Biology and Prostate Cancer: Elucidating Differential Androgen Receptor Cistromes in African American vs. European American Men - Jacob Berchuck

January 30, 2023

Jacob Berchuck shares his insights with Alicia Morgans about his groundbreaking research on racial disparities in prostate cancer between African American and European American men. Dr. Berchuck's study explores the androgen receptor cistrome and its differing effects on prostate cancer biology. He identifies increased androgen receptor binding at genes associated with lipid metabolism in African American men, suggesting a possible biological explanation for the increased prostate cancer aggressiveness often seen in this population. He also discusses the implications of differences in the androgen receptor on transcriptional programs, highlighting the potential for therapeutic intervention. The conversation evolves to address the complex intersection of biological factors and social determinants of health in contributing to racial disparities. Finally, Dr. Berchuck emphasizes the importance of further research, including clinical trials, to understand these disparities and improve outcomes for all patients.


Jacob Berchuck, MD, Medical Oncologist, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here with a friend and colleague Dr. Jacob Berchuck. Dr. Berchuck, thank you so much for being here with me today.

Jacob Berchuck: It's my pleasure. Thanks for having me, Alicia.

Alicia Morgans: Well, it's always good to talk to you and I wanted to speak with you today about a recent publication in cancer research in which you evaluated African American versus European American men, and looked at differences in the androgen receptor cistrome. Can you tell me a little bit about this work?

Jacob Berchuck: Absolutely. So we've known for a long time or the literature suggested that there are racial disparities or ancestral disparities in prostate cancer. Specifically, we've seen that men of African ancestry in the United States are more likely to be diagnosed with prostate cancer, be diagnosed at an earlier age, and have more aggressive disease and be more likely to die of prostate cancer. Now, this has become a lot more complicated in the recent years as we've delved into this disparity a little more deeply. The intersection of ancestry, race, socioeconomic factors, psychosocial factors, and it's become a very complicated space. But I think one thing that we were really interested in specifically addressing in this paper is more about the biology and specifically the potential epigenetic underpinnings of any differences that we may see in prostate cancer biology between men of African and European ancestry in the United States.

Alicia Morgans: Well, and that's so interesting. I think the field of epigenetics is really from my perspective, one that has high potential, but also high risk for confusion. Can you tell us a little bit as an audience, what the cistrome is and what, what role that plays in the analysis of epigenetics of these patients?

Jacob Berchuck: Yeah, absolutely. So the cistrome essentially is a term to define where in the genome specific transcription factors bind. We know that several transcription factors are very important to the development and progression of prostate cancer. The one that is probably best studied is the androgen receptor, which we know drives the development of prostate cancer and progression from localized prostate cancer to castration resistant prostate cancer. And in that process, what we see is that the locations in the genome where the androgen receptor binds shifts as cells develop from a normal, healthy prostate cell to a localized prostate cancer, to a metastatic castration resistant prostate cancer. How we articulate that is that we see shifts in the AR cistrome essentially where it's binding and where the androgen receptor binds has really important implications for prostate cancer biology for cancer aggressiveness.

Jacob Berchuck: As a result of that, we were really interested to see whether the androgen receptor differs in men of African ancestry in the United States from men of European ancestry. And so that's sort of the main question that we were asking in this publication. What we did is we performed ChIP-Seq, looking at where the androgen receptor binds in prostate tumors from African American versus European American men. And what we found is there were a huge number of sites that were different between tumors from men of these different ancestries. And so seeing that, we were really interested to try to understand what's different about those sites? What's important about those sites, what do those sites do? And there were two really interesting findings. The first was that in men of African ancestry, we saw more intense binding of the androgen receptor at genes that associate with lipid metabolism.

So essentially it suggested that tumors from African American the androgen receptor was binding at specific locations to up regulate lipid metabolism. And this is really interesting because lipid metabolism is associated with more aggressive prostate cancer. And so provides a potential plausible biological explanation for what we've observed in the literature with potentially more aggressive disease in men of African ancestry. And more broadly, what we observed is that sites that had greater AR binding intensity in African American tumors from African American men than European American men also associated really strongly with genes that were up-regulated in African American tumors relative to European American tumors.

We saw this as sort of a global phenomenon, which suggests that different binding of the antigen receptor in tumors of men from African ancestry may potentially be driving different transcriptional programs more broadly. The lipid metabolism was the sort of the clear, most egregious, different biological pathway. But certainly I think there's a lot more to uncover in terms of what differential antigen receptor binding and certainly what other transcription factors and other genetic features, how those may be driving different transcriptional programs in men of different ancestral backgrounds.

Alicia Morgans: I think what's so fascinating is that there are really already defined two different sort of ideas around why men of African ancestry might have more aggressive tumors. There's this whole biology of the tumor idea, but there's also this issue of social determinants of health, access to care. This paper really, I think, contributes of course, to the biologic explanation. What are your thoughts on whether it is different biology or perhaps social determinants of health? Is it possible it's both, what do you think?

Jacob Berchuck: Yeah, it's such an important question. I think it's pretty clear that both are really important and both deserve further attention. I think that with the literature that's emerged in the last few years that have looked at equal care, equal access settings and seeing that disparity really tends to disappear and that in several studies, including clinical trials, men of African ancestry actually, there's a suggestion that they may do better. And so clearly access, socioeconomic factors and all of the sort of complicated aspects that go into race in America are at play and need to be understood further. We need to focus on efforts to mitigate that. But I also do think that our paper, what's so exciting about this, is it does suggest that there is different biology as well.

And what's exciting about that is that understanding that may lead to opportunities for therapeutic intervention, identifying therapeutic vulnerabilities that are specific to men of one ancestry or another. I think understanding the biology is the first step to being able to target those to improve outcomes for patients, regardless of ancestry. Specifically, with our finding that lipid metabolism is up-regulated. What's exciting about that is, inhibitors make sort of these, this pathway is making it into the clinic. And as clinical trials of lipid metabolism inhibitors are being opened in prostate cancer, I think this is exactly where that question ties in because we know that African American men and men of other races and ancestry are underrepresented in clinical trials.

I think as we understand the biology of prostate tumors in African American men and how it differs, we need to sort of really work to increase the infrastructure and enrollment in clinical trials. I think that gets exactly to your question about sort of the access and all the other factors that go into this. I think a long answer, but in short, I think both are incredibly important and we need more work in this space.

Alicia Morgans: Well, and it is such an intertwined world. A person is certainly biology, is also environment. And so many aspects come into play here. But to your point too, it's really exciting to think that there is some biologic basis. And now I wonder there are differences identified, and you made reference to this yourself in terms of response to different treatments by ancestry, which I think is really interesting. And I wonder if your work specifically addresses whether there may be differences in response to, in one paper, Cabazitaxel, in another paper Abirace, there were differences in PSA responses though not statistically significant to Abiraterone. Do you see this pathway actually contributing to differences in responses that we see in any of our therapeutics, the ones that are currently available?

Jacob Berchuck: I can provide a few ideas. I think we should be careful to acknowledge these are hypotheses and we didn't prove any of this definitively, but I think there's a suggestion that what we found could sort of start to provide insights into this differential response. After lipid metabolism, the pathways that we saw most sort of intensely bound in by the androgen receptor in African American relative to European American tumors was actually immune response in cytokine signaling. We saw in a match cohort of RNA seek data, transcriptome data that likewise several immune cell types were up-regulated or had higher expression in African American tumors. Sort of subsequent analysis of the clinical trial that led to approval of Sipuleucel-T. The vaccine that we use in prostate cancer suggested that actually African American men may derive more benefit, may have better response.

Seeing sort of that we're seeing the biologies potentially suggest greater or at least different immune activation in prostate tumors from African American men than European American men. And seeing this corollary clinical data where they're more likely to respond to an immune therapy, it does start to suggest some really exciting potential avenues for further investigation to sort of deconvolute what we're seeing in the clinic by better understanding the biology.

Alicia Morgans: It's really exciting. And of course this is hypothesis generating, but what an exciting time for us to be able to generate hypotheses about the basic biology in these clinical trials that we've seen. And certainly exciting as we move forward with novel therapeutic development. So if you had to give a closing message to the listeners regarding this work, and of course the ongoing work that you're doing in this space, what would it be?

Jacob Berchuck: Yeah. So I think this was the first report of the androgen receptor cistrome in African American men. And I think it speaks to how epigenetic analysis of prostate cancer can provide really key insights into potential differential biology between African American and European American men that will allow us to identify therapeutic vulnerabilities and ultimately better treat our patients, improve outcomes for our patients through a better understanding of the underlying biology.

Alicia Morgans: Well, I sincerely appreciate your time and your efforts embracing our differences to understand them better and to get better outcomes for patients is so important right now, and always will be. And certainly we appreciate your efforts in trying to unravel this. Thank you for your time and your expertise.

Jacob Berchuck: Thank you.