Zachary Klaassen: Hi, my name is Zach Klaassen, urological oncologist at the Georgia Cancer Center in Augusta, Georgia. We are at the PCF Scientific Retreat for UroToday in Carlsbad, California. I'm delighted to be joined by Dr. Karen Sfanos, who is a pathologist at Johns Hopkins University of Medicine. Karen, thanks so much for joining us on UroToday.

Karen Sfanos: Thanks so much for having me here.

Zachary Klaassen: So you are hosting a really exciting session looking at the microbiome in prostate cancer, how to harness that. And it's almost similar to the AI session, this is something that's come about in the last few years. So maybe just walk through some of the seminal work that's not only really exploding this field, but led to a full session on the scientific retreat.

Karen Sfanos: Absolutely. So I think what's really exciting in the microbiome field right now is whereas in the past, we used to be asking very simple questions like, what are the types of microbes, trying to profile what's there in terms of fecal microbiota, urinary microbiota, I think what's exciting now and what's ended up in a session is that we're getting to a point where we're starting to understand functionally what microbes are doing in the gut and elsewhere, and specific mechanisms of how that might be influencing prostate cancer. So in this session, we have talks that are about androgen production in the gut and how that might interfere with anti-androgen therapy that we give for advanced prostate cancer. We have talks about bacterial or fungal translocation into metastatic tumors and how that might influence the immune microenvironment or therapy response. And then, super interestingly, we have a talk, it's on breast cancer, but the talk is about how the gut microbiome can metabolize, can change cancer drugs that are taken orally. The talk that we had was about tamoxifen, which of course is an endocrine therapy for breast cancer, but what they have shown is that different people, depending on what microbes are present in your gut, can metabolize tamoxifen differently, leading to differences in treatment response. And we think that this is very possibly analogous to what might go on in prostate cancer as well, where there are several different oral drugs that are given for the treatment of prostate cancer that might be influenced differentially among people by the gut microbiome.

Zachary Klaassen: That's a great overview of the session. I want to focus a little bit on the topic you gave, looking at, again, mCRPC. Just give us the highlights of that talk looking at androgen resistance.

Karen Sfanos: Yeah. So my talk was specifically about gut androgen production and how that might contribute to therapeutic insensitivity to abiraterone acetate treatment. And what we have found is that there are specific species of bacteria in the gut that can convert things like glucocorticoids... Which I know that's a big word. An example of a glucocorticoid is prednisone, which is given alongside abiraterone acetate in the treatment of individuals with advanced prostate cancer. There are microbes in the gut that can metabolize that prednisone into an androgen. And the whole point of the therapy that we're giving, called anti-androgen, we're trying to shut down androgen production in the human, but there's the capacity for bacteria in the gut to produce their own androgens, and we hypothesize that these can be absorbed and circulate and perhaps influence cancer growth and contribute to what we call castration resistance.

Zachary Klaassen: Sure. So just jumping off of that, is there a target potentially down the road where we can alter that gut biome to not produce androgens? Is that the goal?

Karen Sfanos: Absolutely. I get asked that question quite a bit. People ask me, "Should we be taking broad spectrum antibiotics to try to eliminate these gut bacteria that can produce androgens?" And my answer always is that's one strategy I don't think that's going to be the long-term strategy. A better strategy is to try to develop, for example, small molecule inhibitors against the specific bacterial enzymes that we think are responsible for converting androgens.

Zachary Klaassen: So not wiping out the whole-

Karen Sfanos: Not wiping, because you need your microbiome.

Zachary Klaassen: Sure, absolutely.

Karen Sfanos: It's actually detrimental to wipe out your microbiome and it might not fully recover and all the things involved in that. A better strategy is a targeted strategy, and we're actually currently funded by a prostate cancer challenge award to develop small molecule inhibitors of those bacterial enzymes.

Zachary Klaassen: It's so fascinating, because I think the average clinician watching our discussion probably doesn't have that insight in the microbiome, so this is, in terms of early resistance or even late resistance, hugely impactful potentially. So how do you see this field, and you kind of alluded to it a bit, how do you see it going in the next two to five years, getting it into clinic, and what are the steps you guys think will have to be taken?

Karen Sfanos: I think that in the next few years, we're entering this space now, where we're not just asking who's there, we're starting to understand what they're doing, and now it's the question of, well, how do you modulate that? And it's been tricky to understand how to modulate the microbiome because it's very complex. And I will take the opportunity to just make the statement that still the best way to modify the gut microbiome is through diet, we can't forget that. But understanding the specific microbial pathways that are in play in terms of cancer, prostate cancer, across the entire spectrum, I think is now leading to a more targeted approach, therapeutic approach, small molecule inhibitors, specific ways to not just change the entire microbiome or eliminate the entire microbiome, but to modulate those species that are the bad actors, and I think that that's where the field is going.

Zachary Klaassen: We spend a lot of time in the clinic talking about cardiotoxicity and exercise and diet, is there a specific diet microbiome-related that patients should be thinking about?

Karen Sfanos: I say it over and over and over again, but it's still true and it's always going to be true, high fiber diet.

Zachary Klaassen: Okay, perfect.

Karen Sfanos: Across the board, it's shown to improve the good microbes that promote health. So diets always high in fruits, high in vegetables, moderate amounts of meats, definitely not processed meats, all the things that you hear all the time.

Zachary Klaassen: So I can tag that onto my cardiovascular diet is also probably good for the gut as well.

Karen Sfanos: And pay attention to how much fiber you're getting per day. It's not that hard to get your 25 grams of fiber.

Zachary Klaassen: That's right. Awesome conversation, really enjoyed it. Any take-home messages, conclusions, for our listeners?

Karen Sfanos: My biggest take-home message is that I can't appreciate the Prostate Cancer Foundation enough, because they were on the microbiome very early. They've supported me from the very beginning of my career, and the whole reason why I've managed to get where I am in studying the microbiome in prostate cancer is because of PCF.

Zachary Klaassen: Perfect. Great way to end the conversation.

Karen Sfanos: That is actually true.

Zachary Klaassen: Thanks so much. I appreciate that.