Alicia Morgans: Hi, I'm so excited to be at AUA 2022 with Dr. Lauren Cooley, who is at Northwestern University. Thank you so much for being here with me today.

Lauren Cooley: Thank you so much for having me.

Alicia Morgans: Wonderful. So I wanted to talk with you about some of your work on gender differences in bladder cancer. From a basic science perspective, you've really found some fascinating differences in some of the models that you've been working on. Can you tell us a little bit about it?

Lauren Cooley: Yes, for sure. So, I mean, a lot of our research has really stemmed from a clinical observation that men are far more likely to be diagnosed with bladder cancer compared to women. In fact, it's about three to four to one, but when women are diagnosed they tend to be postmenopausal and they tend to have more aggressive disease. So we really wanted to see if there was a biologic basis that could help to understand why that's happening. So we're using a mouse model of bladder cancer. We're essentially the mice are exposed to a chemical carcinogen and we're able to see in a time kind of course perspective how tumor develops and if there's any differences from a genomic perspective and from an immunologic perspective.

Alicia Morgans: I think that's really, really important. And of course, using a mouse model lets us get a better understanding of the time course, which we of course could not do in people. So in these mouse models, have you found differences in terms of the female versus the male mice in terms of the bladder cancers that develop?

Lauren Cooley: So we have. So interestingly, men far more quickly develop muscle invasive tumors compared to females, despite being exposed to equal carcinogen for an equal duration of time. When you look at the actual tumors that develop what's interesting is that they're fairly identical between men and women. So when we look at the tumors that are shared, the non-muscle invasive tumors, only 21 differentially expressed genes, most of them are X and Y linked. So that's essentially telling us that the tumor that ultimately develops is similar, but the interesting part is actually what's leading up to that tumor. And that is what we found to have differences. So even if you look for instance at just baseline, normal male and female bladder, there's nearly 1200 differentially expressed genes. And multiple of them are in carcinogen metabolism pathways that are highly up regulated in females compared to males.

So already showing that there's some sort of barrier defense, that's different between males and females. Early on in carcinogen exposure, we find that males are far more reactive to it. They have differences in their DNA damage repair pathways. They also have differences in their native immune response to the carcinogen, very high levels of inflammation early on, followed by quick regulation, specifically in kind of their myeloid compartment. So they're innate immune response to the tumor. Whereas females, it tends to see that they don't really see that carcinogen for a little bit longer and their response is quite delayed compared to men.

Alicia Morgans: That's really interesting. So the response to the carcinogen is later yet they have a later time of onset of cancer cells. So really interesting that the earlier response is tied then to the development of cancer, maybe sort of a dysregulated immune response or the mutant response may be fine, but there's a dysregulation in sort of attacking and clearing. It just leads to this ongoing inflammation. I think all of that is really just me hypothesizing and trying to come up with something, but really you and your team are trying to investigate this more. What do you think the implications are? Tell me what you think.

Lauren Cooley: We're hoping that castration models are really going to tell us kind of what is this defense barrier or this defense mechanism that females have to kind of delay this onset. Because what we see in people is that it's not until women are post-menopausal that they tend to develop tumors and aggressive tumors at that. So we're hoping that with these castration models, we'll be able to see kind of where is that kind of on and off switch that all of a sudden women lose this barrier of defense and then they get tumor.

Alicia Morgans: So interesting. So I really think that these are absolutely as you said, going to be potential targets for therapeutics in the future or approaches in the future. Do you see that this might be an opportunity to identify cancers or there might be an opportunity to identify cancers in women earlier? Or how do you see this playing out to benefit women?

Lauren Cooley: Yeah, so I mean likely the reason that women have more aggressive tumors is probably multifactorial. There could be issues with delay in diagnosis and things like that. But I think we really do have an opportunity here to give more precision to how we're treating patients. So for right now we kind of have a one size fits all way in which we treat bladder cancer. It's highly based on your stage and your grade, but this could have the ability to target certain, you say androgen or estrogen signaling pathways that we don't even know right now are critically important to developing muscle invasive tumors. And specifically when we look at non-muscle invasive tumors, one of our big barriers is trying to prevent progression and recurrence. And I think that might really be where this research specifically will kind of hone in.

Alicia Morgans: This is really interesting. Well, so what would your message be? What are the next steps to investigate for you and your team?

Lauren Cooley: As I said, we were really focusing kind of on these castration models and seeing whether or not we can identify that on and off switch, whether that be in the immune system or in genomic regulation, that kind of leads from carcinogen exposure. And then that change in the urothelium to eventually become muscle invasive tumor. And if we can kind of get these snapshots in time and see where are really these on and off switches.

Alicia Morgans: That sounds wonderful. Well, thank you so much for your time and your expertise today, Dr. Cooley.

Lauren Cooley: Thank you so much for having me.