On this episode of the Healthcare Triage podcast, Aaron is talking to Dr. Karen Pollok and Dr. Jamie Renbarger about their research into the treatment of osteosarcoma and other pediatric cancers using personalized medicine. You'll learn about the development of cell lines and creation of models that can be used to battle cancers. We'll also hear about the experiences of one patient, Tyler Trent, who wondered about how the tissues he contributed to the research were used, and whose curiosity and willingness to share what he learned with the public has helped raise awareness of this kind of treatment.
The Healthcare Triage podcast is sponsored by Indiana University School of Medicine whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education, research and patient care.
IU School of Medicine is leading Indiana University's first grand challenge, the Precision Health Initiative, with bold goals to cure multiple myeloma, triple negative breast cancer and childhood sarcoma and prevent type 2 diabetes and Alzheimer’s disease.
Dr. Aaron Carroll: Hi, welcome back to the Healthcare Triage Podcast. This Healthcare Triage Podcast is sponsored by Indiana University School of Medicine, whose mission is to advance health in the state of Indiana and beyond by promoting innovation, and excellence in education research, and patient care. IU School of Medicine is leading Indiana University's first Grand Challenge, the Precision Health Initiative, which we're going to talk about in detail today. With bold goals to cure multiple myeloma, triple negative breast cancer and childhood sarcoma, and prevent type 2 diabetes and Alzheimer's disease.
We have two guests today, one of them is returning, it's Jamie Renbarger. She's the Caroline Symmes Professor of Pediatrics and Pediatric Cancer Research, at Indiana University School of Medicine. And joining her will be Karen Pollok, she's an Associate Professor of Pediatrics at Indiana University School of Medicine, and the Well Center for Pediatric Research. I guess that's the Herman B Wells Center for Pediatric Research. But both of you welcome.
Dr. Jamie Renbarger: Thank you. Welcome.
Dr. Karen Pollok: Thank you so much.
Dr. Aaron Carroll: So, we've talked to Jamie before, who is an MD and a Pediatric Oncologist, but I wanted to talk a little bit with you Karen, and talk about what you do and how you got here. So, first of all, specifically, what is your area of focus on research?
Dr. Karen Pollok: Sure, my background is I got a PhD at the University of Kentucky. And so, I continued with Immunology Training for my first Postdoctoral Fellowship at IU, and got very interested in using my basic research skills and applying it to patients and getting a little bit more into the preclinical type of research. And so, the Herman B Well Center had been established at IU, and I did a second Postdoctoral Training Fellowship over in the Well Center for Pediatric Research, and I've been there ever since. It's a great training ground to really take your basic skill sets and start applying it to clinically relevant questions. So, that's how I ended up in the Well Center, was an interest that I had.
Dr. Aaron Carroll: So, can you expand on that a little bit more when you talk about taking basic science and then applying. Because I think when most people think about basic science, it's either working obviously in a lab, but small specific things that I hear people talk about, they got to get into a niche, and you got to really focus, focus, focus. So, when you talk about taking something and then applying it, what exactly do you mean?
Dr. Karen Pollok: So, when I started my training, it was, as you said, very kind of niche oriented, you worked on one element of cancer, maybe. But what's happened now with more bridge between basic scientists and clinicians is that it's become very multidisciplinary research. So, where you may have been on your own one little lane as you move up in your career to establish a successful research program, you have to know a lot about many things. And you can't necessarily be an expert in everything, but you begin to develop teams that you work with. So, I had very basic skills working in cell culture, how do cells respond to specific drugs, we also do a lot of mouse modeling where we work with human tumor samples.
And so, I was doing all this type of work in the Well Center, working on various cancers. And then Jamie and I started talking about five or six years ago, to kind of start bridging things a little bit more. And that's when really the Precision Genomics program was starting. So, I started with really good basic skill sets working in the laboratory. But then being able to take that knowledge and start addressing clinically irrelevant questions that the oncologist will pose.
Dr. Aaron Carroll: I think lots of listeners will be surprised to know that's not common in the idea that you're going to take research here and then try to figure out how do we advance it to the next level, or how do we make it actually more clinically relevant? Is a relatively new thing in research, and then some a lot of institutions are clearly doing it better than they used to, but it is amazing how siloed things usually are. So, I wonder if you could just talk about that a little bit.
Dr. Karen Pollok: Absolutely. I think that's one thing that we are really proud of is that we're not working in silos. So if you go to the Well Center for Pediatric Research, there is a walkway that connects our research building to the clinical side. And on each side of it, it says connecting research with kids. And so that is a big mission of the Well Center is to really find ways to bridge that gap. And one way we have done it, is getting patient samples. Children of high cancer at Riley Hospital come in, and in certain cases there is sufficient tissue to donate to research.
And so, one example would be the Tyler Trent case, where Tyler was able to donate two samples. The samples of course get the diagnosis done. We work with the pathology department. When there is extra tissue, we can bring it back to the lab and actually begin to make different types of models to study very rare relapsed osteosarcoma in the case of Tyler Trent. And so, that is one connection we have. But it's even more than that. We get the patient tissue, we make models that we can study for years to come. But we also analyze these samples and then talk with Jamie and the Oncology Group about, how do we prioritize all of these different options we have to look at different therapies to treat in this case, the Tyler Trent osteosarcomas samples.
Dr. Aaron Carroll: So, one of the things we wanted to talk about today is, it's specifically known as the Tyler Trent model. But it's a specific, I believe, research model and way of doing this and growing tissue with a patient that we actually know, which is pretty rare. I think in pediatric research, where most times donations are anonymous and not connected to individual patients. So, could you talk about that for a bit?
Dr. Karen Pollok: Yeah, a couple of things. I think the main thing is Tyler himself. I think it was one of those situations he was a young adult. At the time, he's a freshman at Purdue. He really established a platform and that he was so inquisitive about what was going on. And when we get tumor samples to the lab, we do not know who they came from, because HIPAA regulation, everything's de-identified. We don't know anything. Jamie and her group may know who they came from. But that's how we go about the research business, is that you have this channel, I guess cavern between the two, you don't know the name.
But what happened in the Tyler Trent case is he was so curious about, "Hey, guys I know twice when I went through surgery, I donated a sample. Do you know what happened to that?" And so Jamie and the group talked with Tyler, they talked with his parents, and said, "This is not typically the way it goes, but you guys are giving us permission. We'll contact Dr. Pollock's lab, and they'll break their code."
And so, we already had the models. That would have been fall of 2018, we had the models. And Jamie said, "Can you all look that up, we've got permission." And we're like, "We actually have two models from this one." And these models are what we call well behaved in terms of, unfortunately under very aggressive models. But every time you take that cell and you put it in the mouse, it grows. It's very well behaved model. So, we already had two that we were working on. And so, that's how it went. And then Tyler was already so engaged wanting to know what was going on. And it just went from there, really.
Dr. Aaron Carroll: I've got to be honest, I'm a bit surprised. So, I understand people want that anonymity that they absolutely should get it, but I would think lots of people would want this to happen, that they'd want to know what happened with this with the tissue that they donated, and what is going on with it. It's that not the case?
Dr. Karen Pollok: Definitely. Since this has started, there have been a couple of families that are particularly interested. We're very careful-
Dr. Aaron Carroll: As we should be. Anonymity should be the default, there's no question.
Dr. Karen Pollok: And that we had a lot of a lot of discussion before making a decision about what to do in Tyler's situation, and how to manage his request. Because we felt strongly and clear that this was an information that could be used to help inform his treatment. And at the time, he was actually approaching end of life. And really felt like he wanted this information while he was still around to see the potential impact that his donation and that the work that our team has done with his tissue, and how that may be able to help other people. So, we went to their home just a couple of weeks before he passed away. And had a long conversation with him, including reviewing results. That was really, really powerful.
Dr. Jamie Renbarger: The families that do get involved, you can see it really helps them. And I think with Tyler's family, we had lots of discussions about... We had a lot of press a couple of weeks ago and back in December, and we have many groups asking us, "We want an update, we want an update. We know that you all made these models a year ago. So, what's been going on?" And we were very cognizant of the fact that, we have things to say, but we want to be reasonable about what we say and not over promise. But before that, we want to make sure that the family knows what's going on. And so, we held off on a lot of press releases until we had Kelly and Tony Trent come down to the medical center. And we actually had my lab meeting and Jamie joined as well, and talk to them about what we had, what it meant. And I think that's one reason the Tyler Trent case went so well, is we made sure we were always educating. Not over promising.
Dr. Aaron Carroll: So, important. Totally important.
Dr. Jamie Renbarger: It really is. Because I know if it was my child, I would want to grab hold of any and everything I could. But I think the trends have been so gracious. And so, they really listen. And they ask questions. And of course, they've been in this for a while, but a very special family. It's helped us in a lot of ways.
Dr. Karen Pollok: What I would add that it's not only impactful, I think for the families that are involved, but it's incredibly impactful for our team. Especially, it's been a really unique and special experience, I think to have interested families of kids with bad disease, come into the lab-
Dr. Jamie Renbarger: Very brave for them to come down there.
Dr. Karen Pollok: ... and sit down with our team and be so engaged. I think it really has given our team just a whole new level of motivation.
Dr. Aaron Carroll: I totally imagine too, we talked about siloing before, but to have all the way to basic science connected to these are the patients that you're trying to help but incredibly-
Dr. Karen Pollok: Never in a million years that I think I would be going to the home of a child who was dying from osteosarcoma. It's like a life altering experience for them. But just you know, the fact that the trends would come down there and be so brave too, after their son has even passed away, go into the laboratory and see their son cells growing in a Petri dish. I still haven't totally.
Dr. Aaron Carroll: I get. Wow!
Dr. Karen Pollok: But that's where we are with really connecting all these things, the basic scientists, the clinicians, and the community.
Dr. Aaron Carroll: That's a fantastic example. Here you have a tissue sample of a cancer. I'm assuming it's a particularly aggressive cancer, which is why would study it. So, what does that actually mean to make models? What do you do with it?
Dr. Karen Pollok: We have several different types of models we make. The ones that simulate the most of what's going on in a patient, or when we take the tissue and we put it in a mouse model. They're kind of special mice, they're immunodeficient, which means they do not have an immune system. So, you can take human samples, and you can implant them into the animals. And so, we have a whole team that we work with, that goes from the operating room and the pathology, brings the tissue... We actually had a case just last night was a Ewing sarcoma, and we have someone in the OAR watching making sure we get the type of sample we need that it's put in the right type of preservation media, and then the samples come back to the lab and within a couple of hours, they are already in the mice.
It can be very challenging sometimes to make these models. But this mouse model, you can take very small pieces of tissue. As an example would be Tyler, second surgery was an August of 2017. We got the sample in August, but it took us to January of 2018, to have sufficient tissue growing in the animals, so we could then start expanding it.
Dr. Aaron Carroll: So, in other words, you're trying out therapies for treatment purposes then.
Dr. Karen Pollok: Exactly. It's still fairly early discovery what we work on, but the beauty of the system is that we have Jamie and her colleagues backing us up and helping us prioritize what we should work on and what we shouldn't work on. Because you can imagine in science, there are tons of questions that you could ask. So, in the Tyler Trent case as an example, once we know we've established what we call xenograft, is what it's called, we then molecularly characterize that just like they did in the clinic to make sure we have the same mutational profile as the original sample. And for the most part we do, we're able to take that and so then we can look at that and start looking at what are some combination therapies that are under studied that haven't been explored.
Dr. Aaron Carroll: So, Jamie, is the treat the individual like Tyler, or is this now we want to find new ways to treat the broad cancer?
Dr. Karen Pollok: That's a great question. So, as Karen was describing, often the time from actually implanting the tumor in the initial mouse to propagating it into a whole group of mice that then you can use for a whole series of experiments can take many, many months. And so, this particular system isn't meant to inform treatment for that specific patient. But being able to correlate the results that we get in the animal model, with what actually happened with the patient can be incredibly valuable. So, really this is research that's intended to inform future treatment options.
Dr. Aaron Carroll: So, the idea is now we have tissue that we took from Tyler, and we now build a model.
Dr. Karen Pollok: And other patients as well.
Dr. Aaron Carroll: But just as an example.
Dr. Karen Pollok: Yes, absolutely.
Dr. Aaron Carroll: You're taking tissue from patients to build new mice models that then you can test therapies against, and hopefully find out things more quickly than you would with humans, is that correct?
Dr. Karen Pollok: Yes, and I think another beauty of this system too is that, we are establishing an integrated database, where you're going to have the mouse modeling data, but it's also linked to the clinical history of the patient. So, it isn't like it used to be in the old days, where maybe I walked down the lab hallway and said, "Hey, can I get an osteosarcoma line for you, I want to test it or whatever." Now, we're at a totally different layer, where we have samples from Riley Kids, where they know their whole treatment clinical history, and now we have the laboratory data. And so, what we're working on with the bioinformatics group through the precision Health Initiative, is to... In the computer, link all of this data. So over time, you have more and more of these cases, and over time it will clearly inform therapy.
Dr. Aaron Carroll: Are the cancers similar enough, that if you find out what works for one particularly aggressive form of osteosarcoma, it works for other osteosarcoma?
Dr. Karen Pollok: There's certainly main drivers; things that drive the cancers. So, what we find is there are overlaps for sure, but then there are differences. But we are grouping them into different buckets, like these are responders, these are more like a non-responder. Why does one group respond better than another group? And you can do that at the genomic level.
Dr. Aaron Carroll: And are there really big differences to what drugs the cancers will respond to?
Dr. Karen Pollok: There is. I think, in terms of the osteosarcomas, we found a novel combination therapy that hasn't been tested. And we find that in osteos, it looks like that might be the way to go, whereas in Ewing's we're not so sure about that. Even though they have some of the same molecular signatures, there's clearly some differences.
Dr. Aaron Carroll: And are you testing different drugs, or different amounts of the same drugs, or both?
Dr. Karen Pollok: Both.
Dr. Aaron Carroll: Interesting.
Dr. Karen Pollok: Yes. And that actually is a very insightful question.
Dr. Aaron Carroll: Thank you.
Dr. Karen Pollok: Because one of the challenges of doing this work is it's extremely expensive. And so, scientists are always looking for ways to find a cheaper way that's going to really have predictive value of what's going to happen in a mouse model or a patient. And so, we do a lot of drug screenings, where we're looking for, what is the concentration of each drug and combination that works better? And can we achieve those concentrations of drugs in the mice, and does that have any sense for a patient?
So, we're constantly looking at patient data for say a particular drug. And saying, "Well, what was the level of that drug they could achieve in the patient? Are we working in that range in the mouse model, in the tissue culture?" So, we're constantly going towards the human data when we can to look at concentrations of drug. Are we in a relevant range or in a range that doesn't have any bearing on reality?
Dr. Aaron Carroll: Why is it so expensive to do this kind of research?
Dr. Karen Pollok: First of all, there's a lot of regulation. We have lots of supplies that we have to use. You have to pay a lot of technical staff. I have 12 people in my lab that predominantly work on pediatric sarcomas. So, it takes a whole team to really do it. And then in this era of genomics, the price of doing all of these analysis is getting less expensive. But a lot of the more experimental approaches such as how do tumors adapt to a therapy, that's a big area that we're working in through the Precision Health Initiative, is the tumor adaptive response. Those types of tests are very expensive.
We just got a data set back on actually the Tyler Trent model on, we can halt the growth of Tyler cells, but if we take them off therapy they start growing back. How are these cells adapting? And so, we work with a core down at IU called the Proteomics Core. And just to do one experiment, just for the proteome analysis is going to be about $20,000, let alone probably the 30,000 that we had to donate towards the mice and the drugs and all that. So, it gets expensive really quickly.
Dr. Aaron Carroll: A lot of words that I need to ask about. So, you said genomics first, which is what I was thinking about when you said proteomics, but we'll get to that in a second. But when you say we'll check the genomics, what do we mean?
Dr. Karen Pollok: There's lots of layers to that. So, where we start over in the clinic is on a particular group of patients, they will do clinical grade genomic analysis. They actually take the sample and they ship it to a company, and they can get, it's called CLIA approved level, it's a very different level clinical grade sequencing.
Dr. Aaron Carroll: It was not 23andMe, we're looking?
Dr. Karen Pollok: Yeah, it's not 23andMe, exactly. And so, the precision genomics team, then they can take that data, how much ever they can get, and that can begin to help guide some of the treatments. So, that's step one. Over in our lab, we will then look at the DNA to make sure the DNA we're looking at out of our mouse model is identical to what they had in the patient. And then we can begin to look at the protein level, which is the level above the DNA level.
Dr. Aaron Carroll: I've asked this a multiple guests, and you've been really good. So, I'm hoping you're going to make me understand. When we say we look at the DNA, there's a gazillion, and that's the technical number, DNA pairs to look at. When we say look at the DNA, what do you actually mean? Is there just a computer that's spitting out-
Dr. Karen Pollok: Basically what happens is, the genome of whatever product you present to the company or to our research lab, they have a way that they can take small pieces of DNA that have been worked out ahead of time, and they can find where these small pieces of DNA will align with all the test sequences. And then you can begin to look at those sequences by amplifying them up. So, you have ways to go across the entire genome, because of previous samples, previous knowledge that you have, and look at the entire sequence.
Dr. Aaron Carroll: But isn't everyone's DNA different? How do you know?
Dr. Karen Pollok: There a lot of similarities. So, you have databases of normal people's DNA. So, even a normal person is going to have little differences anyway. We're going to respond to drugs differently, all these things. So, there is a lot of similarities. One of the filters that our bioinformatics group uses is called the 1000 normal genomes. So, they basically took either skin or peripheral blood from 1000 people, and they sequenced it, and they said, this is our range of normal. And they take the normal, and then they can filter it against the patient.
The other thing you do with a patient is you also take their peripheral blood. So, you have what you call their germline DNA. So, you have that, and then you have their tumor which is called their somatic. And you sequence both of those, and then you can also compare it that way as well.
Dr. Aaron Carroll: That makes a lot more sense to me. Because I think part of it is that, how do we know when we check someone against the 1000 normals? What would also be just normal variation versus this is bad?
Dr. Karen Pollok: Some people can have a bad gene, and they're still normal. Because it's in the context of their whole genome. So, Tyler Trent is a good example, we found what we call copy number variation where pieces of DNA have been amplified. There's like many of them. Instead of one MEK gene, there's four MEK genes, for instance.
Dr. Aaron Carroll: What's a MCEK gene?
Dr. Karen Pollok: So, MEK is a gene that encodes for a factor that increases growth of cells. Rapidly increases growth of cells. So, in Tyler's case, we found that he had an amplified MEK. And the interesting thing that you can do with the genomics is we got his samples and May and August of 2017, we made our models, we were like, "Oh, we're finding this MEK amplification once he's had this relapse." Eventually, we were able to go back to his original biopsy, from 2014 because they had stored a little piece of that tissue. And we weren't really expecting it, but that MEK gene was already amplified in his primary tumor. Down the road what Jamie and her group are doing is they want to find better predictors of relapse right up front, so they can bring that into the equation. And I think that's where the science really is now.
Dr. Aaron Carroll: And when you say better predictors, you're thinking like in others, we should start sequencing all the tumors to see if for instance, that there was that type of MEK mutation, to begin with?
Dr. Karen Pollok: Exactly. I think one of the key things, while what we're doing now, clinically with patients at the time of relapse, sequencing their genome, really selecting treatments based on what seems to be driving disease, with the hope that that's more likely to be beneficial than randomly selecting a traditional chemotherapy drug that that is much less specific. And we're finding that for some patients, even in Tyler's case, they can have great responses to that. But that's really scratching the surface. In the end, we don't want these patients to relapse. Because at that point, those tumors have evolved so much and adapted so much, that they are really good at finding ways to get around whatever we throw at them.
And so, our main goal really is to understand and to identify factors that are highly predictive. Even in people who we clinically wouldn't predict would go on to develop a recurrence, just these signals that say, "You need to watch this kid a little more closely or we need to consider modifying their treatment upfront to totally avoid recurrence at all."
Dr. Aaron Carroll: How do you change therapy to try to avoid recurrence? And then why don't we do that for everybody? What would be the, why not?
Dr. Karen Pollok: So, I think the simple question to why don't we do that for everybody right now is, we're not sure what to do with all that information at this point. Particularly in the setting of pediatric cancers, it becomes somewhat of an ethical question. If you have a disease, and you're treating a vulnerable population, so a child for something that with traditional therapy we may cure 70% of that population. Throwing something new into the mix without having a clear rationale, or having some way to predict that that patient, for example, a child with metastatic disease at the time of diagnosis, so not just a primary tumor, but also tumor that spread to other parts of the body, we know that that patient is at higher risk.
And so certainly, there are sub populations, there are groups of patients where we know it's okay and we need to be a little more aggressive because their risk of developing recurrent cancer is higher. But beyond that, certainly with certain types of diseases, and sarcoma is one of them, we don't necessarily have a great predictive algorithm or way to identify patients who are at high risk.
Dr. Aaron Carroll: I'm also assuming that trying to do things to prevent recurrence would involve a higher level of therapy that have a lot of bad side effects or problems that could potentially come from it as well?
Dr. Karen Pollok: Well, many of the newer, more molecularly targeted agents, as a group of drugs often have fewer side effects than traditional chemotherapy. What we don't necessarily understand so well is the risks when we combine them with standard chemo. And so yes, our concern is are we increasing the side effect profile? Are we putting kids at risk? However, one of the things we're really interested in is, in taking an approach similar to what's been done in diseases like breast cancer for a long time. And that is something called maintenance therapy, where patients get their upfront treatment, and then transition on to maybe even a single agent for a prolonged period of time in hopes that this simple or more targeted drug can actually take care of any cancer cells that are hanging out still. That we can't see on scans or measure in any way.
Our hope is to use the molecular profiling or baseline tumor sequencing to understand what's driving that disease. Select a targeted therapy, to transition patients on to when they're done with their standard chemo as a maintenance therapy for a more prolonged period of time to evaluate whether that may actually decrease risk of relapse or recurrence. In kids who we know when it comes back is bad.
Dr. Aaron Carroll: What do you mean by targeted therapy?
Dr. Karen Pollok: When we sequence a tumor, and in particular, a pediatric tumor, we can learn a lot about that disease and the cells that make up that tumor. Including not only DNA level information, but also what genes are revved up, RNA and protein levels, to really understand are there particular cell growth pathways that are making these cells grow. And then drug companies actually are now producing compounds drugs, newer agents that specifically target certain growth pathways as a way to disrupt that whole process. Again, rather than with traditional cytotoxic therapy, which I like to think of as a big hammer, much less specific, we're actually going after whatever process seems to be a driver in this cancer growing.
Dr. Aaron Carroll: Correct me if I'm wrong. I'd say like cytotoxic chemotherapy is mostly we go after cells that are just rapidly growing. And so, when you're talking about targeted therapies is not something so broad, but we're trying to actually go after certain proteins or things that are getting developed, and which brings me back to proteomics. When you say proteomics, is it instead of looking at the DNA you're looking at the proteins that it's making?
Dr. Karen Pollok: Yes. And the proteins are really the guys that are either keeping things normal or really messing it up. So, MEK is a good example, and that in Tyler's case, there was at least four copies of this. And so, he has had a high level of MEK proteins. So, you have DNA that gives you that first sequence. And then you have a process called transcription that comes along and makes RNA which is an intermediary, and then that RNA can be translated into protein. So, you can see there's multiple steps where things could get really dysregulated and messed up. So, in Tyler's case, and many of the cases we look at, there high levels of MEK protein, because that drives the cells to grow. And it can promote metastasis. It's a really bad guy when it's dysregulated.
Dr. Aaron Carroll: Why do we need proteomics and genomics?
Dr. Karen Pollok: Good question. So, there can be cases where you actually do have an amplification of a gene, but you don't make any more protein than a normal person. So, that DNA level is just... That technology is so well tuned these days, it's pretty accurate in everything but it doesn't give the whole story. And you can take samples that have been sitting around a while and you can get very good DNA out of them. When it comes to RNA and protein samples have been sitting around while things start to get messed up and can be degraded and things like that.
But in the models we have, we're getting a samples really quick and all this. And so, we can really look to see if there truly is protein dysregulation, meaning high levels of the protein affecting multiple growth factor pathways, for instance.
Dr. Aaron Carroll: Are you also trying to develop the treatments and the drugs as my target this, or is it you're you're coming up with these things and then reaching to the shelf of what already exists and trying to throw them at this?
Dr. Karen Pollok: So, that's the beauty of an academic center, we do both. So, we have biochemist at IU, that work in the realm of very early drug discovery actually making new compounds to target pathways and cancer that are dysregulated, where there's not a lot of drugs on the market. Wrasse is an instance where we have folks at IU working and many companies working on it too. So, you have that layer of early discovery, but it takes a long time for a drug to get to the clinic. So, the Precision Genomics program, our bigger focus is we want to work on drugs where something's known about an impatience. That's another challenge that Jamie and her group have is figuring out the doses to actually use in the pediatric patients.
Dr. Aaron Carroll: Because that I'm assuming it's different.
Dr. Jamie Renbarger: Sure, absolutely.
Dr. Karen Pollok: Can be.
Dr. Jamie Renbarger: It's one thing and someone like Tyler, who's a young adult or even an adolescent, but certainly for thinking about the practical application. Actually using a new drug with limited experience in children, in a five year old, or three year old can be very challenging.
Dr. Karen Pollok: How do you figure it out? Is it just a dose by weight? How do you figure that out?
Dr. Jamie Renbarger: So, often it's not a simple dosing by weight or extrapolation down. We do use body weight or more often body surface area to calculate dosing for children. The challenge is that it's not often a simple extrapolation down from what would have been given or what is given to adults. And so, even after a drug is in common use in adults or has gone through all the phases of drug development, clinical trials and adults, we redo those in children with a more aggressive timeline, because more is known about the drug than when it's first introduced into an adult. But certainly we have to go through very structured clinical trials to gradually work up the dose or increase the dose to ensure that it's safe. And in some cases now, even that we see biomarkers or predictors of the fact that it's reaching biologically relevant concentrations.
Dr. Karen Pollok: When we talk about osteosarcoma, how many drugs are there? Is it so many so you can think about it or is it like a handful, or something in between? I don't [crosstalk 00:34:22] I have no idea.
Dr. Jamie Renbarger: When we talk about osteosarcoma, certainly there are a handful of drugs that we use as part of our upfront treatment. And in fact, that same cocktail or group of drugs has been used for over 20 years. As we think about the opportunities for adding in newer compounds that becomes overwhelming there. The number of directions you could go certainly is finite, but there are many possibilities out there, many, many.
Dr. Karen Pollok: Are we talking like tens or hundreds? Is it just any drug you can imagine or it is-
Dr. Jamie Renbarger: I would say hundreds.
Dr. Karen Pollok: I would say hundreds.
Dr. Aaron Carroll: Really?
Dr. Karen Pollok: Yeah.
Dr. Aaron Carroll: This is why I literally have no idea.
Dr. Karen Pollok: And what happens is, you have different companies that will make a similar drug to the same protein. But those drugs will have little different behaviors to them.
Dr. Aaron Carroll: You're blowing my mind because I have no idea.
Dr. Karen Pollok: One of the drugs that we work up, Well, MEK is a good example. There are no drugs that directly inhibit MEK, but there are drugs that will prevent the transcription of MEK on it's way to becoming a protein. So, you're indirectly affecting it. And there are a number of these drugs out there. And they all have little different nuances about them on how they're going to work, how they're going to be metabolized in the body. So, we are constantly having discussions on which one... Say, we'll work with more of them in tissue culture, trying to understand the predictive value of these models. How can we prioritize the... We probably have thousands of drug combinations we've tested now and reached out on plastic. And only a few of them even go into our mouse models.
Dr. Aaron Carroll: When you say hundred, which again, I'm still trying to wrap my head around because I didn't know that. Is that for all kinds of cancer, or those are like hundreds of basically cancer drugs in general, or is it just specific?
Dr. Karen Pollok: Yeah. In general.
Dr. Aaron Carroll: And then it's just can't-
Dr. Karen Pollok: A lot of cancers as we said have similar pathways that can be dysregulated.
Dr. Aaron Carroll: I feel like in a regular Ron, I only hear about a handful, maybe it's just the ones they've commercials for, but it's-
Dr. Karen Pollok: Well, a lot are called a drug for a while, and then they get to trial, and they don't work and then they become what you call a research tool. So, they get worked at with in the laboratory a little bit more.
Dr. Aaron Carroll: And then if you figure and find an actual use for it, that's when they go back and they...
Dr. Karen Pollok: Unless there was toxicity, which is usually the biggest no-go.
Dr. Aaron Carroll: So, translating this to action and actual clinical care, what do we do with this now to treat patients?
Dr. Karen Pollok: In terms of the therapies that we've developed looking at Tyler's health?
Dr. Aaron Carroll: Is it now that you ask patients to get genomics and proteomics and see if there's similarities and that's how you choose different therapies?
Dr. Jamie Renbarger: It's probably at least two pronged. So certainly, as Karen described, creating buckets of tumor types, or of maybe osteosarcoma buckets, it's really based on the molecular profile on what we see. When we do sequence the tumors allows us to maybe better predict how they'll respond, and to use that in the future. Not quite yet, but in the future to help inform therapy. Really with some of the ongoing work now, where I see that going is a phase 2 clinical trial. A trial that would specifically evaluate a novel combination, so a new combination of drugs to be used in the setting of osteosarcoma, in this case, that recurs.
Dr. Aaron Carroll: We're not yet at the stage of truly targeting an individual's therapy, but this is helping us to find new therapies in general for perhaps like aggressive sarcoma.
Dr. Jamie Renbarger: Yeah, we do? [crosstalk 00:38:25] Yeah, certainly, we do target individuals therapy in a very specific way when we see them at the time of relapse. And certainly, I think the work that's going on in the lab is really helping us to refine our clinical decision making for those specific instances. My goal certainly is that some of the work that's happening in the lab now can actually be translated to not only the setting of relapse, but again, potentially ways that we would modify therapy treatment at the time of diagnosis to avoid relapse. And those require much more structured clinical trials.
Dr. Aaron Carroll: And you would figure that out by doing again, genomics and proteomics in early on?
Dr. Jamie Renbarger: More than likely, yes. Again, with the idea that modifying treatment for everybody doesn't necessarily make sense. But certainly if we can relatively cleanly predict kids with a high risk of relapse. So, maybe starting with a population that has disease at more than one site or metastatic disease at the time of diagnosis, to then add in novel agents to their standard, what we would consider a standard treatment if that makes sense.
Dr. Aaron Carroll: Is this something we're doing, something we are studying, or something we should study?
Dr. Jamie Renbarger: Through our cooperative groups, the Children's Oncology Group being the biggest in the United States. There always ongoing studies of new treatments often in the setting of relapse disease. But also even upfront treatment trials, we consider them or we call them clinical trials that are used at the time of diagnosis, where we make small changes in the what's considered the standard of care treatment, to try to make it better. Those studies are always ongoing. The trial is looking specifically at relapse disease, there always are a handful of those as well. And I think that will continue. Our hope is that the work that we're doing can really help to move things along a little more quickly, by giving us information to help refine our decision making, so that we can do a better job choosing treatments to add in for specific patients, if that makes sense.
Dr. Aaron Carroll: So, this has absolutely been fascinating. And I will tell you that I feel like I learned something, so hopefully everyone else did as well. But Jamie, Karen can't thank you enough. And I'm sure we'd love to have you back in the future to talk about advances and where things are going.
Dr. Karen Pollok: You bet. Thank you.
Dr. Jamie Renbarger: Yeah. Absolutely. Thank you.
Dr. Aaron Carroll: And again, this Healthcare Triage Podcast is sponsored by Indiana University School of Medicine, whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education, research and patient care.