Joshua Meeks, MD, PhD – Targeting Unmet Need in Urothelial Carcinoma

Joshua J. Meeks, MD, PhD, is an associate professor of urology, biochemistry, and molecular genetics at the Northwestern University Feinberg School of Medicine and section chief of robotic surgery at the Jesse Brown Department of Veterans Affairs Medical Center in Chicago, Illinois. His expertise is in diagnosing, treating, and managing bladder cancer.

We sat down with him to better understand the course of his career, ongoing research in treating patients with non-muscle-invasive bladder cancer (NMIBC), and the future of urothelial carcinoma care.

Why did you become a bladder cancer specialist and surgeon? What was your inspiration?

Dr. Meeks: My journey into urology began in medical school. My rotation with the urologists led me down this path; they were the best people to work with, seemed to have the most fun, and their patients were grateful for them. So, naturally, I was attracted to that. Then, bladder cancer became my home during my fellowship at Memorial Sloan Kettering Cancer Center. I had great mentors, including Bernard Bochner, Harry Herr, and Guido Dalbagni. There was also Dean Bajorin and Jonathan Rosenberg on the medical oncology side.

Along with superb mentors, the bladder cancer field seemed to me a place where I could contribute the most as a surgeon. At the time, plenty of very smart people were working on problems related to prostate and kidney cancer, but bladder cancer was a field that needed some attention. The disease is complex, and the surgeries are similarly complex. Furthermore, patient survival was (and still is) so poor, and there was an obvious opportunity to make an impact. So, everything sort of came together. All of this worked in alignment with my interests.

How did you end up at Northwestern University and the Jesse Brown Department of Veterans Affairs Medical Center?

Dr. Meeks: I have a joint position with Northwestern and Jesse Brown, and I’m fortunate enough to care for patients in both places. Northwestern was one of the few institutions in the US that offered very strong translational work for physicians while also allowing them to see patients. There are quite a few outstanding clinical institutions, but young surgeons struggle to carve out a path at them. A problem we’re seeing throughout the country is that when young clinicians finish their PhD program or basic training, it can take almost 20 years to get back into a laboratory.

Northwestern took a leap of faith on me, providing some protected time, startup funds, and excellent mentors on my way to starting the Joshua Meeks Laboratory, where our goal is to cure urothelial carcinoma. Jesse Brown has been just as important, providing me with generous grant funding to study problems in our veterans with bladder cancer. The Laboratory wouldn’t be possible without both environments supporting my research ambitions. Hopefully, we’ll be able to contribute back to both.

What has been your most meaningful or impactful contribution to the field of bladder cancer?

Dr. Meeks: There is plenty we can contribute going forward, but one of the first and most notable research studies was looking at intravesical therapies for NMIBC. It’s a study, at its core, about why people respond to BCG—the standard of care for most patients with high-grade bladder cancer—with consideration of other possible treatments that we could be using. The intravesical pembrolizumab trial proved that we can treat patients with checkpoint inhibitors and achieve a systemic response.

Now, it must be noted that this is early work with early data, so more work needs to be done. But from an innovative perspective, we have been able to dial down at the molecular level on how those therapies could work. My hope is that this approach could be done with other therapies to understand in advance which patients will respond.

Let’s talk more about the Joshua Meeks Laboratory. What are your current research endeavors?

Dr. Meeks: The Laboratory is focused solitarily on bladder cancer and, in particular, epigenetic therapies, because we know the largest group of genes that have mutations in bladder cancer are epigenetic regulators. We’ve dedicated ourselves to understanding whether we can design epigenetic therapies to overcome treatment resistance.

I have the added benefit of working with Ali Shilatifard, who is 10 feet down the hall from me and discovered most of those epigenetic regulators some 10 to 20 years ago. We’re attempting to build upon that work by harnessing the power of new technologies that use next-generation sequencing and single-cell approaches to solve basic clinical problems that have plagued the field for 40 years.

Another area of interest for us is better understanding why people get bladder cancer in the first place. It’s generally thought of as a smoking-related cancer, but approximately half of patients with bladder cancer are nonsmokers. So, our hunch is that there are different, less direct mechanisms compared with other smoking-related cancers.

Lastly, we’re curious about the gender dimorphism in bladder cancer. Approximately 33% of patients are women. We do not have answers to this discrepancy yet, but there’s a developing interest in the field. Should we diagnose women patients differently, follow them differently, or even treat them differently? It is a strong, active area in our group, and we’re not alone. We are looking at all levels of gender and sex to identify what mechanisms there may be.

What cutting-edge research, technologies, or surgical procedures are you most excited about at the moment?

Dr. Meeks: It’s a contradictory thing to say, but as surgeons, we’d love for patients to not need their tumors resected. Furthermore, we’d love for patients to avoid bladder removal. In almost every solid tumor, organ preservation is a topmost goal. The reason we treat tumors with such a blunt strategy like surgery is we don’t have safer drugs or better nonsurgical ways to treat them. In many cases, surgery for bladder removal is the safest thing for patients, which suggests that we don’t really know much about these tumors. So, in essence, moving the field to a place where our therapy options are safer and more effective than surgery to achieve bladder preservation is my highest motivation.

One question that has my attention is whether it is possible to obtain a specimen of urine from a patient, use it to profile his or her tumor, and then either develop therapies or follow his or her treatments and de-escalate. As a field, we treat patients with bladder cancer for the better part of 3 years because we believe they need that much treatment and for that long. But the truth is, many patients do not, and if we work to better understand the molecular happenings within tumors, we could potentially find opportunities to de-escalate treatment. Of course, doing so would save patients from unnecessary therapy and benefit them financially.

In short, the 2 areas of interest in my eyes are (1) efforts to develop and advance precision therapies toward specific genes that drive tumor growth and (2) enhanced, sensitive profiling to direct either increased or decreased treatment regimens.

What would you say is hindering growth or advancement in personalized care? What needs to happen to make the biggest difference for patients on a personal level?

Dr. Meeks: There are a few hindrances, starting with therapy development not moving quickly enough. We have the blueprint: the cancer genome atlas. In a sense, we know the basic footprints of a bladder tumor, but we don’t have that many good therapies. We also don’t know how to get them into our patients. Furthermore, we don’t know how to follow our patients at a sensitive level. The best biomarker in bladder cancer is still cell-free DNA, which has helped us determine who needs therapy after cystectomy versus active surveillance. But for those patients who need therapy, we need better drugs.

How do you envision the bladder cancer treatment landscape looking within the next 5 to 10 years?

Dr. Meeks: For the locally advanced, muscle-invasive patients undergoing radical cystectomy, we’ll likely reach a point where we can genotype their tumors. There’ll be multiple therapies for them, and certain patients will go on to receive systemic therapies and nothing more.

The most important advancement will be when radical cystectomy is used only as a last resort. The same is true for NMIBC. As mentioned, we typically give BCG to patients, but there is a shortage, and patients who need it can’t get it. Hopefully, there will be better ways to treat patients that naturally lead to de-escalation. The field is moving toward tailoring therapy to patients and determining the optimal duration of treatment.