Targeting “Sleeping” Cancer Cells with Dr. Angela DeMichele
By BCRF | November 22, 2022
By BCRF | November 22, 2022
Of breast cancer’s many realities, one of the most confounding is the possibility that the cells can travel, hide, be gone, and then reappear as cancer in a new location. It’s called recurrence and metastasis. Researchers like Dr. Angela DeMichele are exploring paths to find out why that occurs, and how it can be stopped.
Dr. DeMichele is a professor of medicine and epidemiology at the University of Pennsylvania, where she leads a multidisciplinary team conducting novel clinical trials including a BCRF-supported phase 2 trial called PALAVY that is focused on answering: How might dormant cancer cells lead to a clearer understanding of the cancer in remission? And what leads some cancerous cells to behave differently than others?
Dr. DeMichele is a member of the NCI Breast Cancer Steering Committee, has authored over 130 publications in high-impact journals, and has been a BCRF Investigator since 2017.
Chris Riback: Dr. DeMichele, thanks for joining. I appreciate your time.
Dr. Angela DeMichele: It's great to be here, Chris. If we could, tell me about you. How did you get into all of this? Was it always science for you growing up? Did you ever believe that, no, instead you might say, be a soccer star or a rock musician?
Dr. Angela DeMichele: Well, as much as I love sports, I'm not very coordinated and I love to sing, but I have a terrible voice. So, it did sort of rule out certain careers.
Chris Riback: So, defaulted into medicine. Yes, I understand.
Dr. Angela DeMichele: But, no, I actually wanted to be a doctor starting in second grade. I always loved medical shows. For some reason, I just was really drawn to medicine and to being a doctor and being someone's doctor. That just was kind of a job that I always thought would be amazing. And I started volunteering as a candy striper when I was 12, and I just loved being in the hospital. So, I came at it mostly in that people part of interacting with people who had medical issues. And when I was a medical resident, I rotated through the oncology ward my second month. And to this day I can recall the patients in each of the rooms, because it had such a big impact on me. And this was 30 years ago.
But, to me, cancer patients are just really special. And there's nothing like cancer that really helps you get your priorities in order. And I just found working with cancer patients to be incredibly rewarding. And then I happen to be training when targeted therapies were just coming into their own. And Herceptin was the first drug that I ever studied in a clinical trial. So, it was an amazing time scientifically to be coming into the field.
So, to me it just is the perfect combination of taking care of people, but also just incredibly interesting [and] creative. I'm always learning. I love to teach. And so, I feel really, really lucky to have this job. And I love it as much, if not more than I ever have. So not many people can say that, I think.
Chris Riback: No, for sure.
Dr. Angela DeMichele: And I will just say, I am also incredibly grateful to BCRF who takes chances on research like this, that's really early and potentially transformative, but not the way people usually do things. And I think that that is what's going to help us really move the needle. And so, the creativity that I love bringing to my work is something that I think BCRF recognizes. And there's not a lot of other groups that will really fund that type of research that I think can be transformative. So, we're really grateful to them for the support.
Chris Riback: Understood. And, yes, the ability to fund creativity and exploration, as you're describing, really matters. I'm left, I just about to say thank you very much, but you realize there's the pertinent question that you just raised that I have to ask you. Which medical show?
Dr. Angela DeMichele: All of them.
Chris Riback: All of them.
Dr. Angela DeMichele: But Medical Center was the first one and then St. Elsewhere, of course. And then ER.
Chris Riback: Of course.
Dr. Angela DeMichele: And now, of course, it's Grey's Anatomy. I mean it goes on and on. I can't help myself. I still watch them. Now with a little more critical eye, but—
Chris Riback: I'm sure. And so, a little more critical eye on their product. And I hope maybe just slightly less drama in your own medical environment.
Dr. Angela DeMichele: That's right. We try to keep it a little cleaner.
Chris Riback: What drew you to focus on recurrence and metastasis? And I know it's the billion-dollar question, why does [breast cancer] occur?
Dr. Angela DeMichele: Well, I really got into this work after, gosh, 10 years of taking care of patients. And we would do a lot of testing to understand their initial diagnosis. We do very extensive therapy with surgery and radiation, chemotherapy sometimes, to really get to a point where I can say to a patient, "Okay, we've gotten rid of all of the cancer that we can see." And they would say, "Okay, well, and now what do we do? How do I know it worked? And how do I make sure that it's not still there?" And I would have to say, "Well, you know what? We don't really have a way to know whether or not it worked. And we don't really have a way to tell you whether or not it's still there." And you can only sit in front of these people for so long and feel that helplessness of, "Gosh, why don't we have these tools to figure out, we better do something about this."
Because really this is the thing, I think for most patients that I encounter is the most stressful part of this whole thing is I can tell a patient that you have a great prognosis, but unless I can say, "I know you're cancer-free, and here's how I know," every single patient's going to worry about this. And particularly for some kinds of breast cancer, like estrogen receptor–positive breast cancers, that risk of the cancer coming back extends for your whole lifetime. So it's just weight on people's shoulders of just waiting for, is this going to come back? And how do I know that it's not still there? That made me want to get involved in this kind of work.
And I'll say that when I was training 30 years ago, we just didn't have the tools to even start to figure this out. That was really after sort of the heyday where we learned that you could give additional chemotherapy and antiestrogen treatments after you removed the tumor, and it would prevent the cancer from coming back. But we didn't really know why. And so only in the last five to 10 years do we now understand the biology and have some tools to help us be able to actually start to think about how to monitor people, how to do more active surveillance, and then ultimately how to intervene if we find any evidence that the cancer is still there.
Chris Riback: And I want to ask you about that biology. But quickly, the first part of what you were discussing and that stress and stress obviously for the patient, and it's got to be somewhat disconcerting for the doctors, scientists, researchers in your position, you've done the medical work, but there's still that gap of you can't promise the future, and you surely want to do more. And you surely want to remove all aspects of that stress.
I watched a YouTube video of you from 2011, it's exactly what you're saying now. You spoke of the importance of providing not just excellent medical care, but also to provide the emotional support and the practical support needed. And even with all of the advancements over the last decade plus since then, that component of what you do, I imagine remains the same.
Dr. Angela DeMichele: It really does. I think this is a life-changing diagnosis, not just while women are and men are going through that initial treatment, but afterwards. And it's been well documented through research that fear of recurrence is the major stressor for breast cancer survivors. And partly that's because we only have watchful waiting to offer people. And so a patient will say, "Well, how do I know if the cancer's come back?" And I'll say, "Well, we watch for symptoms." "Well, what symptoms? Everybody gets a backache, everybody gets headaches. How do I know whether or not it's something I should worry about?"
And some breast cancers can be there and not have symptoms. And yet doing a lot of scans is not the solution. And we do have data that tells us that simply doing scans in patients who don't have any symptoms actually adds to distress, because there's a lot of false positives. We pick up things that turn out not to be cancer. Sometimes we can't even prove that, and that is just going to add to the distress. So, what we needed really are ways to find microscopic tumor cells that are still there, detect them, figure out who's got them and who doesn't. And if a patient has them, figure out how to get rid of them. That really is the goal.
Chris Riback: Let me ask a little bit of the biology as context that I think will help listeners really understand the power of the work that you're doing. Take me through the process of metastasis. How does it evolve? And what is dormancy? And why is it so hard to learn why cells exit dormancy?
Dr. Angela DeMichele: These are great questions, and we don't have all the answers, but we've learned a lot in the last 10 to 15 years about this process. So, it turns out that there are only some cells that have the ability to become dormant, which essentially means sleeping. And so, these cells are able to escape from the tumor in the breast, travel through the bloodstream, and then ultimately find their way to what we would call a niche or a place that's a welcoming environment. Often that's the bone marrow, but it can be in other places. When the cells arrive in this location, they go to sleep. And I think of it about it like a bear hibernating for the winter where it's kind of going in and it's going to sleep, and it doesn't need any external energy sources. And it's not interacting with anyone in its environment, it's just sitting there, and then it'll wake up when the spring comes.
And a lot of what we see with these cells, they go into the dormant state, they sort of power down, the cell's not dividing anymore, all of its electrical systems are turned off. It can sit in this suspended animation for a period of time, and then something triggers it to wake up, power back up, turn all the systems back on, start dividing again, leave that location, go back into the bloodstream and travel to another location.
So, when the cells are in their dormant state, not dividing, we call those disseminated tumor cells or DTCs. When the cells are circulating in the bloodstream, they circulate as circulating tumor cells or CTCs. But we also now have the ability to actually just detect the DNA from those cells. So, you'll hear about a term called circulating tumor DNA or ctDNA, that's the DNA from circulating cells that are dividing, moving their way to another location.
So, if you think about this black box between when there's a tumor in the breast, you remove that with surgery and a tumor that pops up somewhere else. Now you can envision that that black box consists of these cells that have left the breast, traveled to another location, gone to sleep, wake up, travel to that distant location, set up shop, become a metastasis.
Chris Riback: And is it the going to sleep or the waking up that piques your curiosity the most?
Dr. Angela DeMichele: Actually neither, to be honest. I mean, of course it's all important, but one of the key things is what allows them to stay asleep, because that's the part that we believe can go on for years. So certainly, we've seen patients who are diagnosed with their cancer, and then it doesn't come back someplace else for years to decades later. Well, those cells were there, but they were sleeping. So, if we understood what allows them to stay alive and asleep, we could kill them in their sleep. That gives us a really big window of time in which we can find them and target them, because we think that, as I said, that can be months, years, even decades.
It looks like once they power back up and start dividing again, that window may be much shorter. It could only be a year or two or even less between the time that the cell powers back up and the time that it finds its way to the lungs or the liver and starts to form a tumor. So just playing the odds, you'd kind of like to be targeting the cell at a point where it's spending most of its time in that sleeping state. And so, we're really focused a lot on the processes that enable the cell to do that.
Chris Riback: So, this mark's a good time to segue to your PALAVY trial. It opened only last year, I understand. So, we know that there's only so much that has occurred since then. But if you would, what is the status? What is the process? What do you hope to learn?
Dr. Angela DeMichele: So, we are targeting several different features of these disseminated tumor cells. So, I should back up a moment and say that for, gosh, the last 20 years, we've known that if you identify these disseminated tumor cells in the bone marrow, patients who have those cells are more likely to have a metastatic recurrence than patients who don't have the cells. So that tells us that if you find the cells, it impacts a patient's prognosis.
What had never really been done was to then try to intervene and see if we could actually do something at the point where we found those cells to prevent a recurrence. And ultimately what you'd like to be able to do is use the cells as what we call a surrogate marker to say, "Okay, I know that the presence of these cells is associated with a patient having a metastatic recurrence. So ultimately, what if I can get rid of them all, kill them all off? Will that mean the person doesn't relapse?" Well, that's really the question.
So, we are utilizing actually a fairly simple test to find the cells in the bone marrow. We do this using a small hollow needle that is inserted into the hip bone under just some numbing medicine. So, it's done in the outpatient clinic. We take out some of that liquid part of the bone marrow through a series of different techniques where we filter that fluid and enrich for these cells. We then have our pathologists take a look and see if they see any of the cells. If a patient has the cells, then they're eligible to come onto the trial.
The trial is testing several different drugs. We don't know which drugs are going to work, but I work closely with a basic scientist, Dr. Lewis Chodosh, who's also a BCRF-funded researcher, who has developed really elegant models in the laboratory. And in these models, he actually can embed tumors, primary tumors, but these tumor cells are labeled so he can actually follow what happens if you treat or turn off the signals, what happens to these cells? You can see the cells become dormant. You can remove them when they're dormant and figure out what's keeping them dormant or allowing them to stay asleep.
So, utilizing that information, we've worked closely together to study different drugs that would target those things that allow the cells to stay asleep or the things that allow them to wake up. He did testing of these different drugs in the laboratory, and it showed that you could kill these cells. So, we've now been working to bring those treatments to the clinic.
So, in the clinical trial, the patients who we find have these disseminated tumor cells, may receive one of several different treatments. They target some kind of unusual processes. One is called autophagy, it's how a cell uses its own internal energy sources, just like that bear in the cave that doesn't need any external energy. The cell can use its own internal energy. The drug that blocks that, crazy enough, is hydroxychloroquine.
Chris Riback: I read that.
Dr. Angela DeMichele: So, it turns out that hydroxychloroquine was used as a treatment for different infections. It used as treatment for inflammatory disease, but really we all heard about it because it was touted as this treatment for COVID, which of course didn't pan out. But it's a really safe drug. It's been around for a long, long time. It's oral and so it's fairly easy for patients to take it. So that's one of the drugs we're using.
Another drug we're using is actually trying to make these cells visible to the immune system, because, of course, you think, "Well, this cancer cell is there. Why is the immune system not recognizing it? Why isn't the immune system attacking it as foreign?" Well, these cells are really smart, and they've developed what I would call an invisibility cloak. They can stay shielded from the immune system.
So, we're using a drug called avelumab that can basically take off that shield and make the cell visible. And try to turn the immune system on to attack the cell. And then lastly, we're using a drug called palbociclib, which actually stop cells from dividing. So, if the cells are trying to escape, they've got to start dividing. We want to keep them from dividing. We want to keep them in this suspended animation, so that they're sensitive to these other drugs.
So that's the trial and it's open at six different locations around the country. So that's been exciting for us to be able to get this out to other places and to patients outside of the Philadelphia area. Our initial studies were all done here at University of Pennsylvania, and really provided the proof of principle that we could do this. And the patients then subsequently have additional bone marrow aspirates, so that we can see if the cells are going away. And then we will follow to see if the patients relapse. So, it takes time, but the hope is by using this surrogate marker—the bone marrow DTCs—we can figure out if the drugs are working without having to wait for the rest of the person's life.
Chris Riback: And am I understanding correctly the three different drugs, are they attacking or addressing kind of three different stages or parts? And then, two, if they are, is part of what you're then wondering is: Are there combinations of the drugs that might work A and C, B and C, A and B? Or are you looking at each drug individually and then going to, in a sense, pick a winner, or say, "Okay, for people who have these symptoms, or these circumstances use this drug for"? Am I understanding the approach in the initial case? And then how are you thinking about the three drugs going forward?
Dr. Angela DeMichele: Yes, you're absolutely right that this is really considered to be the groundwork that we need to do to understand which drugs are going to work the best and if there are combinations that are better than the single drugs alone. So, we are testing the drugs alone, we're testing them in combinations. We also are trying to figure out how long we need to give the drugs, so we do another bone marrow after three months and then we do another bone marrow after six months. Because we don't want to have to treat people any longer than they need it, but we want to give it long enough for it to work. And we don't really have a sense in people how long this will take.
So, this is pretty common when you're really working in a space that's brand new that we kind of have to figure out, what's going to be the best approach? Because the definitive trials that we'll need to do that would really show us whether this could actually become a standard of care, will need to be pretty big. They're going to be a big investment. And so, a lot of this groundwork is what we do to make sure we've picked the right drugs, the right doses, the right duration, and we have the right biomarker for the trials.
Chris Riback: And how far into testing these drugs with patients are you?
Dr. Angela DeMichele: So, we just finished our pilot trial that included hydroxychloroquine and a second drug called Afinitor® (everolimus) in a little over 50 patients. And we'll be reporting those results out later this year. So, we're in the process of analyzing those results. And then this trial is now, as I said, open in several different locations. I will say about a third of the patients who have the bone marrows have the cells. So, remember that we have to screen three times as many people as we need for the trials to find patients for them. So, we've been screening, and it's fairly early on in the trial at this point.
Chris Riback: Yes.
Dr. Angela DeMichele: There's opportunity for people to get involved. But this is the process. It takes time. But we're learning so much. And I have to say that the patients are amazing who are participating in our trials. They are so willing to do this. When I started, I was talking to an advisory board at one point and someone says, "Patients will never have bone marrow aspirates." And it turns out that the patients get it. What they were telling me all those years was right. They want to know, and they're willing to do this procedure in order to find out.
And more than half our patients came from outside of 50-mile radius of our center to get screened. So, I think that this is something where patients are real partners with us in this research. They talk about our trials on their Facebook groups, because this is something patients really want and need in their lives.
Chris Riback: Can I say, among the many, many, many things I have learned in having these conversations with people like you, and I've been privileged to have quite a number of them at this point, is do not underestimate for a moment, it's more than a willingness that patients, I hear it from so many scientists and researchers like yourself, they want to be part of and it's bigger than themselves.
I mean, sure, you just said they want to know, they learn about themselves, but I'm sure you're finding the same thing. They're not doing these trials necessarily for themselves. They want to help find a cure. They want to help the next people. And I hear it time and again, the selflessness of patients who join these trials and how much they're willing to, I don't know if endure is the right word, but endure.
Dr. Angela DeMichele: No, I think it's true. There's just incredible altruism to really help find the solution to this. And we really engage our patients and patient advocates for that matter in the research. We also are studying the psychological impact of going through this testing on the patients in the trial. I would never want to do something that’s going to cause harm. And to the extent that I knew that many patients wanted to know these things, sometimes you want to know. But then once you know, can’t unknow. And we have to always be mindful that we can induce other kinds of stress. That what we do is not without a cost. And so, for all that altruism, we also have to make sure that we don’t do anything that could make things harder for patients who’ve already been through so much. So, it is really a partnership and something that we really treat as a very sacred relationship.
Chris Riback: And your sensitivity and appreciation for that sacredness comes across in what you’re saying. So, what’s next doctor on this trial? I mean, everyone’s happy for whatever you’ve done to date, but it’s what’s next that matters. So, what do you have on that front?
Dr. Angela DeMichele: Well, I think that several things. Number one, as I mentioned earlier, there are kind of two parts to this story. There's the sleeping part, while the cells are dormant and there's the awake part, when the cells are now back to circulating and dividing and finding their way to a new place. So, we can't ignore either compartment or either part of that equation. So, we're also, we collect a lot of blood from patients who are participating in the trials. We're actually looking at the circulating tumor DNA in these blood samples to see if in the patients who have the sleeper cells, at what point do they also start to show signs that they're cells in the bloodstream. And so just trying to really get the whole picture and make sure we're measuring everything that matters is very important.
The second thing is that I'm working really closely with Dr. Chodosh on a new test. A test that's much better than the test we have now for the cells, because the test we have right now, while it's been so strongly associated with relapse, it doesn't allow us to interrogate the cells. So, we can't do anything to figure out what the targets are on the cells. What flavor, if you will, of cell the person has. We'd really like to know that because then if we find multiple treatments that can work, well, then we could actually tailor the person's treatment to the kind of disease that they have, the cells that they have, and be that much better at finding something that will work for them. And also, to find new targets. So, if we can interrogate the cells, then we can figure out what else are we missing that we could be targeting with our treatments.
We're also doing a lot of immune profiling. So, when we try to interact with the immune system to target these cells, what happens? And do people who have the cells differ from people who don't have these cells in terms of how their immune system functions? Because maybe part of the problem is some patient's immune system does find these cells and they're never going to relapse because their immune system gets rid of the cells. And maybe other patients have the cells because there's something wrong with how their immune system is functioning, and maybe we could fix that.
So, I think those are the main things that we're focused on. And also, just really honing in on different subtypes of breast cancer and not just right after diagnosis, but even five or 10 years later trying to find those patients who are still at risk. So, a lot of work to do. I'll be busy for a while.
Chris Riback: Yes, you'll be busy for a while. There are always deeper additional questions. And I'm certain there'll be items that you discover in this research that surely will advance other questions.
Dr. DeMichele, thank you. Thank you for your time. Thank you for the work that you do.
Dr. Angela DeMichele: Well, thanks for having me. It was fun, and I really enjoyed talking to you, Chris
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