The Intersection of Cardiovascular Disease and Genitourinary Cancer Treatments - Javid Moslehi

Javid Moslehi joins Alicia Morgans in a conversation on the cardiovascular health of cancer patients. Javid Moslehi's laboratory focuses on mechanistic understanding of cardiovascular toxicities that result from novel “targeted” cancer therapies.  In this conversation, they discuss the cardiovascular toxicities associated with androgen deprivation therapy (ADT) and the physiologic mechanisms and management strategies that should be apart of treatment decisions. They also discuss the clinical course of immune checkpoint inhibitors (ICI)-associated myocarditis. Myocarditis is uncommon but potentially fatal,  and the toxicity of ICI has not been well characterized. Dr. Moslehi stresses the need for multi-disciplinary efforts to manage cardiovascular health and cancer treatment in patients.

Biographies:

Javid Moslehi, MD, Director, Cardio-Oncology, Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, Tennessee 

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.


Read the Full Video Transcript

Alicia Morgans: Hi, I'm so excited to have, here with me today, Dr. Javid Moslehi who is an Associate Professor of Medicine at Vanderbilt University, and a cardiologist. Thank you so much for coming to speak with me today.

Javid Moslehi: Thanks so much, Alicia. It's great to be here.

Alicia Morgans: Wonderful. So I think either we should definitely start by telling the viewers what a cardiologist or cardio oncologist has to do with prostate cancer.

Javid Moslehi: Yeah, so that's a really good question. So I'm a clinical cardiologist who's interested in cardiovascular health of cancer patients, specifically prostate cancer patients. One thing we've realized with cancer therapies, as there are more therapies and there's more efficacy, patients with cancer can have cardiovascular issues. First, because they beat the very cancer itself, so the cancer doesn't kill them and cardiovascular disease is common among the general population. And second, we've realized for every cancer type, specifically prostate cancers, the therapies can have adverse cardiovascular effects. And that's one of the hopes that we have in terms of studying these toxicities better.

Alicia Morgans: Absolutely. I think, you know it has been well documented over time that there are cardiovascular complications even to things like GnRH agonists. There's a whole controversy about GnRH agonists versus antagonist, if there's any difference. But there are many additional medications that are coming into our domain, as oncologists and urologists in prostate cancer, that can also have adverse effects.

Javid Moslehi: So that's a really good point. So for example, we know androgen deprivation therapy with GnRH agonists can have adverse cardiovascular effects. It can raise your blood pressure a little bit. It can certainly change your cholesterol. It can raise your sugar a little bit. All of which are really bad for the heart. In addition, the complication now is we're now using therapies in combination. So when you combine abiraterone with a GnRH agonist, you see the patients' blood pressures go up, and we've known for 50 years now that the high blood pressure is bad for the heart. And so one of the goals of us, as a group and as a program, is how we can better introduce cardiovascular health, and diminish these toxicities from these very therapies.

Another area that I think is interesting is the use of PARP inhibitors, where they can be combined with any of the androgen deprivation therapies, including abiraterone, where we seek a clear cardiac signal when you combine therapies. So these are all the issues that we're trying to study better because this is really an uncharted territory for us. It's really a testament to the good job you as oncologists have done, in terms of taking care of patients. But now we're seeing new issues arise in these patients and that's a big area that we're very interested in. And why cardiologists would kind of be in this space.

Alicia Morgans: Absolutely. And I was fortunate enough to practice with you at Vanderbilt, and have a nice partnership between cardio-oncology and medical oncology, really for those high-risk patients even when they were just on traditional androgen deprivation therapy or ADT. And I think that's something that certainly we always advocate for in community centers if they're able to do that, for those high-risk patients who may need some extra considerations around lowering cardiovascular risk. That, of course, could even vary over time depending on the medications that we're using to fight the cancer.

Javid Moslehi: Absolutely. And this is true with the older therapies or the established therapies, but one particular area we're interested in, and one thing that's really overtaking all of oncology, although to a lesser degree in prostate cancer, is the use of immunotherapies. We've learned over the last few years that in some patients, infrequently, but certainly a significant number, you can have adverse effects from immunotherapies that affect the heart and the vasculature. At least with melanoma and kidney cancer, we see a small yet significant portion of the patients have something called myocarditis, or inflammation of the heart. And the unfortunate thing here is that this can be deadly. And so ways we can come up with which predict who has these adverse events, as well as understanding the pathophysiology, so we can introduce preventive and treatment strategies is really critical. And that's what, something I'll be talking about that the Prostate Cancer Foundation meeting tomorrow.

Alicia Morgans: Absolutely. And I am so glad that you're speaking about that because we are trying to bring those drugs into the prostate cancer realm. But many of the people watching this video may also treat patients with bladder cancer or kidney cancer, who also use these checkpoint inhibitors, for example, that can cause myocarditis. And what I find fascinating about that, before we get into the specifics of your research, is that, and actually perhaps it would address this, that there could be some low level of myocarditis in patients even before they reach that critical threshold that we see clinically. Because once they get there it can be very challenging to bring them back from the edge. And I have had, thankfully success stories, but they have involved balloon pumps and other ways that I would rather not employ, other things I'd rather not employ for patients. Does your work address, as you said, sort of identifying those patients at highest risk, or trying to understand what's going on before we hit that critical edge?

Javid Moslehi: Yeah, so that's a really good point. Besides the small percentage of patients that have fulminant myocarditis, we're increasingly seeing patients that have markers of cardiac damage. For example, their troponin is high. And then the other area that we are very interested in is what happens longterm to the vasculature of these patients. Lots of basic science data indicate that there may be increased vascular disease when you inhibit the checkpoints, in mice for example. So there are two areas we're very interested in besides the patients who get fulminant myocarditis, what is the significance of asymptomatic, yet clear cardiac damage, as measured by cardiac biomarkers? And what is the longterm effects of the checkpoint inhibitors on patients who survive the cancer, but what are the longterm effect on the vasculature and the heart itself? So those are two areas we're very interested in.

Alicia Morgans: Absolutely. And how are you moving that needle? How are you looking into that?

Javid Moslehi: Great point. So we have made a number of mouse models that recapitulate checkpoint inhibitor-associated myocarditis. We found preliminary some very interesting results. That there's a clear sex difference in the mice, something, a signal that we're also seeing in the humans. As well as we're coming up with new treatment and preventive strategies using the mice. And that's introduced some ideas about how best we can treat the patients, besides just giving them steroids, which we now know is not really helping as many patients as it should. So that's one area that we're working in the lab.

In addition, we've started a worldwide database collecting cases from around the world. And we've been able to, for the first time, describe what are the characteristics of the checkpoint inhibitor myocarditis? Is it like the myocarditis we cardiologists typically see, that's not associated with the checkpoint inhibitors? And some of the signals we're seeing is very fascinating. For example, this type of myocarditis is not characterized by the heart pump failing, rather by arrhythmias, the heart electrical activity is affected. Now why that is, we don't really know at this point.

The other very interesting signal that we've seen is with the fulminant cases. We see the events occur shortly after initial treatment with the checkpoint inhibitors. And one of the main risk factors we've identified is when you combine different checkpoint inhibitors together. For example, when you combine a CTLA-4 and a PD-1 inhibitor. But as you know, that is what the trend is in all of oncology, is combining therapies. Either two checkpoint inhibitors together, or a checkpoint inhibitor with the newer immunotherapy, or a traditional chemotherapy with a checkpoint inhibitor, and we're clearly seeing a higher signal of toxicity when you combine therapies.

Alicia Morgans: And we shouldn't forget checkpoint plus TKI also, which can have its own toxicities.

Javid Moslehi: Absolutely. This is a trend we're seeing in kidney cancer, which for all intents and purposes, from where I sit, I see that combining a TKI and checkpoint inhibitor to be basically the way we will treat kidney cancer moving forward.

Alicia Morgans: Well, I am so appreciative of your time, and always learn so much when we talk, and so thank you for doing that. But I'd love for you to share just a parting thought, final message, for the viewers.

Javid Moslehi: Yeah. So we are really in an unchartered territory. We're dealing with issues that affect multiple organs in the same patient. So I cannot stress how much I learned from you, an oncologist, or vice versa. And it really is a need for multidisciplinary efforts to understand and help our patients better. That is really a number one goal. And I think it's also important for funding agencies to really realize this. We're no longer dealing with just the cancer being an issue. And so if you want to really help patients in all ends, cardiovascular and cancer, there's really a need for multi-disciplinary, even multi-institutional efforts. And I think that's something we have to kind of work on as a group.

Alicia Morgans: I completely agree. And as our treatments are helping people live longer and longer, and as cardiovascular disease remains at the top of the list of causes of mortality in people in the United States and around the world, we owe it to everyone to make a difference in the cardiac complications related to these cancer therapies, and just in our patient population in general. So thank you for your continued work. I look forward to hearing more about it, seeing your publications, and I appreciate your time.

Javid Moslehi: Thanks again, Alicia.