City of Hope researchers are working to uncover how cancer stem cells grow, and what can be done to stop them from multiplying. To figure that out, they study how certain proteins interact with a cell’s genetic material — and how that affects the complex processes that make cancer cells divide.
Listen in as Leo David Wang, M.D., Ph.D. explains how our team at City of Hope, comprises stem cell biologists, cancer researchers and clinicians, nanotechnologists, bioinformaticians and graduate students all working toward a common goal: targeting cancer stem cells to suppress tumor formation and enhance patient survival.
Selected Podcast
Targeting Cancer Stem Cells
Featured Speaker:
Board certified in pediatrics and pediatric hematology/oncology, Dr. Wang is the recipient of multiple honors and awards, including a Damon-Runyon Foundation Cancer Research Fellowship, a St. Baldrick's Scholar Award and an Alex's Lemonade Stand Foundation Young Investigator Award.
Learn more about Leo David Wang, MD, Ph.D.
Leo David Wang, MD, Ph.D.
Leo David Wang, MD, Ph.D. earned his undergraduate degree in Molecular Biophysics and Biochemistry from Yale University, followed by his Ph.D. and medical doctorate at the University of Chicago. He successfully completed an internship and residency in pediatrics at the Children’s Hospital of Philadelphia. Dr. Wang then completed his Pediatric Hematology/Oncology/Stem Cell Transplantation fellowship at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and pursued postdoctoral research in the laboratory of Dr. Amy Wagers at the Joslin Diabetes Center and Harvard Stem Cell Institute.Board certified in pediatrics and pediatric hematology/oncology, Dr. Wang is the recipient of multiple honors and awards, including a Damon-Runyon Foundation Cancer Research Fellowship, a St. Baldrick's Scholar Award and an Alex's Lemonade Stand Foundation Young Investigator Award.
Learn more about Leo David Wang, MD, Ph.D.
Transcription:
Targeting Cancer Stem Cells
Melanie Cole (Host): City of Hope researchers are working to uncover how cancer stem cells grow and what can be done to stop them from multiplying. My guest today is Dr. Leo Wang. He is an Assistant Professor for the Department of Immuno-Oncology and Department of Pediatrics at City of Hope. Welcome to the show, Dr. Wang. I would like you to clear up a little confusion for listeners about stem cells and specifically cancer stem cells versus the good kind of stem cell.
Dr. Leo Wang (Guest): It’s a very confusing and complicated question, Melanie. Stem cells, basically, I think of as seeds. Just like you have seeds in your garden, stem cells are seeds in your body and they can grow into whatever they're the seed for. Just as a tomato seed will grow into a tomato, the stem cells that are in your body will grow into any kind of tissue. There are stem cells like embryonic stem cells that are what are called “pluripotent” so they can grow into any tissue within the body. I'm focused more on hematopoietic stem cells that can only grow into any kind of blood cell in the body, and they can also self-renew. Cancer stem cells, as the name suggests, are capable of both self-renewing and growing into cancer. So, they don't grow into normal tissues but they do grow into cancer. The way that I talk about it with my patients is to think of them is as weeds. So, if you're a gardener and you have a garden that's overgrown with weeds, you can take a weed whacker or scissors or whatever and cut off the tops of the weeds but if you don't treat the roots or the seeds of the weeds, then they’ll just grow back when you're done.
Melanie: Excellent explanation. How do you identify early that a stem cell is going to be a cancer stem cell versus growing into something positive?
Dr. Wang: That is the crux of the issues and that is one of the biggest questions that has dogged the field for many years. It is not so much that stem cells can grow either into cancer or healthy tissue, it's that there are cancers and cancers have stem cells, and there are normal tissues and normal tissues have stem cells, and sometimes normal stem cells turn into cancer stem cells that are then only capable of growing into cancer. We need to figure out how to identify and eliminate those cancer-causing stem cells as quickly as possible.
Melanie: That would seem to be an amazing goal in the future of immunotherapy T cell cancer medicine. So, when you're targeting these cancer stem cells, Dr. Wang, are you looking to stop their growth or to kill them, or both?
Dr. Wang: Ideally, we would like to kill them. To go back to the garden analogy, I think of chemotherapy as a very harsh and toxic but effective treatment, but it kills both cancer cells and normal cells. So, it's a little bit like putting some sort of pesticide or herbicide on your garden that kills the weeds but it also kills the normal plants. The most extreme form of that would be a bone marrow transplant, where you're essentially burning the field down so that you can give it a chance grow back. Unfortunately, that often will not kill the cancer stem cells. The seeds that grow into weeds are still there and you need to figure out a way to specifically kill those to make a room for the healthy seeds to grow again.
Melanie: So, if they have this pluripotent capacity, this self-renewable ability, and you stop one but it has already ordered another one, how does it move forward? People think of cancers, Dr. Wang, like leukemia or some of the blood-borne cancers, as being able to sort of remake themselves and continuing and that's why people are so scared of those. Explain how you would stop that forward progression.
Dr. Wang: That’s exactly right. The stem cells have amazing proliferative capacity, and the most rapidly dividing ones are often not the stem cells. Those are responsive to chemotherapy and conventional therapies but we also need to kill the stem cells so that they don't, as you say, grow back and cause leukemia relapse, which ultimately can be fatal.
Melanie: Do you more typically see these cancer stem cells in solid tumor cancers, or are they more in systemic cancers, or both?
Dr. Wang: The cancer stem cells are much better characterized in the so-called liquid tumors like leukemia but there's mounting evidence that they exist in all cancers, and people have identified cancer stem cells in multiple solid tumors as well, including breast and lung, colon and brain cancer. We think that targeting stem cells in any tumor is going to really vastly improve how these cancers are treated in the future, and the goal is, as you said at the outset, to try to identify these stem cells and to try to figure out what makes them different, with their Achilles heel is, and how to use that to treat them.
Melanie: Are there certain biomarkers you look for?
Dr. Wang: There are certain characteristics that these cells all share and trying to figure out more of those and how to use those therapeutically is one of the main challenges that the field faces right now. Unfortunately, they don't often raise their hand, so to speak; they don't wear bright colors that say, “Hey, look at me. I’m a stem cell. They’re a little bit trickier than that.” So, we need to devise ways of identifying them diagnostically and of treating them therapeutically that take advantage of their unique properties of stemness, but we can’t always identify them on priority using the techniques that we have already available in the lab.
Melanie: Tell us about some of your current therapeutic strategies against these cancer stem cells. What are you doing right now?
Dr. Wang: The first step is to, as you said, figure out better ways to identify them because you can’t always tell the difference just by looking. Certainly, when we had microscopes, that was our primary way of diagnosis. It was impossible to tell if it's a stem cell or non-stem cell. Now, we have much more advanced techniques, molecular and flow cytometrics techniques. Even those are not very effective at identifying stem cells. It turns out that most of the functions in cells are executed by protein. And so, there are many protein passwords that get activated that are responsible for the stemness of cells; their ability to resist chemotherapy; their ability to proliferate and to self-renew. We're trying to identify those pathways using a technology called mass spectrometry, which is a way to look at the actual protein molecules in each cell, figure out whether they’re activated or not in a way that discovers new protein pathways in addition to just confirming protein pathways that have already been identified. The hope is that once we identify protein pathways that are specifically activated in stem cells, we can then figure out how to turn those pathways off.
Melanie: Dr. Wang, is there a communication or a connection between immunotherapy and targeted stem cells? We hear about T-cell therapy and this team fighting ability of certain cells. Tell us if there is an interaction there.
Dr. Wang: Melanie, that’s a fascinating question, and one of the things that I have come to City of Hope to study. As you know, and you're listeners probably know, immunotherapy has taken the world by storm, and it's this really that this innovative idea that's been around for a while but hasn't really been brought to the clinic until the past five years, that you can actually train the body's own immune system to fight cancer. One of the most innovative ways to do that, one that we are excellent at at City of Hope, is using what are called chimeric antigen receptor T cells or CAR T-cells. These are T-cells that have been genetically engineered to attack cancer cells specifically. When we put these cells into patients they're amazingly good at killing cancer cells and pretty much only cancer cells. One of the big remaining challenges with these cells is that, especially in solid tumors, they tend to disappear after a while. It’s not entirely clear why that is. It probably has a lot to do with the fact that a solid tumor has a very complex environment that has a lot of immunosuppressant properties to it. It turns out that cancers are pretty good at protecting themselves and hiding themselves and they make it so that the immune system sort of goes to sleep when it enters into the vicinity of a cancer. So, one of the things that we want to do, that I want to do at City of hope, is to figure out how to make T-cells, specifically CAR T-cells last longer and work better. One way to do that is to borrow from the stem cell. We know that stem cells actually are really good at persisting and really good at surviving. So, can we identify, as I said before, protein pathways that are specifically activated in stem cells and introduce those into T-cells or help enable those in T-cells so that our now therapeutic T-cells are more persistent.
Melanie: That's absolutely fascinating. Dr. Wang, in the last few minutes, give us your horizon picture. Where do you see the future of targeting stem cells for cancer and why people should come to City of Hope for their care?
Dr. Wang: I think that the field globally is now realizing the importance of cancer stem cells and how important it is to develop cancer stem cell targeted therapies in treating all kinds of cancers. Unfortunately, although we’ve realized the importance of this, there has not been a lot of progress made to date in actually targeting these cells. It is not for lack of effort, it's just it’s a difficult problem. City of Hope is unique in that it brings together the best possible research, the most innovative and far-reaching research in this field with a very innovative and nimble clinic, so that we can bring some of these very interesting and innovative therapies into patients as quickly as possible.
Melanie: Thank you so much, Dr. Wang, for being with us today. You’re listening to City of Hope Radio, and for more information you can go to www.CityofHope.org. That’s www.CityofHope.org. Thanks so much for listening.
Targeting Cancer Stem Cells
Melanie Cole (Host): City of Hope researchers are working to uncover how cancer stem cells grow and what can be done to stop them from multiplying. My guest today is Dr. Leo Wang. He is an Assistant Professor for the Department of Immuno-Oncology and Department of Pediatrics at City of Hope. Welcome to the show, Dr. Wang. I would like you to clear up a little confusion for listeners about stem cells and specifically cancer stem cells versus the good kind of stem cell.
Dr. Leo Wang (Guest): It’s a very confusing and complicated question, Melanie. Stem cells, basically, I think of as seeds. Just like you have seeds in your garden, stem cells are seeds in your body and they can grow into whatever they're the seed for. Just as a tomato seed will grow into a tomato, the stem cells that are in your body will grow into any kind of tissue. There are stem cells like embryonic stem cells that are what are called “pluripotent” so they can grow into any tissue within the body. I'm focused more on hematopoietic stem cells that can only grow into any kind of blood cell in the body, and they can also self-renew. Cancer stem cells, as the name suggests, are capable of both self-renewing and growing into cancer. So, they don't grow into normal tissues but they do grow into cancer. The way that I talk about it with my patients is to think of them is as weeds. So, if you're a gardener and you have a garden that's overgrown with weeds, you can take a weed whacker or scissors or whatever and cut off the tops of the weeds but if you don't treat the roots or the seeds of the weeds, then they’ll just grow back when you're done.
Melanie: Excellent explanation. How do you identify early that a stem cell is going to be a cancer stem cell versus growing into something positive?
Dr. Wang: That is the crux of the issues and that is one of the biggest questions that has dogged the field for many years. It is not so much that stem cells can grow either into cancer or healthy tissue, it's that there are cancers and cancers have stem cells, and there are normal tissues and normal tissues have stem cells, and sometimes normal stem cells turn into cancer stem cells that are then only capable of growing into cancer. We need to figure out how to identify and eliminate those cancer-causing stem cells as quickly as possible.
Melanie: That would seem to be an amazing goal in the future of immunotherapy T cell cancer medicine. So, when you're targeting these cancer stem cells, Dr. Wang, are you looking to stop their growth or to kill them, or both?
Dr. Wang: Ideally, we would like to kill them. To go back to the garden analogy, I think of chemotherapy as a very harsh and toxic but effective treatment, but it kills both cancer cells and normal cells. So, it's a little bit like putting some sort of pesticide or herbicide on your garden that kills the weeds but it also kills the normal plants. The most extreme form of that would be a bone marrow transplant, where you're essentially burning the field down so that you can give it a chance grow back. Unfortunately, that often will not kill the cancer stem cells. The seeds that grow into weeds are still there and you need to figure out a way to specifically kill those to make a room for the healthy seeds to grow again.
Melanie: So, if they have this pluripotent capacity, this self-renewable ability, and you stop one but it has already ordered another one, how does it move forward? People think of cancers, Dr. Wang, like leukemia or some of the blood-borne cancers, as being able to sort of remake themselves and continuing and that's why people are so scared of those. Explain how you would stop that forward progression.
Dr. Wang: That’s exactly right. The stem cells have amazing proliferative capacity, and the most rapidly dividing ones are often not the stem cells. Those are responsive to chemotherapy and conventional therapies but we also need to kill the stem cells so that they don't, as you say, grow back and cause leukemia relapse, which ultimately can be fatal.
Melanie: Do you more typically see these cancer stem cells in solid tumor cancers, or are they more in systemic cancers, or both?
Dr. Wang: The cancer stem cells are much better characterized in the so-called liquid tumors like leukemia but there's mounting evidence that they exist in all cancers, and people have identified cancer stem cells in multiple solid tumors as well, including breast and lung, colon and brain cancer. We think that targeting stem cells in any tumor is going to really vastly improve how these cancers are treated in the future, and the goal is, as you said at the outset, to try to identify these stem cells and to try to figure out what makes them different, with their Achilles heel is, and how to use that to treat them.
Melanie: Are there certain biomarkers you look for?
Dr. Wang: There are certain characteristics that these cells all share and trying to figure out more of those and how to use those therapeutically is one of the main challenges that the field faces right now. Unfortunately, they don't often raise their hand, so to speak; they don't wear bright colors that say, “Hey, look at me. I’m a stem cell. They’re a little bit trickier than that.” So, we need to devise ways of identifying them diagnostically and of treating them therapeutically that take advantage of their unique properties of stemness, but we can’t always identify them on priority using the techniques that we have already available in the lab.
Melanie: Tell us about some of your current therapeutic strategies against these cancer stem cells. What are you doing right now?
Dr. Wang: The first step is to, as you said, figure out better ways to identify them because you can’t always tell the difference just by looking. Certainly, when we had microscopes, that was our primary way of diagnosis. It was impossible to tell if it's a stem cell or non-stem cell. Now, we have much more advanced techniques, molecular and flow cytometrics techniques. Even those are not very effective at identifying stem cells. It turns out that most of the functions in cells are executed by protein. And so, there are many protein passwords that get activated that are responsible for the stemness of cells; their ability to resist chemotherapy; their ability to proliferate and to self-renew. We're trying to identify those pathways using a technology called mass spectrometry, which is a way to look at the actual protein molecules in each cell, figure out whether they’re activated or not in a way that discovers new protein pathways in addition to just confirming protein pathways that have already been identified. The hope is that once we identify protein pathways that are specifically activated in stem cells, we can then figure out how to turn those pathways off.
Melanie: Dr. Wang, is there a communication or a connection between immunotherapy and targeted stem cells? We hear about T-cell therapy and this team fighting ability of certain cells. Tell us if there is an interaction there.
Dr. Wang: Melanie, that’s a fascinating question, and one of the things that I have come to City of Hope to study. As you know, and you're listeners probably know, immunotherapy has taken the world by storm, and it's this really that this innovative idea that's been around for a while but hasn't really been brought to the clinic until the past five years, that you can actually train the body's own immune system to fight cancer. One of the most innovative ways to do that, one that we are excellent at at City of Hope, is using what are called chimeric antigen receptor T cells or CAR T-cells. These are T-cells that have been genetically engineered to attack cancer cells specifically. When we put these cells into patients they're amazingly good at killing cancer cells and pretty much only cancer cells. One of the big remaining challenges with these cells is that, especially in solid tumors, they tend to disappear after a while. It’s not entirely clear why that is. It probably has a lot to do with the fact that a solid tumor has a very complex environment that has a lot of immunosuppressant properties to it. It turns out that cancers are pretty good at protecting themselves and hiding themselves and they make it so that the immune system sort of goes to sleep when it enters into the vicinity of a cancer. So, one of the things that we want to do, that I want to do at City of hope, is to figure out how to make T-cells, specifically CAR T-cells last longer and work better. One way to do that is to borrow from the stem cell. We know that stem cells actually are really good at persisting and really good at surviving. So, can we identify, as I said before, protein pathways that are specifically activated in stem cells and introduce those into T-cells or help enable those in T-cells so that our now therapeutic T-cells are more persistent.
Melanie: That's absolutely fascinating. Dr. Wang, in the last few minutes, give us your horizon picture. Where do you see the future of targeting stem cells for cancer and why people should come to City of Hope for their care?
Dr. Wang: I think that the field globally is now realizing the importance of cancer stem cells and how important it is to develop cancer stem cell targeted therapies in treating all kinds of cancers. Unfortunately, although we’ve realized the importance of this, there has not been a lot of progress made to date in actually targeting these cells. It is not for lack of effort, it's just it’s a difficult problem. City of Hope is unique in that it brings together the best possible research, the most innovative and far-reaching research in this field with a very innovative and nimble clinic, so that we can bring some of these very interesting and innovative therapies into patients as quickly as possible.
Melanie: Thank you so much, Dr. Wang, for being with us today. You’re listening to City of Hope Radio, and for more information you can go to www.CityofHope.org. That’s www.CityofHope.org. Thanks so much for listening.