Know Thyself: Precision Genomics and Pediatric Cancer
Hi Welcome back to the healthcare podcast. This healthcare chairs 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 I you. School of Medicine is leading Indiana. University's first grand challenge the precision health initiative. Which we're GONNA talk about in detail today with both goals to cure. Multiple Myeloma triple negative breast cancer and childhood. Sarcoma and prevent type two diabetes and Alzheimer's disease. We have two guests today. One of them is returning. It's Jamie Ran Bargar. She's the Carolina Sims professor of Pediatrics and Pediatric Cancer Research at Indiana University. School medicine and joining her will be Karen pollock. She's an associate professor of pediatrics. At Indiana University School of Medicine and the Will Center for Pediatric Research. I guess that's the Herman. B Wells Center pediatric research. But both of you welcome thank you thank you so much. So we've talked to Jamie before who is an MD in 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 sir My background is I got a PhD at the University Kentucky and a so I continued with immunology training for my first post doctoral fellowship at IU and got very interested and using my basic research skills and applying it to to patients and getting a little bit more into the preclinical type of research. And so the Herman be well. Center had been established. I you and I did a second post-doctoral training fellowship of the Wall Center for Pediatric Research. And have 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 Wall Center was an interest that I had. So can you expand on that a little bit more when you talk about taking basic science and then applying because I mean I think most people think about you know basic science. It's either working. I mean obviously in a lab but Sharon small specific things people talk but they got into a niche. And you got to really focus focus so when you talk about taking something and then applying it. What exactly do you mean so? When I started my training it was as you said. Very kind of niche oriented. You worked on one element of cancer. Maybe okay 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 began to develop teams that you work with so I had very basic skills. Working in cell culture had a cells respond to specific drugs. We also do a lot of mouse modeling where we work with human tumor samples and so I was already Kinda do. I was doing all this type of work on the wall center working on various cancers and then Jamie and I started talking about five or six years ago to start bridging things a little bit more and that's when we started really the precision nomex program was starting so I started. You know 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. I think lots of listeners will be surprised to know that that's not common in the idea that you're going to take research here and then try to figure how do we you know advance to the next level. Or how do we make it actually more clinically relevant is a relatively new thing In research and that some institutions are clearly doing it better than they used to but But it is amazing. How silo things usually are so I wonder if you could just talk about that a little bit? Yeah 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 wall 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 the one way we have done. It is Getting a patient samples Sherline had 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 to samples and it gets samples of course. Get the diagnosis done. We work with the pathophysiology department. When there is extra tissue we can bring it back to the lab and actually began to make different types of models To study these very rare relapsed. Osteo COMA 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 the ecology group about. How do we prioritize all of these different options? We have to look at different therapies to treat in this case Tyler. Trent OSTER COMA SAMPLES. So one of the things we wanted to talk about today is Specifically known as the Tyler Trent Model But it's a specific. I believe research model and way of doing this growing tissue with the patient that we actually know which is pretty rare. I think in pediatric research. Where most times donations are anonymous and not connected individual patient. So could you talk about that for a bit? 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 you know. 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 hip deregulation. Everything's de identify. 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. You know channel. I guess cavern between the two. You don't know the name but what happened tyler. Trent case is he was so curious about. Hey guys you know I know twice that I when I went through surgery. We 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 you know said you know this is not typically the way it goes but you guys are giving us permission will contact Dr Pollock's lab and they'll break their code and so we already had the models so in that would've been fall of twenty eighteen. We had the models and Jamie said. Can you 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 they're very aggressive models but every time you take that cell and put in the mouth a gross. It's very well-behaved model. So we already had to that we were working on. And so that's kind of how it went and then tyler was already so engaged Wanting to know what was going on. And it just went from there really. I got a bit surprise so I understand that one anonymity that they absolutely get it but I would think lots of people would want this to happen. That they'd want to know what happened with the with the tissue that they donated in what is going on with shirt and not the case. Definitely since since this has started there have been a couple of families that are particularly interested. We're very careful as anonymity. They we had a lot of law discussion. Four sort of making a decision about what to do in tyler situation and and how to manage his request Because we felt clear we felt strongly and clear that That this wasn't information that was could be used to help inform his treatment And at the time he was actually approaching end of life And and really felt like he wanted this information while he was still around to 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 his home to their home just a couple of weeks before he passed away and Had A long conversation with him including reviewing results that was was really really powerful. The families that do get involved. You can see it's 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 as we want an update. We wanted 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 not over promise Louis but before that we wanna 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 a 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 case went so well as we made sure we were always educating. It's not over promise. Totally it really is. Yeah because I know if it was my child I would wanNA grab hold of any everything I could but I think the trends have been so gracious and so They really listen And they asked questions and of course they've been in this for awhile but very special family right. It's helped us in a lot of ways when 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 absolutely especially yes been a really unique and special experience. I think to have interested families of kids with bad disease. Come into the loud brave for them. Bomb known there and sit down with our team. Nb So engaged gauged I think it really has given our team. Just whole new level of motivation Italy. Imagine to like it's yeah but silent before yes to have all the way to basic science connected to these are the patients that you are. Yeah trying to help. Never in a million never two million years did I think I would be going to the home of a child who was dying from Osteo Sarcoma like a life altering experience for them. Yeah but just you know the fact that the trance would come down there and be so brave to after their son is even passed away. Go into the laboratory and see their son cells growing petri dish that is. I still haven't totally process. I've that's A. That's yeah but that's where we are with really connecting all these things the basic scientists clinicians and the community. No that's that's a fantastic example. Here you have a tissue sample of cancer I'm assuming it's a particularly aggressive cancer. Which is why. Yeah so what? What does that actually mean to make models? What do you do with it? We have several different types of models. We make the ones that simulate the most of what's going on in a patient are when we take the tissue and we put it in a mouse model. These mice are They're Kinda special mice their immuno-deficient 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 pathophysiology brings a tissue. We actually had a case. Just last night was a ewing sarcoma and we have someone in the. Or WATCHING MAKING SURE. We get the type of sample. We need that. It's put in the right type of you know 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 this mouse model you can take very small pieces of tissue as an example would be Tyler second surgery was in August of two thousand seventeen. We got the sample in August but it took us to January of two thousand eighteen to have sufficient tissue growing in the animals so we could then start expanding it so in other words. You're trying out therapies for an act for justice for treatment purposes. Then exactly. It's it's still fairly early discovery. What we work on but the 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 and science. There are tons of questions that you could ask so in the tyler. Trent cases an example. Once we know we've established what we call xenografts is what it's called. We then molecular characterized 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 therapies combination therapies? That are under studied that haven't been explored so Jamie is this. Is this the treat the individual like tyler or is this now we want to find new ways? Treat the broad cancer now. That's a great question. So so as Karen was describing Often the time from actually implanting the tumor in the initial mouse to propagating into a whole group of mice. That then you can use for a whole series of experiments can take many many months And so So this particular system isn't meant to inform treatment for that specific patient But being able to to correlate the results that we get in the in the animal model with what actually happened with the patient can be incredibly valuable So really this is. Research intended to inform future treatment options. So the idea is now. We have tissue that we took from Tyler and we now built other places while 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 yes and I think another beauty the system to is that we are establishing a 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 the you know the lab hallway and said Hey can I get an osteo sarcoma line for you. I WanNa you know tested or whatever now who had a totally different layer where we have samples from Riley kids where they know their whole treatment. History 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 and are the cancer similar enough that if you find out what works for one particularly aggressive form of Osceola Sarcoma. It works for other. There's certainly main drivers things that drive the cancers so what we find is there overlaps for sure but then their differences but we are grouping them until like different buckets like these are responders. These are more like a non responder wide as one group respond better than another group and you can do that at the genomic level and her the really big differences to what drugs the Kansas will respond to. There is I think in terms of the OSTEO SARCOMAS. We've found a a novel combination therapy that hasn't been tested and we find that in. Osteo so it looks like that might be the way to go whereas in Ewing's were not so sure about that even they have some of the same molecular signatures. There's clearly some differences. You testing different drugs or different amounts of the same drugs or both both interest. Yes yes and that actually is a A very insightful question Yes because we 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 We're we're looking for. What is the concentration of each drug in 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 a particular drug and seeing 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 IRRELEVANT RANGE ARRANGE? It doesn't have any bearing on reality. So why when you say it. Why is it so expensive too? It's kind of research 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 twelve people in my lab that predominantly work on pediatrics. Komo's so it takes a whole team to really do it. And then in this era of genomics The price of doing all of these analyses is getting less expensive But a lot of the more experimental approaches such as had a tumor adapt to a therapy. That's 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 okay. 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 a you. Call the podium x corps and just to do one experiment just for the proteome analysis is GonNa be about twenty thousand dollars let alone probably the thirty thousand that we had to donate towards the mice and the drugs and all that so he gets expensive really quickly a lot of words that I need to ask about. So you said genomics I which is what I was thinking about when you said proteome mixed but we'll get to that in a second but when you say we'll check the genomics. What do we mean? 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 you know it's called clear approved level it's a very different level. Clinical grade sequencing does not twenty three and me. We're looking yeah. It's not twenty three and me exactly and so The precision genomics team than they can take that data. How much ever they can get and that can begin to help. Guide some of the treatments that stop 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. So we've I've asked all the action this multiple guests and you've been really good so I'm hoping you're GonNa make me understand when we say we look at the DNA. There's a gazillion and that's the technical number Dna Pairs look how when we say look at the DNA. What are you actually like? Is there just a computer spitting out see? Basically what happens is the 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 were these small pieces of DNA will align with all the test sequences and then you can begin to look at those sequences by amplify 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 but isn't everyone in a different. I mean how do you know 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 right. We're going to respond to drugs differently all these things so there is a lot of similarity so one of the filters that are bioinformatics. Group uses is called the thousand genomes but thousand normal genomes so they basically took either skin or prefer blood from a thousand people and they sequenced and they said this is our range of normal. Ohka and they take the normal and then they can filter it against the the patient. The other thing you do with a patient as you also take their personal blood so you have what you call their germline DNA so you have that and then you have their tumor which is called their semantic and you sequence both of those and then you can also compare it that way as well. That's okay that that makes a lot more sense twitchy because because I think part of it is that how do we know when we check someone against the thousand normals? What would also be just normal variation versus. This is bad. Some people can have a bad gene. And they're still normal right because it's in the context of their whole genome. Right so tyler. Trend is a good example. We found What we call copy number variations pieces of DNA have been amplified. There's like many of them. Instead of one mic gene. There's four mic genes for instance comic June so mic is a gene that encodes for a factor that increases growth of cells. Boca rapidly. Grossest growth of cells so and Tyler's case we found that he had an amplified mic. And the interesting thing that you can do with the genome. Ix is we got his samples in. May and August of two thousand seventeen. We made our models. We were like. Oh we fought refunding. This making implication. Once he's had this relapsed. Eventually we were able to go back to his original biopsy from twenty fourteen because they had stored a little piece of that tissue and we weren't really expecting it. But that nick gene was already amplified and his primary tumor. Okay so 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. And when you say better predictors thinking we should start sequencing all the tumors AC- Brenton's at there was that type of mixed mutation to begin with exactly exactly. I think one of the key things while what we're doing now Clinically with patients at the time of relapse sequencing the genome really selecting treatments based on what seems to be driving disease on with the hope that that's more likely to be beneficial than randomly selecting you know. What a traditional chemotherapy drug that that is much less specific And we're finding that for some patients even in Tyler's case on they can have great responses to that But that's really scratching the surface right 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 you know in. Our main goal really is to to understand and to identify factors. That are highly predictive. Even people who clinically wouldn't predict would go on to develop a recurrence Just these signals that Satan. You need to watch this this kid a little more closely or a lot more closely or we need to consider modifying their treatment upfront to totally avoid recurrence at all. How do you change therapy to try to avoid current shirt and then? Why don't we do that for everybody off the way not? Yeah so I think the simple question to. Why don't we do that for everybody? Right now is we're sure what to do with all that information at this point Particularly in the setting of pediatric cancers becomes somewhat of an an ethical question. Right if you have a disease and you're treating vulnerable population right so a child For something that with traditional therapy we may cure seventy percent of that population throwing something new into the mix without having a clear rationale or having some way to predict that that patient you know 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 has higher risk and so certainly on there are sub populations. There are groups of patients. Where we know. It's okay and we. We need to be a little more aggressive. Because their risk of developing recurrent cancer is is higher But beyond that certainly with certain types of diseases in sarcoma is one of them We don't necessarily have a great predictive algorithm or or way to identify patients who are at high risk so. I'm also assuming that you know trying to do things to prevent recurrence. When involve a higher level of people that have a lot of bad side effects or problems that could potentially come from it as well? Certainly you know while many of the newer more molecular targeted agents Has 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 Right And so yes. Our 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 onto 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 on that. We can't see on scans or measuring any way And so that's our hope is to use the molecular profiling or baseline tumor sequencing to understand what's driving that disease. Select targeted therapy to transition patients onto when they're done with their standard chemo as a maintenance therapy fermo more prolonged period of time to evaluate whether that actually decrease risk of relapse or recurrence In in kids who we know when it comes back as bad. What do you mean by targeted therapy? We sequence a tumor in in particular a pediatric tumor. We can learn a lot about that that disease and the the cells that make up that tumor Including not only DNA level information. But also what genes are revved. Up Right Aren. A 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 so again rather than with traditional set are toxic. Therapy which I like to think of as as a big hammer right much less specific. We're actually going after whatever process seems to be a driver in this cancer growing so correct me if I'm wrong so I'd say like cytotoxic. Chemotherapy is mostly. We go after cells. That are just rapidly growing. And so when you talk about targeted therapies. It's not. We're not something so broad but we're trying to actually go after certain proteins or things that are getting developed in which increase what is says it instead of looking at the DNA. You're looking at the proteins that making. Yes and the proteins are really the guys that are either keeping things normal or really messing it up right. So mic is a good example in that In Tyler's case there was at least four copies of this And so he has a had a high level of Mick proteins you have DNA the gives you that first sequence and then you have a process called transcription that comes along and makes aren a which is intermediary and that are in a can be translated into protein. Says the very so you can see. There's multiple stops where things could get really dis- related and must up so intolerance case. In many cases look up. There are high levels of Mick Protein. Because that drives the cells to grow it can promote metastasis. It's a really bad guy when it's dysregulation. Why do we need promex and genomics good questions so there can be cases where you actually do have an amplification of a gene? But you don't make any more protein than normal person so that DNA level is just you know that technology is so well tune these days. It's pretty accurate and everything but it doesn't give the whole story and it's 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 aren't a and protein of samples have been sitting around a while. Things start to get messed up and can be you know. It can be degraded and things like that but in the models we have were getting a samples really quick and all this and so we can really look to see if they are truly is protein does regulation meaning high levels of the protein affecting multiple growth factor. Pathways for instance. So then are we all. Are you also trying to develop the treatments? Drugs is 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. That's that's the beauty of an academic center. We do both so we have you know. chemist biochemist at. Iu that work in the realm of very early drug discovery actually making new compounds to target pathways and cancer. That are just regulated. Whether is not a lot of drugs on the market. Rask's is an instance where we have folks that you work in many companies working on it too so you have that layer early discovery but it takes a long time for a drug to get to. The clinic said the precision. Genomics program are bigger focuses. We want to work on drugs where something's known about an impatience you know that's another challenge that. Jamie and her group have is figuring out the doses to actually use the pediatric patients. Because that. I'm assuming it's different. Sure absolutely absolutely you know. It's it's one thing in in someone like Tyler who's a young adult or or even an adolescent but certainly for thinking about The practical application rates actually using a new drug With limited experience and children in a five year old or three year old can be reality. I mean is it just a dose by weight or is it I mean. How do you figure that? Yeah so So often it's not a simple dosing weight or extrapolation down. We do use Body weight or more often body surface area to calculate dosing for for children The challenges that it's not often a simple extrapolation down from what would have been given her what is given to adults And so they're even after a drug is is in common use and adults Or has gone through. All the phases of drug development clinical trials in adults. We redo those in children with a more aggressive timeline. Right because more is known about the drug than than it was when its 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 to ensure that it safe And in some cases now even that we we see biomarkers or predictors of The fact that it's reaching biologically relevant concentrations. How when we talk about something Augusta Sarcoma I mean? How many drugs are there? Is it like so many? It's like so he can't think about it or is it like a handful so yeah so so when you talk about When we talk about US yes. Or Coma Certainly. There are 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 twenty years as we think about the opportunities for adding in newer compounds That becomes overwhelming. They're you know the the number of directions you could go certainly is finite but but there are many possibilities out there. Many many every caulking like tens or hundreds I mean I is. It could imagine or hundreds. Yup Yeah Yeah. Yeah and and what happens is You have you know different. Companies that will make a similar drug to the same protein but those drugs will have little different behaviors to them. Because I had so like one at one of the drugs that you know. We work well MIC as sample. Okay and you. There are no drugs that directly inhibit mick but there are drugs that will prevent the transcription of MIC on. Its Way to becoming a pro team. 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 gonNA work how they're going to be metabolized. The body so we are constantly having discussions on which one said. We'll we'll we'll work with more 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 in vitro on plastic so only a few of them even go into our mouse models and when we say 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 are these are these like those are like hundreds of basically cancer drugs in general or is it. Okay General it's just as you can a lot of cancers as we said have similar pathways that can be disrupting the regular road. I only hear about a handful. Maybe it's just the ones they have commercials for but it's 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 okay. So they get worked at worth in the laboratory a little bit more. And then if you figure find an actual use for it that's when they go back and they unless there was talk subsidy which is usually the biggest no go okay so translate into action to actual clinical care like now do how does what do we do with this now. To treat patients in terms of the therapies that we've developed looking at Tyler's so is it. Is it now that we you ask patients to get genomics proteomics and see if there are similarities? And that and that's how you choose different therapies. It's probably at least two pronged right. So certainly kind of as Karen described creating sort of buckets of of tumor types Or of maybe Australia Sarcoma buckets really based on the molecular profile. On what we see when we do sequence the tumors allows us to to. Maybe better predict how they'll respond and And to use that in the future not quite yet but in the future to help inform therapy really with I think some of the ongoing work now Where I see that going is a phase two clinical trial So a trial that would specifically evaluate a novel combination so in new combination of drugs to be used in the setting of Osteo Sarcoma. In this case. That comes back that recurs. We're not yet at the stage of Lake. Truly targeting individuals therapy but this is helping us to find new therapies and general for perhaps like aggressive sarcoma. Yeah we we do. Certainly we do target individuals therapy In a very In a very specific way on when we see them at the time of relapse And certainly you know We 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 our goal Michael. Certainly as some of the work that 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. You would figure that out by doing again. Genomics proteomics at that in the early on 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 irrelevant predict kids with a high risk of relapse so many 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 standard treatment. If we're doing something we are studying or something. We should study so through our cooperative groups. The children's oncology group being the the biggest In the United States We Are. They're always ongoing studies of New Treatments. Often in the setting of relapsed 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 trials looking specifically at relapse disease. There always are a handful of those as well. and 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 pick we can do a better job choosing treatments to add in for specific patients if that makes sense so this has absolutely been fascinating and I will tell you that like 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 would love to have you back in the future to talk about advances. More things are going. You Bet thank you absolutely. Thank you again. This healthcare cheers. Podcast is sponsored by Indiana University. School of Medicine whose mission is to advance health in the state of Indiana beyond by promoting innovation and excellence in education research patient care.