The Future of Bladder Cancer Research
An interview with David J. McConkey, PhD
Bladder cancer research should have ambitious goals that are tied to milestones of clinical impact.
The Johns Hopkins University in Baltimore recently appointed David J. McConkey, PhD, as the first director of The Johns Hopkins Greenberg Bladder Cancer Institute. The institute, which was established in 2014 with a $15 million gift from Erwin L. Greenberg and his wife, Stephanie Cooper Greenberg, and a $30 million investment from The Johns Hopkins University, is the world's only center devoted exclusively to bladder cancer research, diagnosis, and treatment. It already has awarded $500,000 in research grants. Dr. McConkey is the former director of urologic research at the University of Texas MD Anderson Cancer Center in Houston. In an interview with Renal & Urology News, he discussed the institute's mission and goals and what he sees as research priorities.
Why the need for an institute dedicated to bladder cancer?
Bladder cancer has historically been drastically under-recognized as a significant health problem. The institute is needed because the field needs to grow quickly. We've got a great opportunity to generate substantial clinical impact, and all the pieces are in place to do that. The bladder cancer research community is very clearly collaborative, and we've made grass-roots networks already that have been very effective at doing collaborative research. About 2 years ago, the Cancer Genome Atlas Project on bladder cancer was completed and published, and that started a very strong wave of interest in bladder cancer. And then the 1-2 punch came with [data showing] the clinical activity of immune checkpoint blockade, which was published in the fall of 2014 in a high-profile Nature paper (Powles T et al. 2014;515:558-562) pointing out the results of an active clinical trial. The genomic project, combined with the clinical activity of immune checkpoint blockade, has raised a lot of awareness of bladder cancer. The folks behind … the institute recognized that this was the perfect time to establish a focal point for collaborative bladder cancer research, not just within this country, but around the world, and that this serves as a kind of a catalyst for synergistic collaborations worldwide.
The goal is to assemble a program internally that is going to model how we want to aggressively address these clinical issues as efficiently as possible, and then integrate with all the other research teams like this across the country. Some of the funding will be sent out to various investigators in the form of grants, and we are interested in coordinating some of that with the Bladder Cancer Advocacy Network (BCAN) and local research programs (i.e., the MD Anderson Bladder Cancer SPORE) that also have grant funding mechanisms. The grants are solicited through a request for applications, which are circulated not only around Johns Hopkins but worldwide. I oversee the review of the process. The decision-making ultimately is informed by peer review. And we'll be investing in research efforts at home.
David J. McConkey, PhD, is director of The Johns Hopkins Greenberg Bladder Cancer Institute in Baltimore.
What is your vision for the direction of bladder cancer research?
The need here is to stop thinking incrementally, to really have ambitious goals that are tied to milestones of clinical impact. For example, right now, there's Level 1 evidence for the use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer, but the utilization of neoadjuvant chemotherapy is really pretty poor. So the question is, how do we get people to pay attention to Level 1 evidence and use the chemotherapy? The challenge has been the perception that the long-term impact of chemotherapy on survival is somewhat modest, an estimated 5%-15%. Personally, I wouldn't be that satisfied with the benefit observed in unselected patients. The solution in my opinion is to identify the patients who are going to benefit the most from neoadjuvant chemotherapy and then make sure that those patients are getting it.
How much progress has been made in identifying patients who could benefit from neoadjuvant chemotherapy?
As a global community, we're starting to get good biomarkers that identify patients who are most likely to respond to and require neoadjuvant chemotherapy. We should be pouncing on this nationwide. The Southwest Oncology Group, for which I am chair of translational medicine for the genitourinary committee, has a clinical trial called the “CoXEN” trial (S1314). This trial is specifically designed to test a biomarker panel that was developed by Dan Theodorescu (University of Colorado) to predict response to and long-term benefit from neoadjuvant chemotherapy. Essentially every other group with an idea of how to do this is being invited to test it within the context of this trial. For example, recent work by Jonathan Rosenberg (Memorial Sloan-Kettering Cancer Center), Elizabeth Plimack (Fox Chase Cancer Center), and Michiel van der Heijden (The Netherlands) has shown that mutations in ERCC2, ATM, RB1, FANCC, and ERBB2 correlate with sensitivity to neoadjuvant chemotherapy. Therefore, if these results can be prospectively validated within the CoXEN trial, patients should be routinely screened for these mutations, and if at least one of them is present, they should be offered neoadjuvant chemotherapy.
As another example, from our own work at MD Anderson, we've identified an intrinsic subtype of muscle-invasive bladder cancer called the basal subtype that is similar to the basal subtype that was originally identified in breast cancer, and, doing genomics experiments on these tumors in patients untreated and treated with neoadjuvant chemotherapy, we discovered that patients with those tumors are actually the ones who probably benefit the most from neoadjuvant chemotherapy, because patients with basal tumors who did not receive neoadjuvant chemotherapy had the worst prognoses. Interestingly, that's not at all dissimilar to what we see in breast cancer, where patients whose tumors belong to the basal subtype appear to also derive the most benefit from neoadjuvant chemotherapy. There is also preliminary evidence for the existence of an aggressive basal subtype of pancreatic cancer, and it has been suggested these tumors may also be sensitive to chemotherapy.
Therefore, the biology seems very consistent across disease types. Patients with these basal cancers do the worst if they don't get neoadjuvant chemotherapy, but get the most benefit from it. One action item would be to make sure that anybody who comes in with a basal cancer is given neoadjuvant chemotherapy.
By combining genomics tests, we should be able to more precisely identify patients who will not only benefit the most, but also respond to neoadjuvant chemotherapy. This is an action item that should be rolled out immediately.
Will there be a core group of bladder cancer specialists working solely at the institute?
There is already a core group of faculty that will serve as leadership: Noah Hahn (medical oncologist), Trinity Bivalacqua (urologist), Charles Drake (immunotherapy), and George Netto (pathology). We've got dedicated support for administration. We hope to bring in other faculty members and other high-profile basic scientists. The mission is to grow the program, but the core group is already on the ground, and we're already designing collaborative research projects.
What will be unique about the care patients will receive at the institute?
The vision is to have a highly integrated multidisciplinary science-based approach to clinical care. The 4 disciplines I mentioned (medical oncology, urology, immunotherapy, and pathology) are going to be collaborating on every patient. We have a lot of things in the discussion phase at this point. There's nothing we can implement immediately, but one goal that I have, both to benefit our research operations and to more rapidly benefit patients, is to put genomics testing in place to characterize as many of the tumors that come into Johns Hopkins as possible.
Will there be a push to promote the institute in the oncologic and urologic communities to encourage referrals?
We're going to be part of a global team that hopefully refines its vision together. With that said, we aren't going have any credibility unless we strengthen and very aggressively and with some sense of urgency enhance our efforts at home. My hope is that by building a state of the art cutting-edge bladder cancer multidisciplinary research team and clinical operation, referrals will come naturally.