Patients that have residual leukemia stem cells after chemotherapy and other treatments have substantially higher risk for relapse. Survival rates for relapsed leukemia are very poor. Even when patients survive long-term, the very toxic anti-cancer treatments are escalated in treating relapsed leukemia. This particularly risks long-term health and substantially increases the risk of early death due to side-effects of the treatment itself.
John Perry, PhD, faculty member of the Children's Research Institute at Children's Mercy Kansas City is studying how leukemia stem cells resist current anti-cancer treatments.
Join us for this podcast as Dr. Perry discusses the promise of low-dose doxorubicin as a targeted therapy against leukemia stem cells rather than a broadly toxic chemotherapy drug.
Selected Podcast
Targeted Therapy to Reduce Relapse of Pediatric Leukemia
Featured Speaker:
Learn more about John Perry, PhD
John Perry, PhD
John Perry, PhD is a Researcher, Children's Research Institute at Children's Mercy and Assistant Professor, University of Kansas Medical Center.Learn more about John Perry, PhD
Transcription:
Targeted Therapy to Reduce Relapse of Pediatric Leukemia
Dr. Michael Smith (Host): So our topic is targeted therapy to reduce relapse of pediatric leukemia. My guest is Dr. John Perry. Dr. Perry is a researcher at Children’s Research Institute at Children’s Mercy and Assistant Professor at the University of Kansas Medical Center. Dr. Perry, welcome to the show.
Dr. John Perry (Guest): Thank you.
Host: So let’s just start off with understanding a little bit about the whole relapse phenomenon here. First of all, who’s at most risk for relapse?
Dr. Perry: Well it depends on the type of leukemia and some of the leukemias are at very low risk, but others such as, what’s known as AML, acute myelogenous leukemia, have relapse rates of around 50%. They tend to be more rare, which is good but of course they still end up being hundreds of pediatric patients and thousands of adult patients every year. The problem with relapse is that once you’ve gone down that road, you have to escalate the therapy, your treatment options become fewer, and they become much more severe and they cause much worse side effects. So it’s a huge problem and it’s not as well understood as what we would like it to be.
Host: And relapse also has a poor outcome as well, right? So the survival is not all that great if you do happen to go down that path, right?
Dr. Perry: Yeah, so say there’s certain leukemias, like in pediatric patients there are certain types that are more than 90% cure rate, but for that 10% that are not cured and that do relapse, afterwards, it becomes less than half. The majority then will not survive say beyond five years after relapse. So your chances diminish at that point. So understanding that and getting a handle on it to cure it but also to just avoid ever going down that path to begin with because even if you do cure it, you’re going to have such severe treatment, you’re going to have long term side effects that are not going to be good.
Host: Right, right and I definitely want to talk about that a little bit more, but before we do, what do you think? What’s the theory then why some leukemias have a higher chance of relapse, and I guess another way of asking, Dr. Perry, is why do some residual leukemia cells persistent in some patients? What do we know about that?
Dr. Perry: Well that’s a really good question. There are two major theories and they’re not necessarily – they don’t necessarily exclude the other one. One of them is the cancer stem cell model. That’s basically where a cancer will be like a normal tissue in one sense and that it will be maintained and start with a stem cell like population and those stem cells are very rare and they’re relatively resistant to the therapies. So they persist. You can kill almost the entire cancer, 99.9% or more of the cancer, but these very rare cells persist and they have the ability to redevelop the cancer. The other one is just that cancers are just the product of evolution. They evolve and they evolve in part by being very diverse. There’s multiple different clones of the various cancer cells that are genetically distinct and you can kill perhaps the vast majority of them, but just because of the diversity inevitably, in many cases, some will persistent and then they’ll reestablish the cancer later on as they evolve, and those theories both could be true and both are true to different degrees depending on the particular patient and depending on the particular type of cancer and of course your cancer stem cells are also diverse and they can also evolve, so that’s really why that happens but why it happens in particular patients versus others are things we still need to learn a lot about.
Host: So you kind of touched on this a little bit. Obviously if a patient does relapse, the therapeutic options at that point aren’t all that great, and it usually just means more toxic chemo, right? So tell us a little bit about why in your research you decided to look more at some of these targeted therapies to reduce relapse, knowing that there’s not much we can do for somebody other than giving a lot more toxic drugs. So tell us a little bit about how you got into this research.
Dr. Perry: Yeah so initially I was trying to understand how just normal stem cells make more of themselves and we ended up using different mouse models in order to study the process, where you would alter different genetic pathways that would allow or even drive stem cells to make more of themselves, and that was for the purpose of ultimately expanding normal cells and culture potentially for therapy. Of course, in making this mouse model, where we had just this large expansion of normal stem cells, that mouse model, once you alter its DNA to do that, it didn’t just accumulate a bunch of normal stem cells and everything was okay, it ended up getting leukemia, and it got leukemia because some of those previously normal stems cells, by altering those genetic pathways, they formed leukemia stem cells and that fed the tumor, the cancer growth. And so we knew what we had done in order to form those leukemia stem cells and so it was a matter of doing a drug screen to find out what could inhibit that process and surprisingly, the thing that could inhibit it the best was a long use chemotherapeutic agent called doxorubicin. There’s a whole class of drugs that are very similar, and they have been long used chemotherapeutic agents, but we found that it could actually inhibit this process at a very low dose, and so the idea then became well we’re just not going to use it at it’s maximally tolerated dose like the whole theory of chemotherapy is, we’re going to use it as a targeting therapy just to inhibit the leukemia stem cells and to make a long story short, we were able to do that in the mouse model and preliminary evidence suggests we can do it in patients as well.
Host: So just to kind of summarize, what you’re saying is a low dose doxorubicin was able to inhibit the leukemia stem cells from – I guess creating more tumor, creating relapse essentially in the mouse model. So where are we at with this? That’s always my question. What great science, what great research that you’re doing, where are we at in the process of bringing this into clinical practice?
Dr. Perry: Well we’re at a reasonably advanced stage all things considered, but that is still a long way off. There’s a lot of resistance to changing current protocols, especially for pediatric patients, so there’s a lot of work to do in terms of getting around some of the regulations in order to make this current practice, but there is a different formulation of the drug that actually has lower exposure of the drug that works better and so they’re going to use that in a clinical trial comparing that different formulation that actually lower exposure of the drug to just the normal treatment and I’m in the process of getting some of those samples so I can look to see if this is actually inhibiting that leukemia stem cell in those ones that were given the lower exposed dose and then hopefully we can move it further along.
Host: That’s fascinating work Dr. Perry. In summary, what would you like general pediatricians, general practitioners, nurse practitioners, what would you like for them to know about reducing relapse of pediatric leukemia?
Dr. Perry: Well I would like them know that a lot of the drugs that they’re using aren’t always doing exactly what it’s been advertised that they do. They have a lot of different kinds of effects. One of the things that I see with the lower dose treatment is it actually stimulates the immune system to help kill the cancer. Now current practice they use a high dose and that’s actually immunosuppressive. It kills the immune system. Not necessarily a good idea, and also just especially for oncologists, that more is not always better. It seems that in that particular field, you never in any other practice of medicine, you would never think well if I take two aspirin it’s good so I should just take the whole bottle, nobody would ever think that, but for cancer therapy it’s always more, more, more and more is not always better.
Host: Very nice. I want to thank you Dr. Perry for the work that you’re doing. This research is really fascinating and I hope and wish you much success as you continue to study how to reduce relapse of pediatric leukemia. You’re listening to Transformational Pediatrics with Children’s Mercy Kansas City. For more information, you can go to childrensmercy.org, that’s childrensmercy.org. I’m Dr. Mike Smith. Thanks for listening.
Targeted Therapy to Reduce Relapse of Pediatric Leukemia
Dr. Michael Smith (Host): So our topic is targeted therapy to reduce relapse of pediatric leukemia. My guest is Dr. John Perry. Dr. Perry is a researcher at Children’s Research Institute at Children’s Mercy and Assistant Professor at the University of Kansas Medical Center. Dr. Perry, welcome to the show.
Dr. John Perry (Guest): Thank you.
Host: So let’s just start off with understanding a little bit about the whole relapse phenomenon here. First of all, who’s at most risk for relapse?
Dr. Perry: Well it depends on the type of leukemia and some of the leukemias are at very low risk, but others such as, what’s known as AML, acute myelogenous leukemia, have relapse rates of around 50%. They tend to be more rare, which is good but of course they still end up being hundreds of pediatric patients and thousands of adult patients every year. The problem with relapse is that once you’ve gone down that road, you have to escalate the therapy, your treatment options become fewer, and they become much more severe and they cause much worse side effects. So it’s a huge problem and it’s not as well understood as what we would like it to be.
Host: And relapse also has a poor outcome as well, right? So the survival is not all that great if you do happen to go down that path, right?
Dr. Perry: Yeah, so say there’s certain leukemias, like in pediatric patients there are certain types that are more than 90% cure rate, but for that 10% that are not cured and that do relapse, afterwards, it becomes less than half. The majority then will not survive say beyond five years after relapse. So your chances diminish at that point. So understanding that and getting a handle on it to cure it but also to just avoid ever going down that path to begin with because even if you do cure it, you’re going to have such severe treatment, you’re going to have long term side effects that are not going to be good.
Host: Right, right and I definitely want to talk about that a little bit more, but before we do, what do you think? What’s the theory then why some leukemias have a higher chance of relapse, and I guess another way of asking, Dr. Perry, is why do some residual leukemia cells persistent in some patients? What do we know about that?
Dr. Perry: Well that’s a really good question. There are two major theories and they’re not necessarily – they don’t necessarily exclude the other one. One of them is the cancer stem cell model. That’s basically where a cancer will be like a normal tissue in one sense and that it will be maintained and start with a stem cell like population and those stem cells are very rare and they’re relatively resistant to the therapies. So they persist. You can kill almost the entire cancer, 99.9% or more of the cancer, but these very rare cells persist and they have the ability to redevelop the cancer. The other one is just that cancers are just the product of evolution. They evolve and they evolve in part by being very diverse. There’s multiple different clones of the various cancer cells that are genetically distinct and you can kill perhaps the vast majority of them, but just because of the diversity inevitably, in many cases, some will persistent and then they’ll reestablish the cancer later on as they evolve, and those theories both could be true and both are true to different degrees depending on the particular patient and depending on the particular type of cancer and of course your cancer stem cells are also diverse and they can also evolve, so that’s really why that happens but why it happens in particular patients versus others are things we still need to learn a lot about.
Host: So you kind of touched on this a little bit. Obviously if a patient does relapse, the therapeutic options at that point aren’t all that great, and it usually just means more toxic chemo, right? So tell us a little bit about why in your research you decided to look more at some of these targeted therapies to reduce relapse, knowing that there’s not much we can do for somebody other than giving a lot more toxic drugs. So tell us a little bit about how you got into this research.
Dr. Perry: Yeah so initially I was trying to understand how just normal stem cells make more of themselves and we ended up using different mouse models in order to study the process, where you would alter different genetic pathways that would allow or even drive stem cells to make more of themselves, and that was for the purpose of ultimately expanding normal cells and culture potentially for therapy. Of course, in making this mouse model, where we had just this large expansion of normal stem cells, that mouse model, once you alter its DNA to do that, it didn’t just accumulate a bunch of normal stem cells and everything was okay, it ended up getting leukemia, and it got leukemia because some of those previously normal stems cells, by altering those genetic pathways, they formed leukemia stem cells and that fed the tumor, the cancer growth. And so we knew what we had done in order to form those leukemia stem cells and so it was a matter of doing a drug screen to find out what could inhibit that process and surprisingly, the thing that could inhibit it the best was a long use chemotherapeutic agent called doxorubicin. There’s a whole class of drugs that are very similar, and they have been long used chemotherapeutic agents, but we found that it could actually inhibit this process at a very low dose, and so the idea then became well we’re just not going to use it at it’s maximally tolerated dose like the whole theory of chemotherapy is, we’re going to use it as a targeting therapy just to inhibit the leukemia stem cells and to make a long story short, we were able to do that in the mouse model and preliminary evidence suggests we can do it in patients as well.
Host: So just to kind of summarize, what you’re saying is a low dose doxorubicin was able to inhibit the leukemia stem cells from – I guess creating more tumor, creating relapse essentially in the mouse model. So where are we at with this? That’s always my question. What great science, what great research that you’re doing, where are we at in the process of bringing this into clinical practice?
Dr. Perry: Well we’re at a reasonably advanced stage all things considered, but that is still a long way off. There’s a lot of resistance to changing current protocols, especially for pediatric patients, so there’s a lot of work to do in terms of getting around some of the regulations in order to make this current practice, but there is a different formulation of the drug that actually has lower exposure of the drug that works better and so they’re going to use that in a clinical trial comparing that different formulation that actually lower exposure of the drug to just the normal treatment and I’m in the process of getting some of those samples so I can look to see if this is actually inhibiting that leukemia stem cell in those ones that were given the lower exposed dose and then hopefully we can move it further along.
Host: That’s fascinating work Dr. Perry. In summary, what would you like general pediatricians, general practitioners, nurse practitioners, what would you like for them to know about reducing relapse of pediatric leukemia?
Dr. Perry: Well I would like them know that a lot of the drugs that they’re using aren’t always doing exactly what it’s been advertised that they do. They have a lot of different kinds of effects. One of the things that I see with the lower dose treatment is it actually stimulates the immune system to help kill the cancer. Now current practice they use a high dose and that’s actually immunosuppressive. It kills the immune system. Not necessarily a good idea, and also just especially for oncologists, that more is not always better. It seems that in that particular field, you never in any other practice of medicine, you would never think well if I take two aspirin it’s good so I should just take the whole bottle, nobody would ever think that, but for cancer therapy it’s always more, more, more and more is not always better.
Host: Very nice. I want to thank you Dr. Perry for the work that you’re doing. This research is really fascinating and I hope and wish you much success as you continue to study how to reduce relapse of pediatric leukemia. You’re listening to Transformational Pediatrics with Children’s Mercy Kansas City. For more information, you can go to childrensmercy.org, that’s childrensmercy.org. I’m Dr. Mike Smith. Thanks for listening.