Published on July 2, 2018
Breakthroughs in research identifying and understanding myeloproliferative neoplasm (MPN) driver mutations like JAK2, MPL and CALR has led to promising strategies for therapy, like pathway inhibitors, using them as therapeutic targets. Can modern MPN inhibitor treatments disrupt the abnormal molecular signaling in cancerous cells? A panel of MPN experts including Dr. Brandon McMahon, Dr. Naval Daver and Lindsey Lyle discuss the role of telomerase, PLK3 and JAK inhibitors in MPN treatment, how they work to inhibit oncogenes and how proliferative activity and disease course are affected. Dr. Daver also shares data collected in early studies with azacitidine and its’ impact on the spleen and liver. Watch now to learn more.
Produced in Partnership with the University of Colorado Anschutz Medical Campus. We thank Incyte Corporation for their support.
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Transcript | Regulating the Course of MPNs: What Are Inhibitors and How Do They Work?
So, we talked about the genes. JAK2 inhibitors and JAK1 inhibitors. So, Dr. McMahon, so we’re trying to inhibit these onco genes or cancer genes that shouldn’t be running wild. So, a pill like a ruxolitinib (Jakafi) tries to inhibit this, tamp it down. Is that the idea?
Pretty much, yeah. Part of the problem with the driving mutations—we call them driving mutations like the JAK2 mutation—the ultimate endpoint is that the bone marrow’s overactive and over-proliferative. And so, we try to, like you said, tamp that down and prevent that from being overactive. And a lot of the other things you’re seeing on the list work similarly and perhaps it’s a slightly different mechanism. But the end result would be that you wouldn’t have as much of the proliferation in the marrow.
Okay. So, we’re talking about research here. So, this PI3K inhibitor, we haven’t heard much about that. So, it’s a different class of drug? And it would work alone or together?
So, there’s ongoing—yeah. For the PI3K inhibitors, it’s another pathway that works in conjunction with the JAK pathway, and it’s also abnormal. And so, the theory is we block that either alone or in combination. A lot of the studies are in combination with ruxolitinib. You may actually get a better benefit, a symptomatic or a clinical benefit from that.
Lindsey, so people must ask you if you all use this term pathway, what are we talking about? What is this pathway? Is this the road for these genes to do bad things?
So, when we’re thinking about genes and being out of whack or mutated, essentially, there are all of these different hormones and cytokines and signaling that help a cell to work correctly. So, this is all going on in your body all at one time. And miraculously, things are working. But sometimes you get these mutations that cause the signaling to be abnormal. And so, the pathways that we’re talking about is that this molecular signaling may be influencing this molecular signaling. And if we can go and inhibit or stop the abnormal signaling between these two proteins, then we can hopefully restore some order or slow down a process. So, that’s what we mean by pathway.
I don’t want to trivialize it, but it’s like this protein that shouldn’t be active calling the next one and saying, “Okay, now we’re gonna make bad cells.” And you’re trying to cut him off at the pass whether it’s with PI3K or JAK1 or JAK2, you’re trying to put a block there. Okay. And then Dr. Daver, some of these others like, for instance, telomerase inhibitors, it’s just another way of getting at the cells?
Yeah. So, the telomers actually are the long ends of the chromosome. And there’s a lot of research going on with aging related to telomerase. So, what we see is that telomerase, when they’re shortening, they’re associated with aging. Now there is preclinical data and actually, two large clinical trial that show that there was a drug, a telomerase inhibitor that seemed to improve myelofibrosis but not the typical way that we’re used to with the JAK inhibitors. It actually caused what we call complete remissions meaning the fibrosis was gone, the blood counts improved, and the spleen shrank. Now this was a small group of patients, so we don’t know. But that data is emerging.
In the end, there’s a lot of research that goes behind this. So, each of these drugs is about five to eight years of clinical research with more than 100 investigators in ten or 12 labs that are working on it. So, like you said, the MPN Research Foundation, LLS, others, their support is very, very critical. And we look at different pathways, different gene mutations, different signaling proteins. And basically, it’s meticulous work where you block one, you block the other, you block the third, you block combinations, and see which one in human samples or in mouse models is looking good. And then you try to bring it to clinic.
So, this list will only get larger because there are a number of new exciting things being evaluated. But at this time, none of these has made it to the point where we could say there’s a standard of care or be FDA approved. So, a lot of exciting early signals. But we have to wait for the next two, three years.
If you think of it this way, so cancer’s wily. And it’s trying to keep making bad cells. So, if you block one pathway, it tries to find a way around it. And that’s the whole idea between combination therapies. Can’t escape here, can’t escape there. So, you might end up—we might be taking more than one pill or rather more than one—and that’s happened in a number of cancers. If you know people who have been treated for other cancers, breast cancer, etc., they may be on combination therapy. Okay. And just one other one. azacitidine (Vidaza)?
Azacitidine, yeah. So, that’s one which is a little bit more advanced development. That’s actually a trial that we’ve been doing at MD Anderson now for almost five years where azacitidine is in fact, an approved drug for another kind of related condition called MDS. So, you have MPN, and then you have MDS which is myelodysplastic syndrome. So, another chronic bone marrow disease of the myeloid cells. But the disease usually is more with anemia, thrombocytopenia. So, azacytidine is approved there. But we had done early studies with azacytidine alone in MPN, especially myelofibrosis, and it had a 20, 30 percent response. So, it was not huge, but it was active.
So, we’ve done this combination now. And what we’re seeing is that the spleen shrinkage rates, the liver shrinkage rates, and most importantly, the fibrosis improvement has been much higher than what we have seen with Jakafi alone. We have about 60 patients. So, this data will be published soon, but this may be a next combination to do before everything.
Okay. Our Colorado friend. So, Brandon, you have research here too. What looks promising to help these folks?
And I had gone onto clinicaltrials.gov yesterday just to see what else, and there was 1,500 studies that are ongoing. Of course, some of them are not active, and they may not be in the U.S., but there is just an explosion of research out there. We have two trials open here, one with a JAK1 inhibitor, and another with the PI3K inhibitor that they both look promising. Of course, the point of doing them is to see if it does make a big difference with how people feel, how they do short- and long-term.
And the whole point of doing this, particularly with myelofibrosis because it is a disease where people may have more symptoms, they may not do quite as well as with PV and ET, we’re trying to find what we call disease modifying agents where people live longer, they have lower rates of leukemic transformation, they have lower rates of, in the case of PV and ET, transformation to myelofibrosis.
But right now, we don’t have any of these disease-modifying agents that we want, and that’s the whole point of doing these is to say, “Well, geez. Does this really alter…?” we want first and foremost, people to feel better. But we also want them to live longer and have lower rates of complications down the road. So, a lot of these look very promising. In particular, patient subsets.
Lindsey, we heard about ruxolitinib or Jakafi being approved now for several years, and it’s helped me for a long time. I’m very grateful. But there are other drugs similar or slightly different that are in trials, right? Other JAK inhibitors?
Correct. So, ruxolitinib actually inhibits both JAK2 and JAK1 pathways. And so, there are some inhibitors that are specifically to only inhibiting JAK2 or inhibiting JAK1 which may lead to less cytopenias. And by that, I mean reduction in other cell lines. So, ruxolitinib really tries to shrink the spleen and to control maybe white blood cells that are growing without control and help patients feel better.
But at the same time, it may lower the platelet count, and it may lower the red blood cell count, because blood cell production is all along the same pathway. And so, with more specific inhibitors, we get less reduction in the platelet count perhaps. So, that is maybe a reason somebody couldn’t be treated with ruxolitinib. So, now we’re looking at different types of JAK inhibitors that are less toxic to the platelets, so that we can get the same response but preserving the platelet number.
Right. And Dr. Daver, do you expect that there’ll be additional drugs approved in the near term?
Yeah. So, I do. And one of them, as Lindsey was saying, that is in very advanced trials is called pacritinib. So, it’s a JAK inhibitor, and it seems to be now with more than 500 patients treated across trials, very safe for platelets. So, especially for the people who have myelofibrosis with big spleen symptoms and lower platelets where giving the Jakafi has been a little bit tricky because when we try to go up on the dose, the platelets drop, then we have to back off on the dose.
And in some patients, we’re never able to get to a good dose to control their spleen without dropping their platelets. So, the pacritinib seems to overcome that problem, has looks like similar efficacy to the Jakafi, and the FDA is actually reviewing it at this time. So, it may be a next one that’ll become available which is great because we do want multiple options.