Only about 100 infants are diagnosed with acute lymphoblastic leukemia (ALL) in the U.S. each year. Most of these babies respond to chemotherapy treatment at first, but go on to relapse and die of the disease.
Dr. Erin Guest and colleagues at Children’s Mercy are performing genomics research to uncover the reasons why leukemia in infants becomes resistant to treatment. Dr. Guest is also leading a national clinical trial for infants with ALL, through the Children’s Oncology Group.
Listen in as Erin Guest, MD discusses how she is working with researchers from around the globe to design new treatment strategies that will cure more infants with leukemia.
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Cancer Genomics: Researching New Treatment Strategies to Cure Infant Acute Lymphoblastic Leukemia (ALL)
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Learn more about Erin Guest, MD
Erin Guest, MD
Erin Guest, MD, is a pediatric hematologist/oncologist at Children’s Mercy and Assistant Professor of Pediatrics at the University of Missouri-Kansas City School of Medicine. Dr. Guest serves as Director of the Children’s Mercy Cancer Genomics Program and Director of the Children’s Mercy Cancer Center Biorepository. Dr. Guest received her medical degree from the University of Oklahoma College of Medicine in Oklahoma City, OK. She completed a residency in pediatrics followed by a fellowship in Pediatric Hematology/Oncology, both at Children’s Mercy Kansas City. Dr. Guest is board certified in Pediatrics and Pediatric Hematology/Oncology.Learn more about Erin Guest, MD
Transcription:
Cancer Genomics: Researching New Treatment Strategies to Cure Infant Acute Lymphoblastic Leukemia (ALL)
Dr. Michael Smith (Host): Today, our topic is “Cancer Genomics: Researching New Treatment Strategies to Cure Infant Acute Lymphoblastic Leukemia”. My guest is Dr. Erin Guest. She is Assistant Professor of Pediatrics of the University of Missouri-Kansas City School of Medicine. Dr. Guest also serves as Director of the Children’s Mercy Cancer Genomics Program and she is the Director of the Children’s Mercy Cancer Center Biorepository. Dr. Guest, welcome to the show.
Dr. Erin Guest (Guest): Thank you so much. Thanks for having me today.
Dr. Mike: So, we’ve heard a lot that the cure rate of childhood leukemia has improved significantly over the years, but how is leukemia in infants different?
Dr. Guest: So, leukemia in infants is extremely rare and our research is focused on infants who have acute lymphoblastic leukemia or ALL, and there’s really only less than 100 cases in infants who are diagnosed under one year of age in the U.S. each year, and that compares to thousands of older children who are diagnosed with leukemia each year in the U.S. Then, leukemia in infants is to be extremely aggressive. When it onsets, there is often a very high white blood cell count. It’s not uncommon to see white blood cell count of over a million per microliter in the blood. Infants tend to have more CNS disease and more skin disease as well and they often come in very, very sick at the time of diagnosis. So, it’s a really aggressive type of leukemia and then they tend to respond pretty well in the first month of treatment. We can often get them into a remission but then the rate of relapse is extremely high. So, about one in three babies will be cured but two in three babies will actually have a relapse. And then, at the time of relapse, the disease becomes very, very resistant. So, unlike older children who we can usually get them back into remission and then still have a chance of cure with a transplant, if a baby has a relapse, we often--any chemotherapy or treatments that we try to do will not work, and then we just have such a worse cure rate for this group. So, it’s a genetic...
Dr. Mike: So, tell us a little--
Dr. Guest: …disease. It’s a little bit different, too, and so we know that the genetics are different and we know how it behaves but we don’t really understand why it’s so resistant.
Dr. Mike: So, that brings up my next question, then. So, tell us a little bit about the research that you and your colleagues are doing in the Center for Pediatric Genomic Medicine, and how that ties in to the infant leukemia.
Dr. Guest: Sure. So, we’re really interested in figuring out why it’s a leukemia that becomes so aggressive, and why it’s so resistant to treatment. We’re very blessed to have samples from infants who were treated on a national clinical trial. So, these are babies--there were actually 44 babies--who they and their parents have donated samples of their blood and their bone marrow, and these are samples that were taken at the time of their routine care for their leukemia, and then they were donated and stored in a tissue bank. We’re able to now take those samples and do research with those to try and figure out several different questions. So, one of the questions we want to know is why did the babies get leukemia in the first place because that’s really an unanswered question. And another question would be, why do two out of three relapse but then one out of three babies will be cured. So, what’s the difference at the time of diagnosis between the genetics in those from those babies leukemia cells that maybe we can predict which babies are going to have relapse and then that can help us determine which babies might need more aggressive treatment. Then, also the other question then becomes why after the time it relapses, why is it so difficult to treat? What about the leukemia cells and what about the genetics becomes so resistant and how does it figure out how to get around our chemotherapy treatment so we can no longer treat it?
Dr. Mike: I guess one of the most exciting things about genomic medicine and you’re the expert so correct me if I'm wrong here, is being able to look at an individual person and say, not only genetically speaking are you at more risk, but we now know that you might have a worse prognosis or you might be somebody who is going to be resistant to treatment, and that really can have an impact in how we approach the disease for that individual in the treatment, correct? So, the real focus here is translating this into clinical practice and into better treatment. So, where are we at in that process, I guess, of taking all of the research that you’re doing and translating that into a clinical practice?
Dr. Guest: Sure, that such a great question. So, right now, our current standard of care is that babies are all treated with the same chemotherapy program. And these are chemotherapy drugs that have been used to treat infants and children with different types of cancer for years. And so, at the moment, each baby is not really being treated in an individualized way but that’s where we want to go. So, that’s the real goal of this research is to identify certain elements of the genomics that could be targeted by newer treatments. We want to be able to match a drug to a child and to know that the drug is going to benefit that child, and if we can cut back on chemotherapy, that would be great. There have been trials in the past that have tried to intensify the therapy, the chemotherapy, for babies with ALL, but they’ve really just resulted in a lot more toxicity, and have not improved the cure rate. So, we know more chemotherapy is not the answer. We really do need to find those targets in the genomics. One of the things that’s really interesting and unique about infant ALL is that the DNA tends to take on extra methylation which turns off genes. So, we think that one of the mechanisms of ALL development in infants is that the genes that are normally supposed to be cancer suppressors get turned off and then the leukemia is then allowed to develop and become resistant. And so, one of the strategies is to actually give demethylating agents, then to try and reverse that signal and then, hopefully, make the leukemia cells then more sensitive to the chemo.
Dr. Mike: That’s really interesting, isn’t it? And I’m seeing more of that in the research as well looking at hypermethylation, hypomethylation and using those as targets for treatment. Do you see that as something that’s going to continue to grow? And, obviously, there’s still a lot to learn about it, but it seems like supporting a balanced methylation in infants, even in adults, is extremely important. I think, we’re learning that from genetic research like yours, right?
Dr. Guest: Right. We know that not only the promoters of the genes but the entire genome in infant ALL cells is hypermethylated and so there’s actually a children’s oncology group trial that we’re putting together, and it’s going to test that strategy exactly. So, there’s a medication called azacitidine that has been used since the 1970s to treat leukemia and pre-leukemia type myelodysplastic syndrome. And it’s actually FDA approved in adults for myelodysplastic syndrome. It’s been used to treat children with leukemia and we’re going to use it to make an attempt to demethylate the cells right before chemotherapy in the hopes that that will sensitize those infant ALL cells to chemotherapy so ultimately, hopefully, reducing the rates of relapse and leading to better cure rates for these babies.
Dr. Mike: What about some of the natural demethylators? For instance, folate, folic acid is known to inhibit the SAMe cycle which is one of the primary ways we methylate DNA, proteins, etc. Are you looking at some of that as well or it looking just at the pharmaceuticals?
Dr. Guest: I’m not aware of any research with folate that’s going on with infant leukemia cells, but we do use a folate inhibitor when we use methotrexate to treat leukemia and that goes across the board for all different types of ALL. That’s a very effective treatment. We do use that in infants as well.
Dr. Mike: Tell me a little bit more about the Children’s Oncology Group. So, this is a large ongoing trial, right, that Children’s Mercy is a part of?
Dr. Guest: Yes. The Children’s Oncology Group is an international group of all the major pediatric hospitals, and it’s really based in the U.S., and it runs clinical trials for children with all different types of cancer. So, clinical trials are extremely important because that’s where we can learn, we can test new treatments but we can also learn what works and we can learn what the side effects are of different treatments. And so, this trial that’s going to be coming up for babies, for infants with ALL, will enroll up to 100 babies, and that’s pretty remarkable because when there’s less than 100 diagnosed in the U.S. per year, this is actually a pretty large trial of the disease. So, it’s going to take a couple of years to get enough babies enrolled. The first step here is going to actually be testing the safety of the combination, because we know that infants have a lot of toxicities. They treat a lot of side effects already with just the chemotherapy alone. So, we’re going to be adding in a medication that’s been used in infants before, but we just want to first make sure that the combination is safe. So, that’s the real goal of this pilot trial with about 100 babies but to be able to actually answer the question, eventually, is this effective and does it improve cure rates, we’re going to need more infants than that. It takes a much larger trial. So, that’s really exciting because there’s going to be an international infant ALL trial that we’re also participating in, and I've been helping with making the plans for that trial. So, the idea would be, if the pilot trial shows the safety of the combination of the demethylating agent with chemo, then we’ll be taking that on an international level, and we have colleagues in Europe and Japan that are very excited. There’re also testing this in pilot form and then we’re all going to be testing it together in babies around the world.
Dr. Mike: Wow, that’s awesome. I guess the exciting part of this is understanding some of the pathophysiology going, on. The hypermethylation/demethylation makes perfect sense. Of course, we can write that up in biochemistry easy but that always doesn’t translate well into human physiology.
Dr. Guest: Right.
Dr. Mike: So, this is exciting research. This is a tough question, Dr. Guest, but this is an exciting field of medicine you’re in with genomic research. So, when you look at it, not even just in infant leukemia, just in cancer, in general, where do you see us going with genomic medicine? If you had a couple of lines to leave us with, what would you say about the future of genomic research, genomic medicine, and treating cancers?
Dr. Guest: I would say that it’s a critical piece to learning how to treat the cancer. We really need to understand the biology of what’s driving a cancer in the first place. But I think that while it started off as sequencing DNA, it’s going to be so much more than that. So, probably, maybe even more important than the actual sequence changes of the DNA itself will be the expression changes of the DNA. So, what is expressed in the RNA that then leaves the nucleus and goes make protein. So, methylation of DNA shuts off genes, shuts off expression and reversing that can turn genes on and turns back on expression. But there are lots of other epigenetic factors that lead to expression changes, too. So, while we may know that there’s a mutation in the DNA, what I think we really want to know is what gene is expressed, and how it that changed, how is the RNA changed, how is the protein downstream changed because that’s really ultimately the manufacturing pipeline that’s actually driving that cancer.
Dr. Mike: Right. Yes. That’s exciting, isn’t it? A lot of research. You could look at it from the gene level to the RNA level to the protein level and, obviously, it’s much more complicated than we can even imagine.
Dr. Guest: Right. And with the sequencing we’re doing in leukemia cells, we’re taking a comprehensive approach. So, we are sequencing the entire genome but we’re also going deeper and sequencing just the gene--just the exome of the expressed gene. We’re doing whole exome sequencing. We’re looking at the methylation changes of the DNA and then we’re also looking at the RNA expression. So, I think that comprehensive approach is what’s going to be needed ultimately for all different types of cancers to really get a good understanding of the biology that’s driving that cancer to grow.
Dr. Mike: Well, it’s fascinating work, Dr. Guest, and I want to thank you for what you’re doing in genomic medicine at Children’s Mercy and I also want to thank you for coming on this show today. You’re listening to Transformational Pediatrics with Children’s Mercy Kansas City. For more information, you can go to www.childrensmercy.org. That’s www.childrensmercy.org. I’m Dr. Mike Smith. Thanks for listening.
Cancer Genomics: Researching New Treatment Strategies to Cure Infant Acute Lymphoblastic Leukemia (ALL)
Dr. Michael Smith (Host): Today, our topic is “Cancer Genomics: Researching New Treatment Strategies to Cure Infant Acute Lymphoblastic Leukemia”. My guest is Dr. Erin Guest. She is Assistant Professor of Pediatrics of the University of Missouri-Kansas City School of Medicine. Dr. Guest also serves as Director of the Children’s Mercy Cancer Genomics Program and she is the Director of the Children’s Mercy Cancer Center Biorepository. Dr. Guest, welcome to the show.
Dr. Erin Guest (Guest): Thank you so much. Thanks for having me today.
Dr. Mike: So, we’ve heard a lot that the cure rate of childhood leukemia has improved significantly over the years, but how is leukemia in infants different?
Dr. Guest: So, leukemia in infants is extremely rare and our research is focused on infants who have acute lymphoblastic leukemia or ALL, and there’s really only less than 100 cases in infants who are diagnosed under one year of age in the U.S. each year, and that compares to thousands of older children who are diagnosed with leukemia each year in the U.S. Then, leukemia in infants is to be extremely aggressive. When it onsets, there is often a very high white blood cell count. It’s not uncommon to see white blood cell count of over a million per microliter in the blood. Infants tend to have more CNS disease and more skin disease as well and they often come in very, very sick at the time of diagnosis. So, it’s a really aggressive type of leukemia and then they tend to respond pretty well in the first month of treatment. We can often get them into a remission but then the rate of relapse is extremely high. So, about one in three babies will be cured but two in three babies will actually have a relapse. And then, at the time of relapse, the disease becomes very, very resistant. So, unlike older children who we can usually get them back into remission and then still have a chance of cure with a transplant, if a baby has a relapse, we often--any chemotherapy or treatments that we try to do will not work, and then we just have such a worse cure rate for this group. So, it’s a genetic...
Dr. Mike: So, tell us a little--
Dr. Guest: …disease. It’s a little bit different, too, and so we know that the genetics are different and we know how it behaves but we don’t really understand why it’s so resistant.
Dr. Mike: So, that brings up my next question, then. So, tell us a little bit about the research that you and your colleagues are doing in the Center for Pediatric Genomic Medicine, and how that ties in to the infant leukemia.
Dr. Guest: Sure. So, we’re really interested in figuring out why it’s a leukemia that becomes so aggressive, and why it’s so resistant to treatment. We’re very blessed to have samples from infants who were treated on a national clinical trial. So, these are babies--there were actually 44 babies--who they and their parents have donated samples of their blood and their bone marrow, and these are samples that were taken at the time of their routine care for their leukemia, and then they were donated and stored in a tissue bank. We’re able to now take those samples and do research with those to try and figure out several different questions. So, one of the questions we want to know is why did the babies get leukemia in the first place because that’s really an unanswered question. And another question would be, why do two out of three relapse but then one out of three babies will be cured. So, what’s the difference at the time of diagnosis between the genetics in those from those babies leukemia cells that maybe we can predict which babies are going to have relapse and then that can help us determine which babies might need more aggressive treatment. Then, also the other question then becomes why after the time it relapses, why is it so difficult to treat? What about the leukemia cells and what about the genetics becomes so resistant and how does it figure out how to get around our chemotherapy treatment so we can no longer treat it?
Dr. Mike: I guess one of the most exciting things about genomic medicine and you’re the expert so correct me if I'm wrong here, is being able to look at an individual person and say, not only genetically speaking are you at more risk, but we now know that you might have a worse prognosis or you might be somebody who is going to be resistant to treatment, and that really can have an impact in how we approach the disease for that individual in the treatment, correct? So, the real focus here is translating this into clinical practice and into better treatment. So, where are we at in that process, I guess, of taking all of the research that you’re doing and translating that into a clinical practice?
Dr. Guest: Sure, that such a great question. So, right now, our current standard of care is that babies are all treated with the same chemotherapy program. And these are chemotherapy drugs that have been used to treat infants and children with different types of cancer for years. And so, at the moment, each baby is not really being treated in an individualized way but that’s where we want to go. So, that’s the real goal of this research is to identify certain elements of the genomics that could be targeted by newer treatments. We want to be able to match a drug to a child and to know that the drug is going to benefit that child, and if we can cut back on chemotherapy, that would be great. There have been trials in the past that have tried to intensify the therapy, the chemotherapy, for babies with ALL, but they’ve really just resulted in a lot more toxicity, and have not improved the cure rate. So, we know more chemotherapy is not the answer. We really do need to find those targets in the genomics. One of the things that’s really interesting and unique about infant ALL is that the DNA tends to take on extra methylation which turns off genes. So, we think that one of the mechanisms of ALL development in infants is that the genes that are normally supposed to be cancer suppressors get turned off and then the leukemia is then allowed to develop and become resistant. And so, one of the strategies is to actually give demethylating agents, then to try and reverse that signal and then, hopefully, make the leukemia cells then more sensitive to the chemo.
Dr. Mike: That’s really interesting, isn’t it? And I’m seeing more of that in the research as well looking at hypermethylation, hypomethylation and using those as targets for treatment. Do you see that as something that’s going to continue to grow? And, obviously, there’s still a lot to learn about it, but it seems like supporting a balanced methylation in infants, even in adults, is extremely important. I think, we’re learning that from genetic research like yours, right?
Dr. Guest: Right. We know that not only the promoters of the genes but the entire genome in infant ALL cells is hypermethylated and so there’s actually a children’s oncology group trial that we’re putting together, and it’s going to test that strategy exactly. So, there’s a medication called azacitidine that has been used since the 1970s to treat leukemia and pre-leukemia type myelodysplastic syndrome. And it’s actually FDA approved in adults for myelodysplastic syndrome. It’s been used to treat children with leukemia and we’re going to use it to make an attempt to demethylate the cells right before chemotherapy in the hopes that that will sensitize those infant ALL cells to chemotherapy so ultimately, hopefully, reducing the rates of relapse and leading to better cure rates for these babies.
Dr. Mike: What about some of the natural demethylators? For instance, folate, folic acid is known to inhibit the SAMe cycle which is one of the primary ways we methylate DNA, proteins, etc. Are you looking at some of that as well or it looking just at the pharmaceuticals?
Dr. Guest: I’m not aware of any research with folate that’s going on with infant leukemia cells, but we do use a folate inhibitor when we use methotrexate to treat leukemia and that goes across the board for all different types of ALL. That’s a very effective treatment. We do use that in infants as well.
Dr. Mike: Tell me a little bit more about the Children’s Oncology Group. So, this is a large ongoing trial, right, that Children’s Mercy is a part of?
Dr. Guest: Yes. The Children’s Oncology Group is an international group of all the major pediatric hospitals, and it’s really based in the U.S., and it runs clinical trials for children with all different types of cancer. So, clinical trials are extremely important because that’s where we can learn, we can test new treatments but we can also learn what works and we can learn what the side effects are of different treatments. And so, this trial that’s going to be coming up for babies, for infants with ALL, will enroll up to 100 babies, and that’s pretty remarkable because when there’s less than 100 diagnosed in the U.S. per year, this is actually a pretty large trial of the disease. So, it’s going to take a couple of years to get enough babies enrolled. The first step here is going to actually be testing the safety of the combination, because we know that infants have a lot of toxicities. They treat a lot of side effects already with just the chemotherapy alone. So, we’re going to be adding in a medication that’s been used in infants before, but we just want to first make sure that the combination is safe. So, that’s the real goal of this pilot trial with about 100 babies but to be able to actually answer the question, eventually, is this effective and does it improve cure rates, we’re going to need more infants than that. It takes a much larger trial. So, that’s really exciting because there’s going to be an international infant ALL trial that we’re also participating in, and I've been helping with making the plans for that trial. So, the idea would be, if the pilot trial shows the safety of the combination of the demethylating agent with chemo, then we’ll be taking that on an international level, and we have colleagues in Europe and Japan that are very excited. There’re also testing this in pilot form and then we’re all going to be testing it together in babies around the world.
Dr. Mike: Wow, that’s awesome. I guess the exciting part of this is understanding some of the pathophysiology going, on. The hypermethylation/demethylation makes perfect sense. Of course, we can write that up in biochemistry easy but that always doesn’t translate well into human physiology.
Dr. Guest: Right.
Dr. Mike: So, this is exciting research. This is a tough question, Dr. Guest, but this is an exciting field of medicine you’re in with genomic research. So, when you look at it, not even just in infant leukemia, just in cancer, in general, where do you see us going with genomic medicine? If you had a couple of lines to leave us with, what would you say about the future of genomic research, genomic medicine, and treating cancers?
Dr. Guest: I would say that it’s a critical piece to learning how to treat the cancer. We really need to understand the biology of what’s driving a cancer in the first place. But I think that while it started off as sequencing DNA, it’s going to be so much more than that. So, probably, maybe even more important than the actual sequence changes of the DNA itself will be the expression changes of the DNA. So, what is expressed in the RNA that then leaves the nucleus and goes make protein. So, methylation of DNA shuts off genes, shuts off expression and reversing that can turn genes on and turns back on expression. But there are lots of other epigenetic factors that lead to expression changes, too. So, while we may know that there’s a mutation in the DNA, what I think we really want to know is what gene is expressed, and how it that changed, how is the RNA changed, how is the protein downstream changed because that’s really ultimately the manufacturing pipeline that’s actually driving that cancer.
Dr. Mike: Right. Yes. That’s exciting, isn’t it? A lot of research. You could look at it from the gene level to the RNA level to the protein level and, obviously, it’s much more complicated than we can even imagine.
Dr. Guest: Right. And with the sequencing we’re doing in leukemia cells, we’re taking a comprehensive approach. So, we are sequencing the entire genome but we’re also going deeper and sequencing just the gene--just the exome of the expressed gene. We’re doing whole exome sequencing. We’re looking at the methylation changes of the DNA and then we’re also looking at the RNA expression. So, I think that comprehensive approach is what’s going to be needed ultimately for all different types of cancers to really get a good understanding of the biology that’s driving that cancer to grow.
Dr. Mike: Well, it’s fascinating work, Dr. Guest, and I want to thank you for what you’re doing in genomic medicine at Children’s Mercy and I also want to thank you for coming on this show today. You’re listening to Transformational Pediatrics with Children’s Mercy Kansas City. For more information, you can go to www.childrensmercy.org. That’s www.childrensmercy.org. I’m Dr. Mike Smith. Thanks for listening.