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The Road to Curing MPNs

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Published on December 11, 2020

Are We on the Road to Curing MPNs?

What does the road to a cure for myeloproliferative neoplasms (MPNs) look like? With new research, treatment possibilities and innovative combination therapies on the way, is a cure on the horizon? In this Answers Now program, Dr. Ross Levine, MD, physician-scientist at Memorial Sloan Kettering Cancer Center’s Ross Levine Lab, answered these questions as more as he shared his expert insight on the path to a cure for MPNs and the near future of MPN treatment. Host and patient advocate Ruth Fein, along with patient advocate Kevin Walsh, joined the discussion. Keep watching to learn more.

This program is sponsored by Incyte and is produced in partnership with the MPNRF. This organization has no editorial control. It is produced by Patient Power. Patient Power is solely responsible for program content.

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Transcript | The Road to Curing MPNs

Ruth Fein: We're talking today about what the road to a cure looks like for MPNs; essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Full disclosure, we'll be digging into the science here today. Joining us today is physician scientist, Dr. Ross Levine. He's the Lawrence Joseph Dineen Chair in leukemia research at Memorial Sloan Kettering Cancer Center in New York. Dr. Levine, let's talk about your own MPN research. What are you most excited to tell us about?

What Should Patients Know About Current MPN Research?

Dr. Levine: For us, research into MPNs is sort of a career pursuit. I've been working on them since I was a post-doc in the early 2000s, so it's been almost 20 years, and we really, I guess, think of it on both ends. We want to understand, as best anybody can, what is the genetic basis for the different MPNs, and how do they evolve from normal stem cells, and what makes them different? And the other thing I guess I would argue is that we have sort of a dogged, almost Moby Dick-like pursuit of what JAK2 is and what it does, and can we find new strategies to target JAK2? That's not the end-all, be-all, obviously, but we think it remains the biggest question that we want to go after.

Ruth Fein: Can you just walk us through pretty briefly, just when we're talking about ET versus PV, MF, the work you're doing, how does that apply to each differently?

What is the Role of the JAK2 Mutation in ET, PV and MF Research?

Dr. Levine: Well, we've known now for 15 years that almost all patients with polycythemia vera, and about half, maybe slightly more, of essential thrombocytosis and myelofibrosis patients, their blood stem cells that are involved in the disease have mutations in this JAK2 gene. And we've learned since then that a significant fraction, probably 30 to 40%, have alternate genetic drivers, that all results in the same thing, which is activated JAK2 signaling.

So, we believe, although we haven't found it in every single patient, that in almost every patient, we can find the genetic event that activates this JAK2 pathway. And that has led my lab to spend years trying to understand what that is and what it means. And then we have one approved drug, ruxolitinib (Jakafi)... actually two now, fedratinib (Inrebic) as well, that target JAK2, and we think we can even innovate and go from there and develop either additional new drugs that do it better, or combination strategies where we combine other agents with those approved agents, the idea being to, one, improve our ability to target JAK2, and other features of MPN cells for therapeutic benefit.

Ruth Fein: Here's a question from a PV patient whose name is Kevin Walsh. He lives in Westchester, Pennsylvania, not Westchester, New York. Kevin runs a Facebook group called MPN Investigation and Discovery. And he and his group members compiled a few questions.

Kevin Walsh: The theme for this discussion today is the road to curing MPNs. I think all of us, it goes without saying, that have an MPN, have concerns about the future of our diseases. And I think every one of us is also ready for the next MPN research breakthrough. Are you encouraged about that road that we are on for a cure? And if so, why do you feel this way?

Are We on the Road to a Cure for MPNs?

Dr. Levine: I am encouraged for a couple of reasons. The first is that I believe that our understanding of what MPNs are, what makes them tick, is at a more advanced stage than ever before. The genetics, the biology, all of that. The second is that I've seen examples for other targets like JAK2 and other blood cancers, and in other cancers, where we now are able to use a more advanced toolbox of chemistry and drug development.

And I've seen some great solutions that have come out. And the last is, which is really important to really understand, is that our fundamental understanding of what JAK2 is and what it does in terms of its basic biology and biochemistry is more advanced, and that informs the first two of those. So I'm really excited, and I think we're at a position where the knowledge we have has the potential to lead to new therapeutic approaches that could have great, great clinical impact. And that's why I'm here, and that's why I'm excited.

Ruth Fein: So, let's take another question from Kevin Walsh, and he's with the MPN Facebook group, he's doing a great job. Thanks.

Kevin Walsh: So a few months ago I emailed you, Dr. Levine, and had some questions on behalf of the Facebook group. And part of your response in your email, you stated that there are now paths to new potential therapies. Can you please discuss what these are and how optimistic you are about each new therapy?

What Are the New Potential Therapies for MPN Patients?

Dr. Levine: The way I think of what are coming down the pike for MPN patients and therapeutics, I can really lump them, I would argue, into four categories. For JAK2 itself, which I think is still the most tractable therapeutic target, we can think of two approaches. One is to make better and more potent JAK2 inhibitors, and that's an area that we think is being explored in many fronts. And the second is the idea for the 60% of MPN patients that have JAK2 V617F, we can now imagine a world where we might be able to have drugs that target only the mutant JAK2, and that will obviously help the other 40%. But for that 60%, if you could, with incredible razor like precision, go after the mutant JAK2, I think we have great potential for that. And that really comes out of an understanding of JAK2's structure of biochemistry we just didn't have before. So I think you're going to see a lot in the next three to five years after that.

The other is what about the other mutations? And the one that I think is the exciting one is the calreticulin mutation. And I think there's a lot of people who believe that the mutant calreticulin for the 20 or 30% of ET and MF patients who have mutant calreticulin, that that leads to some approaches like you can block how it interacts with other proteins, that we might be able to ultimately target mutant calreticulin in ways that have unique benefit for that group. And I'm very excited about work, not in my lab, but work by others.

And then the last is, I think, the group where we're seeing traction in the clinic today, and that is these combination strategies that Ruth mentioned. We believe that there are other biological features or pathways that mutant cells use in addition to JAK2 or calreticulin; BRD4, PRMP-5, others. And we're very excited about that. In the long-term, our hope is that we're getting an innovation on each of these fronts and that we're not going to rely on one of them to be the answer, but we'll develop an armamentarium that in different patients will have different either therapies or combination strategies based on the genetic blueprint of their MPN.

Ruth Fein: Can you explain what we mean by a combination therapy?

What Is a Combination Therapy?

Dr. Levine: The example I give people, which is outside of MPNs or even cancer, for those of you who saw the Nobel Prize announced earlier this month, was hepatitis C. Hepatitis C was a very challenging disease to treat when I was a doctor in training. It was, if not a death sentence, an incurable disease. And we had treatments, including interferons, but they were modestly effective.

The most important thing that hepatitis C scientists and doctors learned was how to figure out what were the three paths in the maze that the virus can take, and to develop drugs that cut off all three. And when they did that, treatments that were effective by themselves, ultimately together really have resulted in high cure rates. And we need that sort of strategy for MPNs, and that's what I spend my day, when I'm not on Zoom with all of you, talking to people in my laboratory down the hall about. And how do we do that?

Ruth Fein: A lot of times we spend most of our time talking about PV and MF. I wondered, on the ET front, if there's anything that you wanted to tell us about, any research you’re excited about specifically related to ET. Or is ET research really still focused on preventing clots, thrombotic events, et cetera?

Any Updates on Essential Thrombocythemia Research?

Dr. Levine: ET has the good challenge that patients on the average live a long time and do really well. And what that means is that treatments have to be really efficacious and safe before we give it to people with ET relative to MF, or even to some degree PV. And that I think has created a barrier where it's been harder to get new therapies to ET, but I believe that, for example, a targeted JAK2 or calreticulin mutant strategy will be of great value in ET for those subsets. And I believe that you have to imagine those therapies going there.

There is data that ruxolitinib is effective in that group, but it's been very hard to do the long trials to show long-term benefit, including preventing clots. But I think with more effective potent therapies, we'll see it. I think there may be a role from the newer interferons in that group. But what I don't see happening is combination strategies for ET. It's hard to imagine for an ET patient that they would want to be on combination therapy for years, if not decades. And that's an opinion, and we'll see how the data rolls out in the next couple of years.

Ruth Fein: How can targeted therapies for genetic mutations slow or eliminate the progression of more serious disease? The second part of that is, which mutations respond best to which particular therapies if any?

Dr. Levine: So the first question is sort of something that we're consumed with all the time, which is, whether it's targeting JAK2 or mutant calreticulin or another feature, does it not only have benefit with respect to how the disease is today but does it change either the evolution of the disease or if a disease has evolved, does it work even later stage? And that's an area that we're spending all of our time thinking about. The short answer is stay tuned. I promise you we're working on that. We're quite obsessed with that. And we believe that the challenge is integrating therapeutics and biology with the continuum of the disease in patients, and asking not only do we intercept the disease when someone's got a big spleen and has lots of symptoms, but can we go earlier, or go later in patients that have more advanced bone marrow failure? And we want to really think of what patients need and not just what the science said is possible yesterday.

Ruth Fein: Are there any drugs that specifically target fibrosis in the bone marrow? And if so, what are the clinical results?

Dr. Levine: Yeah. It's early days. There are two strategies. Work we did in mice a number of years ago showed that this BRD4 pathway appeared to be important for the generation of fibrosis through inflammation. And we showed in our studies that if you combine that with ruxolitinib, Jakafi, we can reduce fibrosis. And that's one strategy.

And it has other benefits. The other is that there are a number of drugs that are being tested in much earlier trials... and the short answer for that is that there's a randomized trial underway that will give us the answer about whether you can reduce fibrosis with the two drugs together versus the one drug alone. But the other is that now there are earlier drugs where people are going after fibrosis development only, saying, "You know what? I may not be able to kill the MPN cell, but I'm going to block its ability to make bone marrow fibrosis or starring." And those trials are just too early. I'm very hopeful about them, and we'll see how they play out. And so they're worth paying attention to.

Ruth Fein: Here's my favorite question I saved for last. What I really want to know is what are your younger investigators, not that you're not young, because you are-

Dr. Levine: I'm not.

Ruth Fein: But what are those really young investigators going to be looking at 20 years from now?

What Is the Future of MPN Treatment and Research?

Dr. Levine: I think the long-term thing is really to do two things. It's really to understand how an MPN cell and every facet of its genome, its proteome, is really different than a normal cell. And then to understand what parts of that, if you could actually reverse it, cause the MPN cells to go away. What we're looking for in the long-term is a curative strategy. So the analogy I love to use is the Jenga puzzle analogy. What these young scientists are doing now, and will be doing, is figuring out how the MPN is built, like the blueprint, and then figuring out what parts of it, with therapies that we can pull out, that cause it to crash down.

And that's really what I see the next generation already doing with great enthusiasm, and the tools to do that are amazing now and getting better. So I think what you'll see is iterative sort of, "Well, I figured out how this part works," and, "Oh my God, I can do this at greater resolution." "Oh my God, now I have drugs that can take out that piece." And I think what's going to be fun is we're going to see great success, I think, in the next eight to 10 years. And I'm quite hopeful that the next decade, or even two decades, are going to be much better for our patients than what we've already done, which I'm proud of.

That there's never been a better time for science to really have impact for patients. And I think that there's never been a better time for that to be true for patients with MPNs. And I promise you that we are going to leverage this amazing moment and opportunity in every possible way, and we're going to work hard to bring that benefit from the science to each and every one of you.


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