Upper Tract Urothelial Carcinoma Has a Luminal-Papillary T-cell Depleted Contexture and Activated FGFR3 Signaling - Bishoy Faltas
October 14, 2019
Alicia Morgans hosts Bishoy Faltas in a discussion about a Nature Communications publish article Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling which Bishoy was a co-author on with Brian D Robinson et al. In this study an integrated analysis of whole-exome and RNA sequencing of upper tract urothelial carcinoma (UTUC) was performed to define the biological features driving the distinctly aggressive clinical phenotype of UTUC.
Alicia Morgans, MD, MPH is an Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
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Alicia Morgans: Hi. This is Alicia Morgans, medical oncologist at Northwestern University. I am thrilled to have here with me today Dr. Bishoy Faltas, who is a Medical Oncologist joining us from Weill Cornell where he is the Director of Bladder Cancer Research of the Englander Institute for Precision Medicine, and also an Assistant Professor of Medicine of cell and developmental biology. Just many, many talents, and thank you so much for joining me today, Bishoy.
Bishoy Faltas: Thank you so much for having me.
Alicia Morgans: Of course. I have been following your work and your lab's work for some time. Have been really excited about both advances that are coming out addressing upper tract urothelial cancer, as well as bladder-initiating urothelial cancer. I just wanted to speak with you about some of these really exciting advances that your team has made, starting with the upper tract urothelial paper that you recently had in Nature Communications. Can you tell us a little bit about that and how you're really trying to dig into the drivers of upper tract disease?
Bishoy Faltas: Of course. This is something that we've been working on for quite some time. As you know, upper tract urothelial cancers are rare, constituting about 10% of all urothelial cancers, but they're usually presenting at more advanced stages and sometimes associated with worse clinical outcomes. In my lab, our approach in general, is that to try to understand the biology of the disease as really the key to making clinical advances. With that in mind, we've been working on trying to understand what are the molecular underpinnings of upper tract urothelial carcinoma, which I will refer to from now on as UTUC, and how are these different or distinct from bladder cancer, from run of the mill bladder cancer, which is the most common location for bladder cancer and the most common location of urothelial cancer or the most common presentation of urothelial cancer.
We started by having a cohort of patients from Weill Cornell. We also had a collaboration with Serena Muttin and Seth Lerner, and we had another cohort from Baylor College of Medicine and MD Anderson, and looking at these two cohorts together and considering them alongside the TCGA bladder cancer cohort, we were able to have a fairly complete picture of what the molecular profile of these tumors looks like. And initially, we performed [inaudible 00:02:55] sequencing and we found that there was an enrichment or a higher prevalence of STF-43 alterations, as has been reported before by others, including John [inaudible 00:03:06] and Serena Muttin and also the Memorial Sloan Kettering group. And we looked at the APOBEC mutational signature. So really what's driving this mutational profile. And in my lab we're really focused on the APOBEC enzymes, which is a family of seven cytidine deaminases that mutate cytosines.
And, when we looked at urothelial carcinoma to try to see what was the driving force behind these mutations. And we found that it was really APOBEC induced mutagenesis as the dominant mutagenic mechanism in these tumors. And we then looked at several DNA repair genes and the reason we looked at these, the majority of upper tract urothelial carcinomas are sporadic and we wanted to understand if the canonical DNA mismatch repair genes play a similar role in sporadic upper tract urothelial carcinoma, compared to that arising in the context of Lynch syndrome.
I would like to point out that our cohort and the majority of diagnosed upper tracks are actually sporadic and not associated with Lynch syndrome. So when we looked at our cohort, we found that there was a decreased expression of several of these genes, MLH1, PMS2, MSH2 and MSH6 and we confirmed this at the RNA level, we confirmed this at the protein level, but the real litmus test for whether this deficiency in these MMR genes is translating into a defective MMR process and an increase in microsatellites is at the DNA level.
So we measured, actually, microsatellites and we, using a bioinformatic tool called MSI sensor, and to our surprise, we found that upper tract urothelial carcinoma actually did not have increased levels of microsatellite instability compared to conventional urothelial carcinoma. In fact, when we looked at upper tract urothelial carcinoma, we found that it had a lower total mutational burden compared to bladder cancer. And, I would like to point out, that there was a recent paper from Andrew Shay and Petros Grivos at the University of Washington that confirmed this observation. And there were also additional observations that were made by Matt Galsky in an abstract that was presented last year at ESMO that reported similar observations. So, we are starting to see a pattern emerge here and we're starting to think that this is actually the case.
Alicia Morgans: It's fascinating because as you said, there's this description of there being this association and perhaps the association is not necessarily as tightly tied as we thought. And I'm wondering too, particularly around the FGFR alterations, what are your thoughts, and I think you lay out plans for potential trials. What are your thoughts about trials of therapies that might be particularly useful given what you found in terms of potential drivers for upper tract disease?
Bishoy Faltas: That's a great question. To summarize the FGFR3 aspect of this, we found that the majority of upper tract urothelial carcinomas were consistently clustering within the luminal subtype or more specifically the luminal papillary subtype, which is associated with activation of FGFR3. We also found that the majority of upper tract urothelial carcinomas are associated with a T-cell depleted immune contexture and the higher FGFR3 expressions. We believe that these two things are actually tightly linked together. And in fact, when we looked at a dataset where there was silencing of FGFR3 using SHRNA, we found that there was up regulation of interferon gamma response genes. And we went on and we used erdafitinib, which is a targeted FGFR3 inhibitor. And we were able to replicate this effect pharmacologically.
And we showed that there was a significant up regulation of BST2, which is one of the genes that are considered to be one of the hallmarks of interferon up regulation. We also, at the same time, I think a few days before our paper was published, there was another paper that was published by Dr. Galsky's group in European Urology and if you look at that paper in an independent cell line dataset, you will see that it was also converging on the interferon gamut pathway as a pathway that gets dysregulated with FGFR3 inhibition. So, that leads us directly to therapeutic implications, which is to consider that since there is up regulation of FGFR3 in upper tract urothelial carcinoma, then maybe targeting FGFR3 or a combination of FGFR3 inhibition, and immune checkpoint inhibition would be a particularly effective rational strategy in upper tract disease. That remains to be tested. I believe there are already efforts underway to test these concepts and I think it would be very exciting to see those results.
Alicia Morgans: Absolutely. And, as we think about clinical trials, that is a trial that hopefully, maybe your team will be able to design for the near future. It seems pretty rational and it doesn't seem like a hard combination to tolerate. So we'll have to see where that goes. But your team actually has a currently ongoing clinical trial that is, I think, really unique and innovative and is looking at actually bladder cancer, not upper tract disease, but it's this co-clinical trial that I wanted you to kind of review and tell us about.
Bishoy Faltas: We have this very interesting concept of trying to understand how the disease evolves over the course of therapy. So we call this trial CLONeva or cell cycle inhibition to target the evolution of urothelial cancer. And this is a window of opportunity study, which essentially means that between the time the patient is diagnosed with muscle invasive bladder cancer via a transurethral resection of bladder tumor and the time that they get their cystectomy, there is a window of time where we could intervene. So for patients who are cisplatin eligible, as you know, the standard of care is to give them a cisplatin-based neoadjuvant chemotherapy followed by a radical cystectomy, but up to 40% of patients are ineligible to receive cisplatin. So we designed this trial for those patients who cannot or would prefer not to get chemotherapy and those patients are going to be getting four weeks of this drug, which is a CDK 4/6 inhibitor called Abemaciclib.
This is a drug that is approved in breast cancer patients in combination with aromatase inhibitors but also as monotherapy for patients with advanced breast cancers. Now I would like to point out that this is given on a trial basis for these patients with bladder cancer. I'd also like to point out that amongst the other CDK 4/6 inhibitors, this is the drug that has the most significant activity as monotherapy, so that was one of the reasons that we chose this drug. So patients come in, they get their TURBT, they get Abemaciclib for four weeks and then they get their cystectomy. At the time that they come in, we take the tumor, we establish what is called patient derived organoids, which are essentially mini-tumors in the lab and that's where the co-clinical trial comes in, because we're able to take these organoids and we're able to test them with the same drug that we're giving to the patient and with other drug combinations and we can build a profile that will predict how that particular patient's tumor will respond to additional therapy should that become necessary in the future.
At the same time, we're also collecting circulating tumor DNA from each patient at different time points to monitor the evolution of the disease by looking at the particular mutations that we identified in the tumor, in the circulating tumor DNA and monitoring that serially over time.
Alicia Morgans: So, Bishoy, that's a fascinating approach and actually one that makes a lot of sense rationally, but as we think about this as clinicians, it's actually not easy to get patient-derived organoids to grow to allow you to do this kind of testing, is it?
Bishoy Faltas: No, it's not easy. I wouldn't describe it as easy. It's definitely something that is challenging. We have some experience in this area, so we've published some work before with Mark Rubin and Shantel Polly is the first author on the paper that showed the feasibility of developing bladder cancer organoids. I would say that our success rate needs to improve, but we're continuously working in parallel to this effort to try to optimize our protocols to develop bladder cancer organoids. At this point I would say our success rate, defined as developing stable organoids that we would establish over several passages, is about 40%, but we are also coupling this with trying to establish patient derived xenografts, which hopefully would also increase our success rate.
And ideally, I think over the next couple of years, I think it wouldn't be out of the realm of possibility to reach a success rate of 80 to 90% using a combination of these different approaches. It is definitely not cheap, and there is a lot of work that's involved, but I think that's why we're doing this at a relatively small scale upfront in this patient population. So in this trial we're aiming to accrue 20 patients that will all have attempts of making organoids.
Alicia Morgans: That's just fantastic. As you continue to optimize that approach, whether it's just organoids or whether you're involving these xenografts as well, this is something that is truly moving the needle for this disease and is fascinating. So I will continue to watch as this evolves so that we can really target the disease that is in our patient, and then know upfront what may or may not work or what may have a higher or lower likelihood of working for future treatment of that patient. So, that's just fascinating, and I wanted to make sure that we acknowledged that it is a big ask that you're doing, and really pushing the envelope there. So at this point you have some patients on this trial, I think, and what should patients do or physicians do if they want to get their patients involved in this highly innovative study?
Bishoy Faltas: Yes, we've definitely enrolled patients on this study who have received the drug, and I would encourage all physicians who have had patients who may qualify for this study, or they think, or they simply have a question to contact us at Weill Cornell or visit the clinicaltrials.gov website to get more details about the study.
Alicia Morgans: Awesome. Well, thank you so much for your time, Bishoy. Keep up the excellent work and we look forward to talking to you again in the future.
Bishoy Faltas: Thank you. I enjoyed our conversation.