, is associated with increased prostate cancer risk, worse pathology, as well as an increased incidence of lymph node metastasis and metastasis at diagnosis and increased prostate cancer mortality. By comparison, homozygosity for the adrenal permissive HSD3B1 allele is again 7% to 10% of the population. There's no association with prostate cancer risk. There's no association with pathology for localized disease. This is borne out, again, in the Million Veterans Program study, and there's no association with metastasis at diagnosis. There is an association with prostate cancer mortality, and this comes specifically after the institution of hormonal therapy. So the observations here are completely in line with the mechanism because we don't expect that if something, again, in this context with the development of disease or development of metastasis in the absence of hormonal therapy, when gonadal androgens, that's the overwhelming majority of androgens, we don't expect there to be much of a contribution from the adrenal permissive allele. It's really largely, or mainly after gonadal testosterone suppression that this has an effect. And that explains why you see an increased prostate cancer-specific mortality after hormonal therapy.

So in summary, the adrenal permissive HSD3B1 cellular phenotype increases androgen biosynthesis. There's a human phenotype, where it consistently confers hormone therapy resistance and is met with prostate cancer treated with testosterone suppression. It's a predictive, not prognostic, biomarker, and it's the most common monogenic inherited driver of prostate cancer-specific mortality at 7% to 10%, and this is based on data from the Million Veterans Program. It's also directly pharmacologically targetable. I want to stop by thanking the people who actually did the work. These are current members of our group, former members of our group, Kai-Hsiung Chang in particular, made the initial discovery, and Jason Hearn did much of the biomarker work initially. He's now an associate professor of radiation oncology at the University of Michigan. I want to thank my colleagues in Miami as well as collaborators from many places. And our funding sources, Sylvester Comprehensive Cancer Center, Desai Sethi Urology Institute, the NCI, Prostate Cancer Foundation, and others. Thank you.

Alicia Morgans: Nima, thank you so much. That was really a wonderful presentation, and I know this is many years' worth of work, and as we saw in that final slide, so many people involved. As you think about this and you think about where it goes from here now that there's been a characterization of the prevalence and really the activity of this gene, I know you mentioned that you think it might be druggable, and I wonder, I haven't yet seen the drug hit the market. And I wonder, what are your thoughts? What does inhibition of this gene do? What happens if this gene isn't doing what it needs to do in our regular function? So what might the side effect profile be, and how likely do you think we might be able to target something like this?

Nima Sharifi: Terrific. Two questions. One is pharmacologic targeting of HSD3B1, or the enzyme 3-beta HSD1. There are at least two ways of going about doing this. One is that not that long ago, we actually identified a phosphorylation site on the enzyme that seems to be important for activity. The kinase that actually phosphorylates the enzyme for activity is called BMX. BMX is a very closely related kinase to BTK, where we have lots of inhibitors out there. And in fact, there's a trial that we had initially opened up, led by Dr. McKay through the Prostate Cancer Clinical Trials Consortium. And so what happened is that that company and that drug ended up not doing well. So I'm hoping that we'll have an alternative partner for that trial.

The second way of blocking the enzyme is for direct enzymatic inhibition. And this is something that we're very interested in. It's not a mature area, but it's a real possibility. I think your second question was about the side effect profiles of blocking the enzyme. The enzyme itself doesn't appear to be necessary for any essential function. There's a very closely related enzyme, 3-beta HSD2, which is actually expressed in the adrenal gland, and that's required for making mineralocorticoids and glucocorticoids. If you can selectively inhibit isoenzyme 1 without blocking isoenzyme 2, then there shouldn't be any side effects. But that might be a challenge.

Alicia Morgans: Well, I am hopeful that we can do it. With drug development these days and the way that we have computational-based targeting at different proteins, you never know. But that would be really interesting. And I wonder, in daily practice right now, should we be testing for the permissive versus restrictive polymorphisms here? Should we be thinking about this in day-to-day practice?

Nima Sharifi: Yeah, that's a great question. And I would say that up until the MVP data were published, my answer is maybe, but probably not. I'm not sure we had enough data, but now with a clear prostate cancer mortality associated with homozygosity and the fact that we could pick this up in the germline. So if you take, for example, someone who has localized disease and a conversation is, "Should that person get radiation? Should they get androgen suppression plus radiation therapy?" If you already know they have some intrinsic level of resistance to radiotherapy, then that might change your treatment decision-making. Maybe they need more intensive hormonal therapy upfront. Maybe they need alternative therapies. Maybe you'll pull the trigger for localized therapy a bit earlier than you would otherwise, given that they're not going to respond as well to hormonal therapy later on. So I think we're really at the stage where we should be thinking about this.

Alicia Morgans: Well, this final question is actually inspired by clinic today. There were two patients, two separate practices, but one is mine and one is a colleague's. And she talked to me about this individual that appeared to have intrinsic resistance to GnRH agonist therapy. So we're starting a treatment trial, lowering testosterone production. I assume that this should not have anything to do with that necessarily, but I wonder how quickly might we see resistance with a rising PSA despite standard androgen deprivation if we have patients who have these alterations?

Nima Sharifi: It's a great question. It's hard for me to say. I can talk about some anecdotal cases where there seems to be an association, but I can't say definitively, obviously. For the studies that I described, the earlier studies, there is a period of response before there's progression, typically. But I think there's lots of variability and lots of other genetic contributors. So it's hard to say, but I think the data I'd say at this point are really overwhelming that this is one of the factors and certainly clinically significant.

Alicia Morgans: Wonderful. Well, I sincerely appreciate your expertise. It is amazing the things that you've been working on over the last few years, and I also really appreciate your walking us through it and helping us understand where this goes next. So thank you so much for your time and expertise.

Nima Sharifi: Thank you so much, Dr. Morgans, and it's great to be here.