Transcription:
Bladder Sparing Treatments: The Genomic Approach

Melanie Cole (Host): Welcome to Better Edge, a Northwestern Medicine Podcast for Physicians. I'm Melanie Cole, and I invite you to listen as we examine bladder sparing treatments, the genomic approach. Joining me is Dr. Joshua Meeks. He's a Urologic Oncologist and Assistant Professor of Urology at the Northwestern University Feinberg School of Medicine. Dr Meeks, it's a pleasure to have you join us again today. As muscle invasive and metastatic bladder cancers are some of the most complex diagnoses to treat, tell us about what you're seeing in the trends and why this need for out of the box thinking when it comes to research in this area.

Joshua J. Meeks, MD, PhD (Guest): Yeah. Thanks Melanie. I mean, I think the real challenge with bladder cancer is that we've made a lot of inroads in almost every other solid tumor in regards to smoking cessation and primary prevention. But unfortunately, if you look at bladder cancer, we've really not moved the needle in improving survival for patients. And so, there's something about it that we need to have a different approach. And that's kind of where we've tried to come from.

Host: Well, then let's talk about your research to explore the genomic landscape of bladder cancers, how chromatin remodeling genes may play a role. Tell us a little bit about where your work is focused and about some of the themes of your research, because it's absolutely fascinating.

Dr. Meeks: I think that what we've tried to really do is build off of the blueprint of a big study called the Cancer Genome Atlas. And our tax dollars kind of went into this major, multi-institutional study to figure out what are the blueprints for how you make a tumor. And in bladder cancer, what we found is that there's a very unique group of genes that you know are mutations, but those mutations actually regulate how the DNA folds and this appears to affect bladder cancer in a very unique way. Now, what these mutations are doing and how they actually cause bladder cancer, that's really what we're trying to figure. Interestingly, we see that patients before they actually get bladder cancer already start showing these mutations in these chromatin regulatory genes.

So, even folks who don't have bladder cancer seem to have these. So, they seem to be changing the field of the urothelial lining and that kind of seems to set them up for bladder cancer. So, what we're trying to do is figure out how these early changes again, set the tone for resulting in bladder cancer.

Host: Well then Dr. Meeks, a recent paper in Nature Reviews Urology explores the concept of genomic heterogeneity as a predictor of treatment outcomes for muscle invasive bladder cancers. Can you explain this concept to us? And where is this body of work headed in terms of new treatments?

Dr. Meeks: Right. So, I think we're all hoping to get to a point in the near future where we can have precision targets, meaning that instead of picking a drug off the shelf that is the first line of therapy that we treat all patients with. And in general, we pick those drugs because they're the most effective. You would love to know that the drug that we're giving you with all of its possible side effects are targeting something that's unique to your cancer and going to have the best effects so that if you're willing to under those treatments that you're really going to benefit. Right now, again, it's kind of a one size fits all.

And then unfortunately we get to the point where we don't really have many targets left. So, the real goal of precision therapy is to target an individual very susceptible gene in your cancer. The challenge comes when you sample different parts of a tumor and there's different targets in every region. And that's really, really gets to that concept of heterogeneity, meaning that if we sample different regions or it's called intratumoral heterogeneity, will you have the same response? So, you can give a drug targeting one specific pathway or one gene, but if two thirds of the tumor don't have that, cause the tumors kind of moved on, then your therapy overall isn't going to be effective.

So, what we're trying to get a sense of is what tumors are heterogeneous. And when that happens, is there a better way we should go about treating them? Is there, should we be combining therapies? Should we, you know, if you have three potential therapies, which one do you start with, or maybe you should give them all together. So, I think that's kind of where we're hoping to go in order to get the best outcome for our patients.

Host: That's so interesting the way that you put that, Dr. Meeks. Is genomic testing accessible? We hear about genetic testing all the time. Is this accessible and how can other urologists take into consideration genetic factors when they're identifying the right course of treatment for their patients?

Dr. Meeks: Yeah. So, this is a topic that's quickly moving. And I think right now, for most patients, there's two kinds of testing that we do. One is testing the tumor itself and for most patients, that can happen when someone's got essentially an uncurable tumor, an advanced tumor that you're treating that is metastatic or thought to be uncurable. The other kind of testing that we do is what's called germline testing. So, that's, what's in every single cell of our body. And outside of those two indications, which are a relative minority of patients with bladder cancer, we don't really have testing available. But I really think about, you know, there's about a quarter of patients who have locally advanced tumors, where we're going to consider something like bladder removal or even chemotherapy and radiation, where if we knew more about their tumor, for example, if we knew how many mutations it has, I think we would probably treat them differently.

So, by and large, I think that this, even though this is changing, I think we'll be doing a lot more testing in the near future. And for example, people like our group are trying to develop relatively small panels of genes that can have an impact on our patients.

Host: We recently did a show on germline testing. So interesting. So, where does immunology response fit into this work you're doing?

Dr. Meeks: So, bladder cancer is in the group of what we consider to be favorably, immunologically responsive tumors. Meaning that, there's some tumors that just have a very low likelihood of responding. Bladder cancer, I would put in a group very similar to, for example, melanoma and lung cancer. And what all three of those tend to have in common is, number one, is they're all caused by carcinogens. In bladder cancer, that's often from smoking. And the other part of it is that they tend to be solid tumors with a relatively high mutation burden. And so, what we look for is, you know, if we can't find a specific target that we could give one drug for, there's a good chance that in some of these tumors, that they're going to be more likely to be responsive to immunotherapy.

So, what we've kind of seen as an example, in lung cancer is that if you don't have a precision target, the best way to begin may just be immunotherapy. So, interestingly, the two may overlap, there may be individual gene mutations that actually cause tumors to be more responsive to immunotherapy. So, I tell you it's really revolutionized how we treat patients with bladder cancer. And I think again, we'll probably be using it both in the precision efforts, as well as in broadly treating patients going forward.

Host: What great points. So, as we're wrapping up Dr. Meeks, what other interesting research is happening in this area and how can we expect it to change the future treatment approaches, taking research to patient bedside? Tell us a little bit about what you see coming in the next 10 years and what you would like other providers to take away from this episode and your research.

Dr. Meeks: I really think that if we listen to our patients and in addition to obviously their first goal is to be alive and to survive. That's number one. But then second, if you, if you had a second choice, it would be organ preservation. And we've seen that all across oncology where if you can try to preserve the organ and still maintain survival, that's sort of the ideal that we're going for.

So, even though I'm a surgeon and we do operations to remove the bladder, because that offers cure, I think kind of the Holy Grail of this is to be able to identify which patients we can try to preserve their bladder, whether that's through systemic therapy, local therapy, radiation. So, I think trying to match therapy with patient with the goal of preservation of quality of life, I think that's really where we'd love to go with all this work in the future.

Host: I could not agree more. And what a great episode and your research is so interesting. Dr. Meeks, thank you for joining us and please join us again to update us as this research continues. To refer your patient, please visit our website@nm.org to get connected with one of our providers.

That concludes this episode of Better Edge, a Northwestern Medicine Podcast for Physicians. Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. Until next time, I'm Melanie Cole.