Richard White, MD, PhD, Discusses His Research into Why Melanoma Metastasizes

Richard White, MD, PhD, from Memorial Sloan Kettering Cancer Center, discussed why patients  with melanoma relapse after effective therapies, as well as a zebra model study he designed to discover why and how melanoma metastasizes, at the 16th International Congress of the Society for Melanoma Research (SMR), held November 20-23, in Salt Lake City.

Transcription:
I think one of the things that’s making melanoma challenging right now is that we’ve gotten effective therapies, especially immunotherapy and targeted therapy, and now we’re starting to see patients who relapse on those therapies, particularly relapse with things like brain metastases, so this requires a lot of different input from different physicians and scientists. How do you handle people who have already been through immunotherapy and are now relapsing in unique sites, we don’t see that in a lot of other cancers because the response to the immunotherapy is not quite as high in other cancers. So, this phenomena of resistance after immunotherapy is fairly unique to melanoma.

I think, meetings like this in particular which are a combination of clinical science or translational science, along with basic science are actually at the forefront of the way we need to think about the problem. In many ways, we already have a pretty good understanding of at least the way we use targeted and immunotherapy. What we don’t have a good understanding of is what are the next steps, how do we combine them, when is the right time to use those, that’s where I think the clinical and translational scientists really come in for figuring out those questions. And then when the basic sciences come in and why meetings like this are important is, how do we begin to think about the more basic approaches to why these things might be failing. And so there really needs to be this constant dialogue between the more clinical people and the more basic people and I think this meeting does a great job of that.

You know, one of the purposes of meetings like this is that it often will take an idea that perhaps is very nascent and nucleate it into something and push it over the edge and say, you know what, I think I’m going to study that problem actually. Now that doesn’t happen every year because, especially for people like me who are basic scientists, the tempo is slow, right, we can’t change projects every year. But if you go to these, the SMR meeting, every year like I do, you begin to see emerging themes. Things that are coming up that you know are important, and that can really change the direction you go in, because over a couple years you begin to see, this is clearly a massive unmet need that’s not being addressed.

I think it’s fairly clear there’s an emergent theme arising around brain metastases. This is a very particular problem in melanoma, and this theme I think has been around, every year I kind of see this emerging, and that absolutely initiated a project in my lab that we’re doing right now to specifically look at that problem. Because I think now that we’re treating people pretty effectively with immunotherapy and targeted therapy, but we’re still seeing lots and lots of brain metastases.

One of the themes, as I mentioned earlier, that I think is emerging is this idea of as we’ve gotten better at controlling, let’s call it systemic disease, I think it’s fairly clear that what we don’t understand in many cases is the biology of why people metastasize or relapse in certain sites like the brain. And I think that came up actually in multiple talks over the course of the meeting. That happens to be a particular research interest of mine is process of metastases.
And I think one thing that is becoming clear is that CNS metastases or brain metastases is clearly a big unmet need that we don’t understand very well. You know, we can have patients who actually are responding to therapy in the rest of their body, but not responding to therapy in their brain or there is no therapy for brain metastases. So, I think that that’s one interesting area that I think needs more attention. I mean, I think most metastatic sites need attention, but this one, because it’s so particularly devastating probably needs more attention.

I think that there’s a real nucleation, not just in my lab in other labs as well, about trying to think creatively about this problem because the brain is special, right? The brain and the way things grow in the brain is not like it grows elsewhere. So yeah, I think that there’s a sort of an emerging feeling that we should be doing more here and looking at that biology differently than the way we look at other places.

So, my lab, so I’m a physician scientist, so I train both clinically and research, but I primarily run a very basic laboratory and wherever we’re interested in this question of how did cancer, specifically melanoma, metastasize right? How did they start in one place and go to another place? So, there were actually two talks from my lab, one by myself and another by a graduate student of mine who’s a MD, PhD student named Nate Campbell. And we both set out to address this question of, how do cancer start and then how do they progress? And we use a model called zebra fish for studying this. So it’s a very unusual way to study cancer, it’s a small animal that lets us do really sophisticated genetics so we can look at gene changes, but then also imaging because the animal’s transparent so this gives us the amazing ability to watch cells as they start in one place and then spread to another place, this process of metastasis. So, both of the talks in one way or another focused on this question. My talk in particular focused on this question of why do certain DNA changes, mutations, occur only in certain cell types that give rise to melanoma? The so-called RNA landscape. So it’s this idea that DNA, which is what we think of as our genetic material, really those mutations occur in sort of an ocean of RNA changes, right, which is the message of how that gets transmitted. And so, we developed a zebra fish model to try and address this question and really understand why do certain cells give rise to tumors more effectively than others, and why might those cells become more metastatic or less metastatic depending on where the DNA mutations occur? And this is a very challenging problem to study because we’re trying to figure out this combination of why do mutations happen in the first place and why does the place where those mutations happen seem to matter a lot? And then the other study which that out of my lab which was presented, which was related, is if we ask that question of these different places or different types of cells can get those DNA mutations, how might those different types of cells cooperate to produce metastasis, right? Which is the question we’re interested in and the student from my lab, what he presented is really elegant data where we could use the zebra fish to ask, is it possible that the different cells actually work together to form metastases in different parts of the animal or the human. And what he found, and I think the really surprising finding here, was that these cells, which seem different, actually cooperate by forming clusters. So, they form these little balls of cells which then travel in circulation and those little balls of cells, those clusters of different cells, are really efficient at metastasizing. And so that leads to the obvious question of, can we target that cluster, right? Can we somehow interfere with that process and we think we have some pretty interesting ways of doing that. So that are the sort of two sides of what we talked about.

You know, both talks because they’re very complimentary, address these fundamental questions. How did the different cell types of melanoma arise in the first place, my talk, and then Nate’s talk, how do those different cell types cooperate to give rise to metastasis?

The outlook for the next year I think is we’re still very much refining questions of when and how to combine different therapies, you know we have lots of interesting and effective therapies now, there’s still huge open questions about how you effectively combine those. You know we’ve made unbelievable progress in melanoma, but still the majority of patients still die with melanoma, and so one I think incredibly important question is, are the therapies that we have right now actually able to cure even more people but we haven’t found just the right combinations, right, to get that to work, so I think that this will occupy people for the next several years. An example of this would be, which I think is really important, many many patients with melanoma present with early stage disease, it hasn’t spread yet, it’s still in the skin or somewhere close to the skin; how do we prevent those patients from developing metastasis, so this is so called adjuvant therapy. You know you’ve cut out the tumor, and then a certain number of patients, we don’t know why, eventually develop metastasis and die from their disease. How do we prevent that from happening? I think that was a very clear theme from this meeting is how do we deal with the early stage disease? You know, that isn’t metastatic yet. That will, I’m pretty sure, be solved over the next couple of years, but we need to understand these combinations.

The bigger question, beyond how do we deal with people with the early stage of the disease, is this really deep question of, if somebody has metastasized and they’re failing all the therapies we have, what’s next? What’s next on the horizon? And that’s where people like me come in, right? The more basic scientist to say, okay, we have targeted therapy, we have immunotherapy, what’s next on the horizon, right, to target these metastatic patients? You know the patient walks in the door, they have tumors all over their body, they failed all of the therapy, what’s next? And that’s where you need basic scientists.