Using Liquid Biopsies in Clinical Practice to Inform Decision Making for Prostate Cancer Care - Joshua Lang

November 30, 2022

Josh Lang joins Alicia Morgans in a discussion on the importance of understanding mechanisms of resistance to targeted therapies through the development of novel liquid biopsies of the human tumor microenvironment. Lang highlights his research which looks beyond tissue biopsy to liquid biopsies of cancer cells from a blood draw to inform decision-making. Research funded by the Prostate Cancer Foundation allowed Lang and colleagues to develop new technologies and new assays, that identify the same kind of molecular changes seen in tissue but now using blood draws. This work led to a Journal of clinical investigation publication entitled clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer where Lang et al. developed and validated a new liquid biopsy to look at these gene expression changes. They were able to identify the development of neuroendocrine, or small cell prostate cancers, some of the most aggressive cancers that are out there that our patients are fighting. They assessed a NEPC liquid biomarker via the presence of neuroendocrine markers and the absence of androgen receptor (AR) target genes.


Joshua M. Lang, MD, MS, Vice Chair for Biomedical Research, Department of Medicine, Carbone Cancer Center, The University of Wisconsin

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to speak today with Dr. Josh Lang, of the University of Wisconsin. Thank you so much for talking with me today.

Josh Lang: Thank you for having me.

Alicia Morgans: So it's really great to have you here, and so wonderful to see how your career has evolved, from a PCF Young Investigator Award, onto a PCF funded Challenge Award, and beyond, and further funding to come. And I'd really love to hear your thoughts on some of the things that we discussed and have heard about in your PCF talk today, as well as in some of your recent publications. Can you tell me a little bit about the concept of molecular profiling, molecular testing, how we use this in our clinics to really inform our decision making?

Josh Lang: Absolutely. Well, it's been one of the revolutions in prostate cancer is just, the importance of molecular understanding, and especially initially focusing on genetics of these prostate cancers that our patients are fighting, and how that can inform new therapies. But there have been incredible advances, really over the last five years, by PCF funded investigators, to identify other molecular changes. So looking at genes that are turned on or turned off, and how that can also drive resistance to the different therapies that we give our patients.

For me, one of the things that I think was most inspiring was that, we often need a tissue biopsy to make that diagnosis. And we started asking ourselves, well, is there some easier way? Something we could do that would be easier for patients, but also allow us to follow the cancer and how it changes over time? So it was this idea of liquid biopsies, that we can get cancer cells from a blood draw.

So that was actually funded by my very first Prostate Cancer Foundation Young Investigator Award and a subsequent Challenge Award. So that allowed us to develop new technologies and new assays, that have allowed us to really identify those same kind of molecular changes that we see in tissue, but now using blood draws. Those blood specimens are ones that allow us, not only to find those changes, but also, see how they evolve, especially when our patient's cancer becomes resistant to the drugs that we're giving. And we hope to leverage that information to identify new treatment options for them going forward.

Alicia Morgans: So tell me a little bit about your talk today. And again, some of the work that was recently published. Can you remind us where?

Josh Lang: Absolutely. So we recently have a publication in the Journal of Clinical Investigation, where we developed and validated a new liquid biopsy to look at these gene expression changes. Within that approach, we're able to identify the development of neuroendocrine, or small cell prostate cancers, some of the most aggressive cancers that are out there that our patients are fighting. So being able to identify that, we were able to do that with an almost perfect accuracy.

Alicia Morgans: So a quick question on that. Neuroendocrine is a sort of basket diagnosis, and has been difficult, I think, to come to consensus around, in terms of a definition. So how do you define this disease entity?

Josh Lang: Absolutely. And I think that's one of the challenges is, that we can't use just looking under a microscope, or looking at specific genetic changes. So that's where those gene expression or RNA alterations, I think, are the ones that are most predictive for this patient population.

Now, it's because of PCF support that we've actually been able to test over 300 patient samples, to identify those patients that either have that when they first present, or that may develop over time. So that's where with that almost perfect accuracy to identify it, allows us now to start thinking about what other therapies should we give those patients? But also how do we make sure that these diagnostic tests are broadly available to everyone?

Alicia Morgans: One, I think, from a clinical standpoint, to having a test that we could perform, that could diagnose an entity, and really kind of reduce the heterogeneity of this particular entity, I think is potentially really, really important. Not just for our clinical care, but for clinical trials and patient identification. So we have a homogeneous patient population to move forward with, and really use targeted therapeutics, and develop treatments that make sense for them.

Josh Lang: It's one of the questions that I see, that I get most often from my patients in clinic, when I talk about having to make a change in care to a new therapy or new trial. It's really that question of, well, what are the chances that this will work for me? And oftentimes in clinic, we just don't have any tools to help us really answer that question, beyond some of our clinical sense or perspective, just on symptoms or other radiographic findings. I think those molecular information is going to be far more predictive, and far more useful for our patients in decision making.

Alicia Morgans: So tell me, where does this molecular information go in the future? Right now, I think there's an under utilization of molecular testing for our patients, even though we do have some clear areas where we can use it. Where do you see it going, and how do you see it potentially, not only helping at a single time point, but perhaps, as a longitudinal tool, where we might be able to, in real time, help personalize care, as you sort of described?

Josh Lang: Exactly. That's the most critical point, I think. Especially when we take these important findings, we need to move them out of the lab, and we need to move them into the clinic.

So we've actually had funding from PCF, as well as the National Cancer Institute, to do what's called, clinical or analytical validation. So we can really define how well does it work at one time point, but also how reproducible is it? So if we see changes over time, that we can truly say this is a change in the disease. It's not just a mistake in the assay.

So now that we're going, we'll be actually opening up a clinically validated, clinically certified assay, by the end of the year. So that way, we'll be able to move this forward into a new clinical trial. We'll be starting with Andy Armstrong and Dana Rathkopf, coming into the summer of next year, to do all the clinical validation. That's the kind of information that we need to really demonstrate the predictive utility, that this could actually predict changes for patients.

And then, with that information, we'll now be able to make that broadly available, not just for patient care, but also for clinical trials, as you said. And I think that's one of the areas where I'm most excited about, is that opportunity to develop new therapies for patients, as their cancer develops resistance to the drugs we've been giving.

Alicia Morgans: One thing that I think we've seen, certainly in our own clinical practices, but even in clinical trials, where we see patients who are in control arms of trials, who end up having poor survival, even though a vast majority of them transfer over into, or crossover to receive the active treatment in the treatment arm, they're really never able to catch up with the group that started on the right treatment in the first place. That lost time is truly lost life for these patients. And it sounds like your approach may help to lose some of that, or get rid of some of that lost time.

Josh Lang: It's one of the most heartbreaking parts of our jobs is that, when we have to make that decision, and we make the best decision, and we help our patients understand why we're making this recommendation, why we should go forward with it. But then when it doesn't work, we always step back. Whether that's on a clinical trial, or even a standard of care treatment, of what could we have done better or done differently? And I've never had a time where I've said, "You know what? More data's a bad thing." Having that information to guide us, I think, is absolutely critical.

And I think especially, again, as we talked about, that when cancer changes over time, and I think some of those other lessons from the tissue based studies, that cancer develops new molecular alterations that associates with resistance to different treatments, we need to be using that information not just in our research, but in our clinical care.

Alicia Morgans: I could not agree more. So if you had to sum it up, what are next steps? What do you and the team still need to make this really come to fruition?

Josh Lang: I think, one of the areas, as we move into a new clinical laboratory and clear certified research opportunity is, really expanding this work. More collaborations with other PCF and other investigators evaluating prostate cancer. We're extending this into other GU malignancies as well, including bladder and kidney cancer.

I think one of the things I'm most excited about, is this new opportunity to leverage that information to identify new therapeutic targets as well. We've had incredible revolutions with new agents, such as radioligand therapies that target PSMA, antibody drug conjugates as well. And that's, I think, another opportunity to identify new therapies.

But to your point, let's get them to the patients where the cancers express those targets, not just give them to every patient who comes in the door. If we can identify those predictive biomarkers at a patient, the right therapy at the right time, that I think, it's going to speed up the drug approval process, but also, it's going to improve quality of life and improve more time.

Alicia Morgans: Absolutely. Well, thank you so much for sharing your expertise, and certainly for the work that you and your team are doing, both in the laboratory, but also in your translation of this, into potentially, CLIA certified tests that you're moving forward very quickly with. And then also, moving this into clinical trials, so that we can ultimately see these available to us in our clinical practices. I really commend you and your team, and of course, thank the patients who are participating in this. And wish you the best of luck, and we will keep an eye on your work.

Josh Lang: Thank you so much.