For kids with cancer, the treatment that cures them can also kill them.
Through the Genomic and Ontogeny Linked Dose Individualization and Clinical Optimization for Kids (GOLDILOKs) program, doctors can find a treatment not too big, not too small, but just right.
Listen as Dr. Jaz Tolbert explains that by finding the perfect dose, doctors can improve treatment outcomes and decrease treatment-related mortality.
Selected Podcast
Pediatric Cancer Medicines: Reducing Treatment-Related Mortality
Featured Speaker:
Learn more about Jaszianne A. Tolbert, MD
Jaszianne A. Tolbert, MD
Jaszianne A. Tolbert, 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. She is one of only a few pediatric hematologists/oncologists nationwide who is fellowship-trained in clinical pharmacology. She is currently conducting research through the Genomic and Ontogeny Linked Dose Individualization and Clinical Optimization for Kids (GOLDILOKs) program.Learn more about Jaszianne A. Tolbert, MD
Transcription:
Pediatric Cancer Medicines: Reducing Treatment-Related Mortality
Dr. Michael Smith (Host): So our topic today is, “Pediatric Cancer Medicines: Reducing Treatment-Related Mortality.” My guest is Dr. Jaz Ann Tolbert. She’s a pediatric hematologist/oncologist at Children’s Mercy and also an assistant professor of pediatrics at the University of Missouri, Kansas City School of Medicine. Dr. Tolbert, welcome to the show.
Dr. Jaz Ann Tolbert (Guest): Thank you.
Dr. Smith: So let’s first talk a little bit about treatment-related mortality. What kind of numbers are we talking about here?
Dr. Tolbert: We define treatment-related mortality in a few different ways, but when you think about children who survive five years from their cancer, about 60% of those who actually die are related to the recurrent disease. A lot of the disease relapses – new diseases are their old diseases, and some of those are actually related to some of the chemotherapy that we administer.
Now there are some of the kids, a good percentage for them, and specific diseases, that will die from the actual treatment that we give, so it’s a huge problem. We still are able to achieve good cures, but we have to figure out a way to fight the cancer, but not make the kids so sick that they don’t live on to enjoy the cure from the cancer.
Dr. Smith: Right, it’s just one of those things where we have these powerful drugs that can target rapidly metabolizing cancerous cells, but they’re not very specific, correct?
Dr. Tolbert: Exactly.
Dr. Smith: So they’re also targeting some of those other metabolic cells – heart muscle, gastrointestinal cells, etcetera, etcetera. So when you look at the problem as a whole – when you see that we have some chemotherapy agents that really can take care of the cancer but have those side-effects, where do you see is the greatest opportunity then in reducing the mortality in these kids?
Dr. Tolbert: I think it’s going to be in the movement that everybody is sort of jumping on right now and it’s in the arena of personalized medicine. When we talk about personalized medicine, we can individualize medicine towards a disease and towards a specific person. That’s actually what we’re working on here at Children’s Mercy. It’s exactly like you said, right now we use the big gun approach where we have these drugs that we’ve had for awhile, and they do a great job at getting rid of the cancer, but they also attack all of the other healthy cells that are not cancerous. That’s how we end up with a lot of these late effects like the cardiovascular effects, obesity, and things of that nature, and even the secondary cancers that they can get from the drugs, but if we focus on the cancer cells themselves, what is unique about each person and their cancer, then we can target the therapies just to those cells and to that person’s unique properties so that they don’t experience as many of these side effects, and we still get the great effect of achieving a cure.
Dr. Smith: Right, so all of this is what is referred to as the Goldilocks Program, correct? Why don’t you tell us a little bit more about that? And specifically, Dr. Tolbert, how are you doing that? How are you identifying that specific cancer in a child and how you go about personalizing the treatment?
Dr. Tolbert: Yes, so the Goldilocks Program is based on the concept of – sort of like “Goldilocks and the Three Bears” is where the name came from. We’re looking for a dose that’s not too big for the child, one that’s not too small for the child, but one that’s just right for the child and the cancer.
Dr. Smith: I see.
Dr. Tolbert: And it doesn’t just apply to hem/onc. We’re actually using it across many disciplines, so all of the disciplines in pediatrics. So what we do in Goldilocks, or what I’m doing, is focusing on oncology and trying to find the right dose for these patients and their cancer that will cure the disease and will not make them sick and will actually prevent the disease from relapsing. The way I do that is to focus not on the actual dose of the drug, but on what we call exposure, so how much of that drug is actually getting into the body and getting into those cancer cells to do with it needs to do? We do that through a variety of ways, by measuring drug levels and then looking at things that affect that exposure, so what actually affects how much of that drug gets into a person. One of the things we’ve found is the genomics. Pharmacogenomics is another arena that we use in Goldilocks, and it looks at the genetic changes that a person or a disease has that affects how they metabolize the drugs and therefore would affect how much of a drug gets into the body.
Dr. Smith: Stepping back for a moment, when we administer chemotherapy, there are things – lifestyle things, genetic things, what have you – behavioral things – that actually can disrupt how well, or increase too much, how that drug is absorbed, how it’s taking to the cancer, so what you’re doing is trying to map out those things that can influence how exactly that drug is going to behave in that person, right? So that’s where you’re able to individualize the dose. How successful have you been with this, Dr. Tolbert, so far?
Dr. Tolbert: So far we’ve actually completed one study, and we have a couple of other studies developing. The first study was to look at how obesity actually affects how much drug gets into the body and how that ultimately affects if somebody’s going to be cured or if they’ll relapse. We know that in childhood leukemias that patients who are obese have a higher risk of having the disease come back and it has been shown that obesity is a major contributor to that. We haven’t really understood why, but there are some enzymes that people who are obese have that people who are not obese to not have. Those enzymes actually break down the drug so they keep you from getting the amount you need into the blood stream to have the effect that it needs to have on the cancer. Our first study focuses on obese patients and non-obese patients with cancer and how much exposure they were getting off a particular drug, which is mercaptopurine, that we use in leukemia patients. That data is being analyzed right now and will be ready for presentation, but we’ve found is pretty interesting, that there are --
Dr. Smith: When you’re saying this story it kind of reminds me of the whole epigenetic-type of research that’s going on. We know that our genes aren’t just set in stone, they’re more like blueprints and certain things that we do – whether it’s being overweight, underweight, drinking – whatever it is, we can influence how some of those genes are expressed, so in this case obesity in children is expressing certain genes that are creating enzymes that are breaking down the drugs and that’s causing them to have less effect. That’s amazing that we’re actually connecting that to this idea of epigenetics now. Besides obesity, what are the other things you’re looking at that may influence how a chemo drug is metabolized in a child?
Dr. Tolbert: The other thing that we’re going to look at going forward are we’re going to focus more on the pharmacogenomics. Some of these patients actually have a genetic mutation, and those specific mutations affect how you metabolize particular drugs. We identify that there are some of these genetic mutations that exist in different people and that in some of these people they have a higher risk of getting toxicities or horrible side-effects from the chemo drugs that we give, but we don’t understand how the two correlate. We’re focusing on that with pediatric cancer drugs in our next two trials here at Children’s Mercy, that I’m working on, and what we’ll do is we can take the mutation that we find, correlate it with how the patients respond to the drug or the exposure that they get and then develop drugs – or use that information to tailor or individualize the dose that they would need.
Right now, the way we dose our drugs in pediatric cancer is we give everybody the same body surface area dose and what we’re realizing is that we really should change that and one of the things we should base that on is whether or not they have specific genetic mutations that cause them to metabolize drugs a little bit differently.
Dr. Smith: This really is changing the way we study pharmacology, right? I see here you did a fellowship in clinical pharmacology, so you’re much more experienced at it than I am. I just remember back in medical school we assumed everybody was the same when we learned the drugs, right? You take a drug; it gets in at a certain rate, the liver metabolizes at a certain rate, you excrete it at a – we call that pharmacokinetics. We assumed everybody was the same in that, but that’s a bad way to learn pharmacology isn’t it?
Dr. Tolbert: It is.
Dr. Smith: We’re recognizing all the ways –
Dr. Tolbert: And now we’re realizing that maybe we made some bad assumptions.
Dr. Smith: Right, right.
Dr. Tolbert: Even when you look at pediatrics compared to adults, we know that a child is not just a small adult and I think we used to be of that thought and now we realize that, no, that’s not correct. We really need to treat these children as an individual population so we can’t just take an adult drug and give it to a child and expect it to behave the same because as you mentioned, pharmacokinetics, pharmacogenomics and all of those things – development in children – it’s all different and so those things change over time as a child develops. We really have to focus on pediatrics as its own entity, and we realize that now and that’s what we’re doing. You can’t just take that one-fits-all-approach, which is kind of how Goldilocks was developed.
Dr. Smith: Right. So, ultimately what you’re doing, Dr. Tolbert, is you’re taking this idea of dose personalization, looking at not just the genetics, but the epigenetic effects as well and you are maximizing benefit and reducing risk as to its lowest point and so the result obviously you should be very successful with this approach. Thank you, for the work that you’re doing. I think that this is really the wave of the future. You’re on the cutting edge of it, and I’m excited to see where your research takes you. And also, Dr. Tolbert, thank you for coming on the show today. You’re listening to Transformational Pediatrics, and for more information, you can go to ChildrensMercy.org, that’s ChildrensMercy.org. I’m Dr. Mike Smith, thanks for listening.
Pediatric Cancer Medicines: Reducing Treatment-Related Mortality
Dr. Michael Smith (Host): So our topic today is, “Pediatric Cancer Medicines: Reducing Treatment-Related Mortality.” My guest is Dr. Jaz Ann Tolbert. She’s a pediatric hematologist/oncologist at Children’s Mercy and also an assistant professor of pediatrics at the University of Missouri, Kansas City School of Medicine. Dr. Tolbert, welcome to the show.
Dr. Jaz Ann Tolbert (Guest): Thank you.
Dr. Smith: So let’s first talk a little bit about treatment-related mortality. What kind of numbers are we talking about here?
Dr. Tolbert: We define treatment-related mortality in a few different ways, but when you think about children who survive five years from their cancer, about 60% of those who actually die are related to the recurrent disease. A lot of the disease relapses – new diseases are their old diseases, and some of those are actually related to some of the chemotherapy that we administer.
Now there are some of the kids, a good percentage for them, and specific diseases, that will die from the actual treatment that we give, so it’s a huge problem. We still are able to achieve good cures, but we have to figure out a way to fight the cancer, but not make the kids so sick that they don’t live on to enjoy the cure from the cancer.
Dr. Smith: Right, it’s just one of those things where we have these powerful drugs that can target rapidly metabolizing cancerous cells, but they’re not very specific, correct?
Dr. Tolbert: Exactly.
Dr. Smith: So they’re also targeting some of those other metabolic cells – heart muscle, gastrointestinal cells, etcetera, etcetera. So when you look at the problem as a whole – when you see that we have some chemotherapy agents that really can take care of the cancer but have those side-effects, where do you see is the greatest opportunity then in reducing the mortality in these kids?
Dr. Tolbert: I think it’s going to be in the movement that everybody is sort of jumping on right now and it’s in the arena of personalized medicine. When we talk about personalized medicine, we can individualize medicine towards a disease and towards a specific person. That’s actually what we’re working on here at Children’s Mercy. It’s exactly like you said, right now we use the big gun approach where we have these drugs that we’ve had for awhile, and they do a great job at getting rid of the cancer, but they also attack all of the other healthy cells that are not cancerous. That’s how we end up with a lot of these late effects like the cardiovascular effects, obesity, and things of that nature, and even the secondary cancers that they can get from the drugs, but if we focus on the cancer cells themselves, what is unique about each person and their cancer, then we can target the therapies just to those cells and to that person’s unique properties so that they don’t experience as many of these side effects, and we still get the great effect of achieving a cure.
Dr. Smith: Right, so all of this is what is referred to as the Goldilocks Program, correct? Why don’t you tell us a little bit more about that? And specifically, Dr. Tolbert, how are you doing that? How are you identifying that specific cancer in a child and how you go about personalizing the treatment?
Dr. Tolbert: Yes, so the Goldilocks Program is based on the concept of – sort of like “Goldilocks and the Three Bears” is where the name came from. We’re looking for a dose that’s not too big for the child, one that’s not too small for the child, but one that’s just right for the child and the cancer.
Dr. Smith: I see.
Dr. Tolbert: And it doesn’t just apply to hem/onc. We’re actually using it across many disciplines, so all of the disciplines in pediatrics. So what we do in Goldilocks, or what I’m doing, is focusing on oncology and trying to find the right dose for these patients and their cancer that will cure the disease and will not make them sick and will actually prevent the disease from relapsing. The way I do that is to focus not on the actual dose of the drug, but on what we call exposure, so how much of that drug is actually getting into the body and getting into those cancer cells to do with it needs to do? We do that through a variety of ways, by measuring drug levels and then looking at things that affect that exposure, so what actually affects how much of that drug gets into a person. One of the things we’ve found is the genomics. Pharmacogenomics is another arena that we use in Goldilocks, and it looks at the genetic changes that a person or a disease has that affects how they metabolize the drugs and therefore would affect how much of a drug gets into the body.
Dr. Smith: Stepping back for a moment, when we administer chemotherapy, there are things – lifestyle things, genetic things, what have you – behavioral things – that actually can disrupt how well, or increase too much, how that drug is absorbed, how it’s taking to the cancer, so what you’re doing is trying to map out those things that can influence how exactly that drug is going to behave in that person, right? So that’s where you’re able to individualize the dose. How successful have you been with this, Dr. Tolbert, so far?
Dr. Tolbert: So far we’ve actually completed one study, and we have a couple of other studies developing. The first study was to look at how obesity actually affects how much drug gets into the body and how that ultimately affects if somebody’s going to be cured or if they’ll relapse. We know that in childhood leukemias that patients who are obese have a higher risk of having the disease come back and it has been shown that obesity is a major contributor to that. We haven’t really understood why, but there are some enzymes that people who are obese have that people who are not obese to not have. Those enzymes actually break down the drug so they keep you from getting the amount you need into the blood stream to have the effect that it needs to have on the cancer. Our first study focuses on obese patients and non-obese patients with cancer and how much exposure they were getting off a particular drug, which is mercaptopurine, that we use in leukemia patients. That data is being analyzed right now and will be ready for presentation, but we’ve found is pretty interesting, that there are --
Dr. Smith: When you’re saying this story it kind of reminds me of the whole epigenetic-type of research that’s going on. We know that our genes aren’t just set in stone, they’re more like blueprints and certain things that we do – whether it’s being overweight, underweight, drinking – whatever it is, we can influence how some of those genes are expressed, so in this case obesity in children is expressing certain genes that are creating enzymes that are breaking down the drugs and that’s causing them to have less effect. That’s amazing that we’re actually connecting that to this idea of epigenetics now. Besides obesity, what are the other things you’re looking at that may influence how a chemo drug is metabolized in a child?
Dr. Tolbert: The other thing that we’re going to look at going forward are we’re going to focus more on the pharmacogenomics. Some of these patients actually have a genetic mutation, and those specific mutations affect how you metabolize particular drugs. We identify that there are some of these genetic mutations that exist in different people and that in some of these people they have a higher risk of getting toxicities or horrible side-effects from the chemo drugs that we give, but we don’t understand how the two correlate. We’re focusing on that with pediatric cancer drugs in our next two trials here at Children’s Mercy, that I’m working on, and what we’ll do is we can take the mutation that we find, correlate it with how the patients respond to the drug or the exposure that they get and then develop drugs – or use that information to tailor or individualize the dose that they would need.
Right now, the way we dose our drugs in pediatric cancer is we give everybody the same body surface area dose and what we’re realizing is that we really should change that and one of the things we should base that on is whether or not they have specific genetic mutations that cause them to metabolize drugs a little bit differently.
Dr. Smith: This really is changing the way we study pharmacology, right? I see here you did a fellowship in clinical pharmacology, so you’re much more experienced at it than I am. I just remember back in medical school we assumed everybody was the same when we learned the drugs, right? You take a drug; it gets in at a certain rate, the liver metabolizes at a certain rate, you excrete it at a – we call that pharmacokinetics. We assumed everybody was the same in that, but that’s a bad way to learn pharmacology isn’t it?
Dr. Tolbert: It is.
Dr. Smith: We’re recognizing all the ways –
Dr. Tolbert: And now we’re realizing that maybe we made some bad assumptions.
Dr. Smith: Right, right.
Dr. Tolbert: Even when you look at pediatrics compared to adults, we know that a child is not just a small adult and I think we used to be of that thought and now we realize that, no, that’s not correct. We really need to treat these children as an individual population so we can’t just take an adult drug and give it to a child and expect it to behave the same because as you mentioned, pharmacokinetics, pharmacogenomics and all of those things – development in children – it’s all different and so those things change over time as a child develops. We really have to focus on pediatrics as its own entity, and we realize that now and that’s what we’re doing. You can’t just take that one-fits-all-approach, which is kind of how Goldilocks was developed.
Dr. Smith: Right. So, ultimately what you’re doing, Dr. Tolbert, is you’re taking this idea of dose personalization, looking at not just the genetics, but the epigenetic effects as well and you are maximizing benefit and reducing risk as to its lowest point and so the result obviously you should be very successful with this approach. Thank you, for the work that you’re doing. I think that this is really the wave of the future. You’re on the cutting edge of it, and I’m excited to see where your research takes you. And also, Dr. Tolbert, thank you for coming on the show today. You’re listening to Transformational Pediatrics, and for more information, you can go to ChildrensMercy.org, that’s ChildrensMercy.org. I’m Dr. Mike Smith, thanks for listening.