Published on February 8, 2017
At ASH 2016, experts from across the nation discuss how genetic testing is affecting the evolution of treatment for MPNs. Dr. Stephen Oh of Washington University School of Medicine explains exactly what genetic testing could mean for patients. Dr. Catriona Jamieson of UC San Diego Health Moores Cancer Center follows by helping viewers to understand what the ongoing learnings reveal and the effect of looking at things at a "nano" level.
Transcript | What Are We Learning From Genetic Testing in MPNs?
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So, Stephen, so people want to know—a patient comes to you in St. Louis and say, "Okay, you're doing this really cool science, and you're looking at things in a much sharper way—in a nano way, if you will—what does that mean for me?" What are you telling people?
Yeah, so I think a good example of that question is, with regard to the different genetic tests that are now available—not just testing for JAK-2 or calreticulin but these 30, 40 or more gene panel tests that are out there from commercial labs—I would say, if you rewound three or four years ago and a patient asked me, "Is this something that I should be tested for?" I would say, "Well, we're doing a lot of research in this area, but it's not really practically useful at this time."
There [are] still really caveats and much to be learned about the implications of this kind of testing, but, for me, at least, there's been a big shift in the past couple of years to using these tests more and more frequently and with more confidence as to what the results might mean.
Okay. So, Catriona, you've sent tubes of blood of mine—the other day, it was seven tubes of blood—and that goes across the country into different labs and your lab, etc. So what are you going to learn from that that can help me and help others.
Well, I think that patients now are getting to be extremely savvy and can consider themselves scientists by asking the question why, "Why did this happen? Did I inherit this? Can I pass it on?"
That's called a germline mutation, and that's really what we're looking for—because we didn't just get your blood, we got your spit. And so, when we get the saliva, we're really trying to understand, from the DNA in the saliva, what did you inherit. And then the DNA in your blood tells us what did you acquire as your disease evolved, and how can we stop it from progressing. And so the reason we're doing that—at a nano level if you want to use that term—is because, now, we're delving into the stem cells. So does every cell matter? If one cell gets a mutation, but it only lives for seven days, who cares? But, if your stem cell gets a mutation, it's going to last your life—your entire life span—if that's a robust stem cell.
So we're now digging into the stem cells and saying, "Are there mutations there?" And this is not unique to us—there are many groups doing this—it's called clonal hematopoiesis. So we can acquire mutations at the level of the stem cell, but what cancer does, especially as it progresses, is it can co-op stem cell pathways in cells that are slightly more mature, and they think they can behave like a stem cell.
So it's like a teenager like my daughter who's going to learn how to drive—she thinks she's going to be pretty good, and I'm not so sure about that. She may not know how to apply the brakes yet. And that's what happens with MPNs as they start to progress—the progenitors that are one step down from the stem cells don't know how to apply the brakes. They co-opped or hijacked these stem cell pathways and then they say, "Great. We're off to the races," but they can't shut them off. So a tangible example of why that matters is we started studying that in another MPN called chronic myeloid leukemia a few years ago, and we found activation of a stem cell pathway at the wrong stage of blood development, and that was called the "Hedgehog pathway."
We foundwe could target Sonic Hedgehog—and Sonic Hedgehog is what is in mammalians—anyway, it seemed like a silly pathway to work on, but it ended up being extremely important. The positive results of the Phase II trial are being presented here in acute myeloid leukemia by Jorge Cortes where the hedgehog inhibitor was used in combination with low-dose chemotherapy for people with AML that had evolved from MDS, or myeloproliferative neoplasms.
So, usually, people want to know, "How did they get this? Can they pass it on to their kids? And what's the likelihood that I'll progress to AML? And if we do progress to AML, what do we do about it?" So the…
…so you're on the trail?
We're on the trail for what we do about it. Things can go from bad to worse. But even if they do, can we pull them back by taking away this bad stem cell behavior that allows these cells to clone themselves? And the answer is yes, we can, in part. So we can take you back to an earlier stage of disease, particularly if you incorporate this combination strategy.