Progress in Bladder Cancer Research - Bishoy Faltas
June 3, 2020
Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Alicia Morgans: Hi. I'm delighted to have here with me today Dr. Bishoy Faltas, who is Director of the Bladder Cancer Research Program at the Englander Institute for Precision Medicine, and an Assistant Professor of Medicine at Weill Cornell. Thank you so much for talking with me.
Bishoy Faltas: Thank you for having me.
Alicia Morgans: So Bishoy, you are always up to many things. And you have your own lab and a really productive research group that you work with at Weill Cornell. I would love to hear what you're most excited about right now, what you and the team are working on in urothelial cancer.
Bishoy Faltas: Thank you. This is a very exciting time for bladder cancer research. It's a very exciting time for us. As you said, we're working on many things. Some of them we were discussing before this. Some of the things that we are working on at Cornell is a new paradigm for clinical trials, including the window of opportunity clinical studies. We have a clinical trial called the CLONEVO Trial, which is a window of opportunity study for platinum and eligible bladder cancer patients who will receive four weeks of abemaciclib, which is a CDK4/6 inhibitor prior to receiving cystectomy. What's really exciting about this trial is that we can collect tissues from the transurethral resections of the bladder tumors prior to receiving the drug and then again from the cystectomy after the drug, and we're able to establish patient-derived organoids, patient-derived xenografts from every patient.
We are also collecting circulating tumor DNA from every patient at each time point, which allows us to really monitor in real-time the evolution of the disease during treatment. And then because we are collecting a lot of CD34 cells, these are hematopoietic STEM cells from these patients, we're also working to establish humanized mouse models that will allow us to reconstitute the immune system of each patient and their tumor in a mouse and then allows us to test lots of different treatments that modulate the immune system because these are in these immunocompetent mice.
Alicia Morgans: Wow. Very exciting. Very challenging technically, I'm sure. How many patients are on the trial so far?
Bishoy Faltas: So right now, I think we opened a few months ago, we've recruited three patients already to the trial.
Alicia Morgans: Wonderful.
Bishoy Faltas: We have several organoids and patient-derived xenografts that are already growing and we started working on the humanized mouse models and we have some very encouraging preliminary results. Our goal is eventually to recruit 20 patients. Those patients are not necessarily very easy to find, but we're spreading the word and trying to get as many patients as we can to know about the trial and as many providers to know about the trial.
Alicia Morgans: Wonderful. So cisplatin in the eligible patient population going to cystectomy?
Bishoy Faltas: That is correct.
Alicia Morgans: Wonderful. So what else is exciting in your arena?
Bishoy Faltas: We're also working on circulating tumor DNA, and we have an abstract that we have been working on with Dr. Vogelzang, where we have looked at a large number of patients who had the commercial testing platform for circulating tumor DNA. And we looked at the correlation between the changes in circulating tumor DNA and clinical progression or response using RESIST criteria from their scans. These are advanced urothelial cancer patients, and what's very interesting is that we can see almost one to one or very proportional correlation, directly proportional correlation between the changes in the variant allele frequency of the mutations that we can detect from the circulating tumor DNA and the clinical response for these patients who are getting treated with a variety of different treatments. We can see that patients who are in clinical remission, particularly sustained clinical remission that this correlates with molecular remission from circulating tumor DNA and this seems to be again true across the board and for a variety of different treatments.
Alicia Morgans: That's really exciting and suggests that in the future we may have a blood-based marker that can help us understand when patients are developing a recurrent disease or progressive disease even before we have radiographic evidence potentially or at least something that we could use in combination with our scans. Because I think in urothelial cancer that's always a bit of a challenge particularly in patients who can't get a contrast to have a really definitive method of understanding disease burden is something that I think will be very valuable in clinical practice over time.
Bishoy Faltas: Absolutely. And I think that the next step would be to try and incorporate this prospectively into clinical trials so we can actually understand the characteristics of the test and actually its sensitivity, its specificity and its predictive value for and how it really correlates in sort of the lead time for detecting changes in the tumor burden in relation to the radiological scans.
Alicia Morgans: Absolutely. So before we wrap up, a final, a really hot topic or something of interest in the Faltas lab or in your group that you wanted to share with us?
Bishoy Faltas: So we are actually starting to look into machine learning and artificial intelligence and how to really apply that to the care of bladder cancer patients. We are starting to look at ways to be able to detect the molecular subtypes, so luminal basal at its simplest form and also the immune status of a given tumor by just looking at the histopathology slides. So we take the histopathology slides, and we essentially feed them to a computer algorithm that we have developed in collaboration with other labs at Weill Cornell, and we are able to detect with a very good area under the curve the molecular subtype and the immune status just based on looking at the histopathology slides, and the ground truth here is RNA sequencing data that tells us what the molecular subtype is. This work is obviously very early, but we have very interesting results that we would be happy to share with a broader community soon and we are working to improve these methods.
Alicia Morgans: That's wonderful. And at this point, luminal basal subtypes don't necessarily distinguish how we choose treatments for patients, but that's now, and what I think is so important about this is that it's really forward-looking to a time when we will use that information to more carefully make decisions for our patients. And there are trials that are really helping us unravel some of that right now, but this, I think, to develop this type of an approach in concert basically with our understanding of the therapeutics and that histologic subtype I think is going to be really, really important.
Bishoy Faltas: Yes, absolutely. I mean the subtyping serves two purposes. One is it's really a gateway to our understanding of the biology of the disease. It's really a way for us to make sense of different subgroupings within bladder cancer or urothelial carcinoma in general and to try to understand what really drives each one of these subtypes and how they respond to different therapeutic interventions.
The other one, as you already mentioned, is then trying to prospectively validate these molecular signatures or subtypes as predictors of response to therapy and that obviously has to be done in the context of clinical trials. As you already mentioned, there are a lot of different concepts that are currently under development, and also we're going back to look at prospectively collected tumors from several trials that are currently ongoing, and we're involved in some of these efforts to again try to correlate that with clinical outcomes and to see really how these subtypes predict a response to therapy. I think it's really important to establish that and get a direct answer from a very solid perspective ideally randomized trials, and I think that would be very important. That being said, I think there is a lot of value to using these subtypes to understand the biology.
Alicia Morgans: Absolutely. Well, thank you so much for sharing these really cutting edge aspects of your work, your group's work, and what we all have come to rely on as really at the forefront of the biologic understanding of urothelial cancer. I really appreciate your time.
Bishoy Faltas: Thank you for having me.