• Podcast
  • Sep 19 2019

Behind the Blue: John D'Orazio and Ramon Sun (UK's Efforts to Beat Pediatric Cancer)

The world of pediatric cancer treatment has seen huge advancements in treatments over the past 60 years – in the 1950s, less than 10 percent of children were cured of their cancer. Today, the number of survivors is nearly 80 percent.

However, that still means that one in five children diagnosed with cancer will not survive. Many childhood cancers can be extremely difficult to treat, and research is key to developing new, better therapies for these diseases. 

Ramon Sun, an assistant professor in the UK Department of Molecular and Cellular Biochemistry, is one researcher embarking on an exciting new project in pediatric cancer – specifically, Ewing Sarcoma, a rare pediatric cancer that often occurs in the bones or the soft tissue surrounding bones and affects children and young adults typically between the ages of 5 and 16. Sun was recently awarded a significant grant to study Ewing Sarcoma from the St. Baldrick’s Foundation, the largest private funder of childhood cancer research grants. The award will fund his work at $110,000 a year for up to the next five years.

With this new grant, Sun will specifically investigate the role of aberrant glycogen in patients with Ewing Sarcoma and explore this glycogen as a therapeutic target. Sun sees the award as not just a coveted accolade, but a chance to identify a potential new cure for Ewing Sarcoma – there have been no new therapeutic options approved to treat Ewing Sarcoma in the past 20 years, and patients who undergo chemotherapy and radiation for the disease may experience lifelong side effects from their treatment.

The disease is in desperate need of research and development of new therapeutic options, Sun says, and the St. Baldrick’s grant will further that goal by focusing on a specific angle of the disease – the role of aberrant glycogen in cancer development.

“Ewing sarcoma is a devastating disease, where aggressive treatments are met with poor disease outcomes,” Sun said. “One of the key observations of Ewing Sarcoma made back in the 1930s is the accumulation of a large amount of glycogen – these tumors store a large amount of aberrant glycogen, and that accumulation has gone largely unexplored. My research aims to understand the reason behind this glycogen accumulation and exploit the glycogen deposits as a possible drug target for treating Ewing Sarcoma.”

On this week’s episode of Behind the Blue, UK Public Relations and Strategic Communications' Allison Perry and Kody Kiser sit down with both Sun and UK hematologist/oncologist Dr. John D’Orazio to talk about pediatric cancer in Kentucky, the magic of DanceBlue, future goals for this Ewing Sarcoma project, and why research funding is so important in helping scientists develop newer, better cures for cancer.

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[MUSIC - "ON! ON! U OF K"] 

On, on, U of K. We are right for the fight today. Hold that ball and hit that line, every wildcat star will shine. We'll fight, fight, fight. 


ALLISON PERRY: From the campus of the University of Kentucky, you're listening to Behind the Blue. 

KODY KISER: The world of pediatric cancer treatment has seen huge advancements in treatments over the past 60 years. In the 1950s, less than 10% of children were cured of their cancer. Today, the number of survivors is nearly 80%. However, that still means that one in five children diagnosed with cancer will not survive. 

Many childhood cancers can be extremely difficult to treat, and research is key to developing new, better therapies for these diseases. Ramon Sun, an assistant professor in the UK Department of Molecular and Cellular Biochemistry, is one researcher embarking on an exciting new project in pediatric cancer, specifically, Ewing sarcoma, a rare pediatric cancer that often occurs in the bones or the soft tissue surrounding bones and affects children and young adults, typically between the ages of 5 and 16. 

Sun was recently awarded a significant grant to study Ewing's sarcoma from the St. Baldrick's Foundation, the largest private funder of childhood cancer research grants. The award will fund his work at $110,000 a year for up to the next five years. 

I'm Kody Kiser with UK PR and Marketing, and I'm joined by my colleague, Allison Perry. On this week's episode of Behind the Blue, we sat down with both Sun and UK hematologist oncologist, Dr. John D'Orazio, to talk about pediatric cancer in Kentucky, the magic of DanceBlue, future goals for this Ewing sarcoma project, and why research funding is so important in helping scientists develop newer, better cures for cancer. 

We are joined today by John D'Orazio, who is the pediatric hematology oncology division chief here at the University of Kentucky with Kentucky Children's Hospital and with the DanceBlue Clinic. Did I get all that correct in there-- 

JOHN D'ORAZIO: Yes, you did. 

KODY KISER: --some way, some how. And also Ramon Sun, who is an assistant professor of biochemistry and a researcher with the Market Cancer Center. Correct? 

RAMON SUN: Yeah, that's correct. 

KODY KISER: Excellent. All right. So first things first that we always like to ask people is tell us a little bit about-- and you can arm wrestle or flip a coin, whoever wants to go first. Tell us a little bit about your background and how you arrived here at the University of Kentucky and the role that you currently have. 

JOHN D'ORAZIO: OK. I guess I can start. This is John D'Orazio, and I came here in 2004 with my wife. We both found faculty positions here, having moved here from Boston, Massachusetts, where I was a hemat fellow at Dana-Farber in Boston Children's Hospital, and Sarah was a postdoc fellow at Harvard Med School, and so we've been here since 2004. 

RAMON SUN: Yeah. So I came here about three years ago because my wife got into med school here, and he supported my career most of our time together. So I thought, yeah, it's about time for her to pursue a career that she really wanted. And UK had a lot of good research capacities and resources to offer, so I thought it was a perfect marriage between where she can get what she needs to be done, and then I get to do work-class research over here. 

Before that, I was in Stanford as a postop, and we both grew up in New Zealand, Auckland. 

KODY KISER: Well, as a researcher, tell me a little bit about some of the work that you do here, some of the specific things that you work on. 

RAMON SUN: Yeah, sure. So we cover a range of different diseases from pediatric cancer all the way to Alzheimer's disease. We work with a metabolite called glycogen that most people have them in the liver after a big meal. And we found that these glycogen molecules are stored in a lot of terminal illnesses, like cancer and degenerative diseases. 

And through research, we found that these are actually really good targets to start looking down the therapeutic intervention pathways. And at the method development perspective, we use a lot of mass-spectrometry based metabolomics techniques in the lab, and we're continuing to innovate and develop new methods and trying to maintain the best in class and the leadership position in this particular field, at least for UK. 

KODY KISER: Dr. D'Orazio, you work a lot in working with pediatric cancer. Talk a little bit about the challenges inherent with that. I mean, it seems like there are probably some things that you face there with that you might not face with adults or other types of cancer. 

JOHN D'ORAZIO: Well, I mean, so the most obvious one is the age of the patients that we treat. So we treat patients all the way up from birth. Some kids have cancer at birth, believe it or not, all the way up now through the upper 20s, in our adolescent young adult or AYA program. This is a special population of patients. They get different kind of cancers than adults get. 

So when you talk about the big cancers that affect most people in the United States, if you exclude the common skin cancers, you're talking about breast, prostate, lung, and colorectal cancer. Well, children don't tend to get that. They get a different kind of range of diseases, mostly leukemias brain tumors, and sarcomas. Sarcomas is what Dr. Sun here is going to be working on with his exciting new grant. 

The challenges, of course, are to provide a child with the best care that we can offer to give them the best chance of cure. But also because now probably something like 80% to 85% of all kids are surviving cancer, we've gotta be mindful about what we're doing to these kids during treatment so that the rest of their lives are meaningful. 

So it doesn't do any good to cure somebody of cancer if you leave them with significant deficits for the rest of their life. So our approaches are always trying to balance the risks and benefits of particular treatments so that we can do what's best in the best interest of our patients. 

ALLISON PERRY: I was going to ask how common pediatric cancer is in Kentucky. How many patients do we see here, not an exact number, but a close estimate. And is that on the rise or trending down? 

JOHN D'ORAZIO: So we are seeing about 220 to 230 new cancer cases overall in Kentucky every year, and that's data provided by Dr. Eric Durbin and the Kentucky Cancer Registry. They're not all being treated at University Kentucky, of course. There's Louisville and other places. 

And so if you look over a five-year period, that's over 1,000 Kentucky kids in the Commonwealth that have been diagnosed with cancer. So the trend is that for certain cancers, they're staying about the same, and for certain ones, they're going up a little bit, and we don't understand. There's actually an active research program going on right now to try to understand why it is that certain geographic clusters inside of Kentucky seem to have a higher incidence of pediatric brain tumors, for example. 

We don't know if that's something related to the geography or exposures to environmental agents or whether that's something in the gene pool of the people that live in these clusters. And so that's kind of an area of investigation right now. 

KODY KISER: It seems too that treatment for pediatric cancer provides its own set of challenges, not just for the patient in a certain sense, but also for the families as well because of its own particular set of-- the support system there. And as an adult facing something like that, you think that maybe adults can sometimes-- one, they can be their own advocate in certain ways and children cannot. And so what kind of challenges-- I mean, that's something to have to think about, I guess, an extra in addition to the treatment as well. 

JOHN D'ORAZIO: Absolutely. So we see all kind of kids with all kind of social support as you can imagine. And you have some patients that are represented by strong advocates within the family, and that's always a good thing to have. And you have other kids that do not have much of that at all. 

And so what we try to bring is we try to fill the holes when we can and try to provide multidisciplinary care. So one of the great benefits of being a part of our DanceBlue Pediatric Oncology Clinic team is that we actually are supported by that philanthropic organization. We've been supported for over 15 years from this. And this has provided things like school intervention support so that-- sometimes these cancer treatments go on for years, two, three years sometimes, certainly a year. 

And you're right. When a kid gets diagnosed with cancer, it is a jarring, out of the blue, typically to a healthy kid that never saw this coming. We don't understand why certain kids get cancers, but most of the time, it just strikes out of the blue, and it seems to be quite random. 

It's not happening more in kids whose parents smoke in the house, although we don't recommend that, of course. But aside from big, huge doses of radiation like in a nuclear power disaster or something like that that can cause leukemia a couple of years later, we don't actually know of a lot of environmental reasons. And one of the things we're getting into more and more is trying to understand the genes that might play a role in this. 

And we now have an appreciation that almost 10% of all kids with cancer can have a gene that put them at risk of that cancer, and that has all kinds of implications. Because not only may that impact how that cancer is treated, because some of these genes also can regulate your determined like the toxicity of therapy, et cetera and prognosis, but also you might be treating that one cancer and they're still at risk for more cancer. 

So how do you do surveillance in the future, and how do you come up with a good plan for that kind of thing? So there's all kind of challenges. But what I'm very grateful for for our division is that we are a very team-oriented approach that can provide multidisciplinary care with social work support and school intervention and dietary and a lot of things that really help enhance the comprehensive care of our patients. 

ALLISON PERRY: Before we start getting into specifics, we're going to talk about Ewing sarcoma, specifically here in a minute. But since you brought up DanceBlue in case there's anyone listening who doesn't know what DanceBlue is and understand the philanthropic efforts, can you briefly-- 


ALLISON PERRY: I know it's hard to summarize. 

JOHN D'ORAZIO: DanceBlue is our guardian angel. They have done so much for this division. I can get real in-depth on this, but this started really a collaboration between Jennifer Mynear, who lost a son to Ewing sarcoma actually, ironically enough, who was this boy-- I didn't know him. He passed before I came here. But the stories I hear about him and the videos I've seen about him, he's an absolute inspiration as is his mother. And they just wanted to make a difference in the world somehow. 

And so she collaborated with Susannah Denomme from our university's philanthropy office and development office. And together they had this vision along with people inside the pediatric oncology division of a student-led organization that would be raising money through a dance marathon for pediatric cancer here. 

And I think the original idea for this may have been at Penn State. They have this program called THON-- T-H-O-N, that happens every year. And I think it's a 48-hour dance marathon now. But that brings in several million dollars a year, and that has supported a lot of their research and clinical care of their patients. 

And so based on that model, DanceBlue was started as a 24-hour dance marathon here on the University of Kentucky's campus. I think over 500 or 600 students danced in this marathon last year. It is an event that happens typically in February, starts on a Saturday night, ends on a Sunday night. And it is an amazing place and an amazing thing to be a part of. I mean, it's so inspirational. 

Not only do you have the 500 or 600 or more students on the floor, and they all practice a line dance. These kids don't sit down for 24 hours, and they dance on the hour to this line dance, and there's all kinds of events that happen in the marathon. But on Sunday, many of our patients come. So the kids come, their families come, even families whose children have died of cancer come. 

And it's become this hallowed and revered event for us where it's just a place to reconnect with our patients in the context of this wonderful fundraising opportunity. And they've been more successful every year, typically, and that effort has allowed us to support a lot of the comprehensive services that we can provide for our patients and some of the research that's being done here in pediatric cancer. 

KODY KISER: And I think it's important to point out that the marathon itself is really, in some ways, it's the culmination of what has actually been going on for pretty much a calendar year. These students have been holding events and raising funds and securing donations throughout the year. And they work in teams, and the work goes into it, and they coordinate all of this. 

High schools have started to do this now, places of employment have started to hold mini marathons, and then they come together. 

JOHN D'ORAZIO: Fraternities, sororities are getting very involved in this. It's just a wonder-- everybody wins. This is an event where everybody wins. The patients win. We win. The students win. The families win. It's just great. 

KODY KISER: And you're right. It is staggering, the amount that they have-- each year have increased the amount of money that they have raised. They've crossed the million dollar mark for the last several years, and it is just a tremendous amount. But that Sunday, it's such a powerful-- just I can't put words into it. It's such an event-- 

JOHN D'ORAZIO: It's spiritual. 

KODY KISER: It is. It really is. And it's a time where the work that these students do and a lot of these children benefit from this can all come together with this shared experience in a sense, and it speaks a lot to the unity of a community that really has a heart for this type of thing. 

JOHN D'ORAZIO: And a lot of these students volunteer in our clinic. They come here the whole year and spend time with our patients. They get to know our patients, the patients get to know them, and meaningful relationships form. And so it's just one thing where everybody wins, and it's just a beautiful thing. 

ALLISON PERRY: All right. I'm going to kind of segue now and get into a little more specific, like as you mentioned, Jeremy had Ewing sarcoma and passed away from it. So tell me what Ewing-- what that means for the average listener. What is Ewing sarcoma, and I understand it's pretty rare. Correct? 

JOHN D'ORAZIO: Yeah, so-- 

ALLISON PERRY: You can both jump in, by the way. 

JOHN D'ORAZIO: Ramon, do you want to start? 

RAMON SUN: No, you go ahead. 

JOHN D'ORAZIO: OK. I'm sorry. I'm feeling I'm hogging the microphone. 

RAMON SUN: Go for it. 

JOHN D'ORAZIO: So Ewing sarcoma is one of the kind of cancers that children can get. Adults can get it too, but it peaks in the teenage years, and it's usually most often in a bone. So it's a kind of bone tumor most of the time, and it's defined really by-- it's a solid tumor, which means it's a mass when it presents. And the symptoms are somebody feels something that wasn't there before or something hurts that wasn't hurting before or you're limping when you weren't limping before. 

And typically, that will get picked up on a physical exam by a doctor's office or the primary care doctor who will get an X-ray or some radiologic study, and you'll see a tumor, and then that's where things really kind of start for their cancer journey. It's a tumor that accounts for about 1% to 2% of all pediatric cancers. I think there are something like 225 children and teens diagnosed yearly in the United States with Ewing sarcoma. 

So it's rare, but it's also a very interesting tumor because of its genetics. It is a tumor that's fueled by a translocation. What that means is that one chromosome breaks and another chromosome breaks and they come together, and they form this fusion protein, and that's what drives Ewing sarcoma. I don't know if you want to take it from there, Ramon. 

RAMON SUN: Yeah. So the reason we got interested in Ewing sarcoma is it's actually been known for decades by pathologists that Ewing sarcoma stains heavily for a PAS stain, which appears bright pink when you look at the actual solid tumor under a microscope. And what these are are glycogen, big glycogen storage, and that's not common in cancers, and that's certainly not common in the bone tissues. 

So that's when we got interested in it because we do a lot of work on glycogen metabolism, and after speaking with the clinicians and scientists, we decided that there's maybe a biological implication over here, and potentially a therapeutic window over here to target these glycogens. And they had not been investigated at all since their discovery. 

So since clinicians have known about the PAS staining in, I think, about 30 years, but for most people when we talk, hey, do you know these are glycogen, they're like what? That says the general response is not sure what these big, giant red blobs are. So they've been pretty much ignored as when you look at a patient, it was Ewing sarcoma. 

ALLISON PERRY: So again, for the average listener, I teach fitness, so I kind of understand glycogen as that's storage energy, more or less. But for someone listening who may not understand what that means or what glycogen does in the body normally, can you break that down a little bit more? 

RAMON SUN: Yeah. So glycogen gets stored in your liver. So when have a big meal especially, a carby meal like Olive Garden, a giant bowl of pasta-- 


RAMON SUN: Yeah, risotto, a lot of excess energy gets stored in the liver, and it gets released later when you're hungry, so it supports your brain and some other functions. And the primary site of glycogen storage is in the liver. And other tissues do have glycogen, but not to the extent that you see the massive deposits you see in the liver as well as Ewing sarcoma. And by our hypothesis, we really think that these large glycogen stores in your sarcoma has been used as a food source for much later during development and during metastases when it goes to a different organ, it's being utilized. 

So that makes the unique, metabolic disease, actually, for Ewing sarcoma. 

ALLISON PERRY: So just to make sure like I'm understanding, it glycogen normally goes to the liver, but in Ewing sarcoma, you're seeing it stored where the cancer is? 

RAMON SUN: Inside the cancer cells. 

ALLISON PERRY: It's like feeding the cancer-- 

RAMON SUN: We believe so, yeah. 

ALLISON PERRY: --and getting growth? 

RAMON SUN: Yeah, it's feeling growth. 

ALLISON PERRY: So it's the hypothesis, I guess? 

RAMON SUN: Yeah, it's back out with certain amount of data, preclinical data. We do have pretty striking preclinical data to show that it's fueled the growth of Ewing sarcoma, which makes it ideal target. Because when-- I'm sorry.

JOHN D'ORAZIO: I was going to ask, but it's not related to eating carbs, right? The tumor cells always have this, unlike the liver that goes up and down, like glycogens. 


ALLISON PERRY: Yeah, we don't want to have some misinformation like don't eat bread or you're going to get Ewing sarcoma. 

RAMON SUN: No. Yeah, Ewing sarcoma glycogen, it's clearly from a metabolic abnormality, which as Dr. D'Orazio said about the genes. That connection we haven't been able to establish, but we know that it should be a genetic factor that drives these glycogen accumulation in the Ewing sarcoma, but unlike the liver, which is driven by how much food you eat. 

ALLISON PERRY: And you said that we've known about this for decades, but the connection has never been made or pursued. Did we just not feel that it was-- it was just kind of felt like it maybe this line of research was a dead end or that there wasn't something that we could see a connection for? What caused us to kind of, I guess, not pay attention to this for a while until we're finally looking at this at this degree. 

RAMON SUN: From a scientific perspective, so now we're talking about a story. It's 100 years in the making. So in the 1930s and '40s, there's a ton of researchers that work on glycogen. And because of that effort in Europe and in the United States, there's this four or five Nobel Prize winners that involved the discovery of glycogen, glycogen metabolism. But suddenly in the '70s, some rumor went around that we know everything there is to know about glycogen in the scientific community. 

And the work, in general, on glycogen, not just in cancer, but in general, stalled since the '70s and '80s. Because if you look at the number of publications, it kind of plateaued after the '70s on the work on glycogen from a molecular perspective. So there's just not a lot of attention paid to glycogen. Because then we thought we'd already know everything there is to know and looking at it in a microscope, a big deposit like that can be various different factors. 

And the fusion protein on paper is definitely a much more interesting target to pursue from a biologist perspective, but glycogen is inherently hard to study. 

JOHN D'ORAZIO: And I would say also pathologists have been using glycogen deposits to characterize biopsies of tumors. So we know the B cell leukemia, for example, has these PAS positive granules that Ramon was talking about, and those are filled with glycogen. And so sometimes you get these observations like, oh, yeah, that defines that tumor under a microscope, they're PAS positive. 

But I think a credit to Ramon and Matt Gentry, whose lab I think this discovery came out of, was that well, maybe it's not just a marker of something. Maybe it's actually functionally important. And that's what's so exciting about this grant and this line of investigation that Dr. Sun is going to be pursuing is because all of a sudden, we're identifying maybe a potential new target against Ewing sarcoma. 

Ewing sarcoma has not had any new drugs introduced for it in more than two decades or something like that. So we were switching around how drugs are being used and stuff, but we're in desperate need for new drugs. Now, the cure rates for Ewing sarcoma, if you catch it early and it's localized, it's something like 70%, but if it's caught a little bit later and it's already moved somewhere else in the body, the metastasis that Dr. Sun was talking about, it's down around 30%. 

So we clearly could use better treatment options, especially patients with advanced disease at diagnosis. 

ALLISON PERRY: You brought up the grant, so let's go ahead and segue into that. Can you tell me a little bit about you've got a grant from St. Baldrick's Foundation. Can you tell me what that organization is, and what grant you got, how much money, and what are you using it to study? 

RAMON SUN: So I believe the Baldrick's Foundation is the largest pediatric foundation in the United States. So they fund, by far, the largest number of grants for pediatric research. And this grant that I got is they call it St. Baldrick's Scholar or Career Development Award, which helps junior faculty to commit to pediatric oncology research. 

And this grant will fund me at about $115,000 a year for up to five years to pursue Ewing sarcoma research. 

ALLISON PERRY: And specifically, looking into the glycogen, which you had just said seemed to fall off the radar a little bit, and now you're getting funding to revisit it and look at it again. 

RAMON SUN: Yeah, exactly. So when we put in a grant, we actually had very exciting, pretty preclinical data at least in cell lines in mice to show that targeting these glycogen granules was significantly impacted how Ewing sarcoma grows. And the most attractive part of this is manipulating glycogen in the whole body. 

Generally speaking, the biggest side effect is weight loss, which is not even that severe You're not losing about 5% weight loss in mice or humans. It's a lot like ketogenic diet, manipulating a liver glycogen metabolism, but obviously, it's different when you look at Ewing sarcoma. 

But when you look at cancer treatment, you have to look at the systemic effect of the actual drug. And the attractiveness of this is that the same drug that targets the Ewing sarcoma glycogen would not have toxic effects like a lot of the chemotherapy have in human, in two other organs. 

JOHN D'ORAZIO: I think it's important to state I think it's way premature to be saying something like ketogenic diet can cure Ewing sarcoma. 

RAMON SUN: Oh, 100% no. We don't even go down that route. That's a way to manipulate liver glycogen. We have zero evidence to show that it even does anything to Ewing sarcoma glycogen at all. 

KODY KISER: Well, I do want to ask when we talk about the research and the work and the glycogen study that just trickled down and stopped in the '70s. So you've got all of these decades where we're not really looking at this. In the meantime, on a global level, we've continued to put money and resources into other types of cancer research. 

So in starting, kind of looking back at this now, is there a level of-- I suppose optimism, and do you have-- I don't know if this works like this. Now you have all these other resources of being able to look at these other decades of other things that have been in other areas of cancer research. So it helps to bring this along maybe a little quicker, or are we really just going back having to start at scratch with some of this stuff? 

JOHN D'ORAZIO: Maybe you could talk a little bit about cancer metabolism and the explosion in research on cancer metabolism over the last 10, 15 years, where people have understood that cancers metabolize energy differently than normal cells. And maybe there's some therapeutic opportunities there. They seem addicted to glucose, for example. And we've turned that observation into PET scans, which have revolutionized the way we stage patients, but they can also maybe be transformed into some new therapies. 

And I think this might represent one of those opportunities. 

RAMON SUN: Yeah. So the way we're seeing it is that this research, although glycogen has been ignored, the metabolism field in cancer has not been. And we're piggy back off of a very solid foundation of decades of scientific research. And a lot of it come out of the UK too. I think Dr. Lin and Dr. Fan at the toxicology has done tremendous amount of work on cancer metabolism in the last decade. 

So there is a wealth amount of information for us to use, to start working off of this. So we're not going-- [BUMPS MICROPHONE] sorry. We're not starting from ground zero, we have a lot of good solid foundation to build off of. 

KODY KISER: I hadn't even thought about that as far as the technology involved in the sense of just being able to do scans. There are things that exist now that we couldn't have dreamed of in the 1970s, 1980s of being able to look at on a cellular level some of the things that we are able to look at now.

So that seems very positive and in that sense. 

RAMON SUN: Yeah, exactly. 

ALLISON PERRY: I was going to ask what are you hopeful for over the next five years with this particular project? What do you want to find out? 

RAMON SUN: Ideally, best case scenario, I like to work with Dr. D'Orazio and Dr. Badger here and to move our preclinical tested compounds and move it forward into the clinics, at least in the clinical testing stage. 

ALLISON PERRY: So now you're doing it in animal models currently, and you hope to actually bring that to actual patients. 

RAMON SUN: Yes. I don't know if that's doable in a five-year time frame. I think that's why I work with Dr. D'Orazio and Dr. Badger a lot on this because I'm not a clinician. I'm just being a naive scientist. We have about five different compounds that hit glycogen at different steps. Some of them are easier to get to the delivery to the tumor, some of them are harder. 

But again, all of that is done in the preclinical setting is outlined in mouse models. And ideally, we would like to bring it in to help the kids. We would hope that one of these agents would be able to benefit kids with Ewing sarcoma in the next five years or a decade. 

KODY KISER: And it's not just you, all your papers spread out in front of you or all the work that you've-- there's a team of people working on this with you. 

RAMON SUN: Yes, of course. We know we could not have done it by ourselves when we sit up on a computer in a lab trying to do this. From a biology setting, maybe we can understand what glycogen does in a cell, but bring it into actually treating patients, 100% to have collaborating clinicians who is willing to collaborate with us and try to offer suggestions and to move this forward. 

KODY KISER: I was going to ask about that. What kind of atmosphere does that provide to be able to be in a place like we have here at UK where that clinical and research, those elements can work hand in glove in a sense that they can be so close together and be at the front of this and know what each of the sides are doing? How important is that? 

JOHN D'ORAZIO: Quite important. It's synergistic, right? We all have patients that have succumbed to cancer, and that is a tragedy, and it hurts. It's personal, and we feel grief as providers. And if you have optimism because you know somebody down the hall is developing something new, potentially, against this kind of cancer, that gives you hope to go on and strength to deal with the next patient that you diagnose. 

However, I should say also this is very exciting. He's focused on Ewing sarcoma, but we don't know that this couldn't be applied to many other kind of cancers. I mentioned that certain kind of leukemias have been long known to have glycogen stores in them. I have no idea if maybe this could be developed into an anti-leukemia approach as well and help those patients. And I know there are other cancers that have these glycogen stores that my colleagues here are studying. And so that's an exciting possibility to me. 

RAMON SUN: Yeah. And in collaborating with the clinicians, they would guide us on the different avenues that we could possibly pursue in the next couple of years and not just limited Ewing sarcoma and hopefully, expand to other pediatric cancers with the goal of helping these patients. 

ALLISON PERRY: I didn't ask this, really, at the beginning, but I want to ask both of you what drives you in your work? What has inspired you to go into this specific field? 

RAMON SUN: Well, I'm a new father, so my son is four months old. Finally, putting myself in the shoes of a parent, I feel for these parents and families who have to put their children through chemotherapy. And I just want to do something that my son can be proud of when he grows up and make a difference. 

JOHN D'ORAZIO: Yeah, for me, so I have an MD and I had no intention of doing pediatrics when I was in medical school until I actually got onto the pediatric floor and met these families and these patients. And I took an opportunity to be a camp counselor at a summer camp for kids with cancer. It was called Reach Out to Cancer Kids in Florida where I was a medical student, and that sold it to me. 

This is a absolutely unique community. These kids are a joy to be around for the most part. They're inspirational always, and everybody who works with them is special. And so for me, it was just this is where I belong kind of feeling. 

RAMON SUN: Just to add to that, I think that's actually a lot of the missing pieces was this research science that we don't get to meet the patients. We don't get to meet their families. And that's actually part of it. I was at a meeting where it was actually not a pediatric cancer meeting, but it was another rare disease that only happens in children. It's called Lafora disease. And when I was at that meeting, I met the families. I met the patients. I don't know how devastating this disease is to affect the families. 

And since my background is cancer, that just gave me additional drive to pursue something that in the pediatric field just after interacting with the families and patients. 

KODY KISER: I was thinking about-- we were talking about DanceBlue earlier, and I think about the types of students who take part in this. And I think about that. We encourage academic research at a very early start. When freshmen come into the university, they can start getting involved in research, and I think about it in the context of wouldn't it be great. 

It's tremendous potential there for students who want to go into biochemistry, want to go into the medical field who are inspired by the work that goes on with DanceBlue, but also on the clinical side and on the research side who then want to contribute to this type of thing. And I think that's another factor there where you're continuing to bring up bright minds who are inspired and want to make that change and want to find those keys that can help unlock the secrets to this stuff. 

ALLISON PERRY: I wanted to talk to you about the-- make sure I'm reading it correctly-- the Pediatric Cancer Research Trust. So all these great breakthroughs we're talking about can't happen without research, which requires money. Everyone laughs a little bit. Can you talk a little bit about, one, how great it is that St. Baldrick's is giving you money to do this, but then also, UK is part of this research trust and what that is and what that's going to hopefully help accomplish. 

JOHN D'ORAZIO: Yeah. So you're right. Research is expensive. It costs a lot of money to keep animals and do testing with purified reagents and some of the high technology that Ramon is talking about here with mass spec and what have you. So St. Baldrick's is a wonderful organization that provides funding for pediatric oncology types of research. 

We're very fortunate in Kentucky, actually, that our State governor and our State legislatures, a few years ago appropriated nice a bit of money for pediatric oncology research in the Commonwealth. And so this was appropriated at, I think, $5 million over two years to be split between UK and University of Louisville. And that money has started to be realized by the researchers, and people are doing research and I can comment on that. 

University of Louisville is developing a CAR T-cell program. This is an advanced immunotherapy program that they're going to have up and running very shortly, as I understand it, which is very exciting to have it as a resource in the State. At University of Kentucky, we chose to take advantage of our NCI designated Cancer Center and pair some of our pediatric oncology clinicians with researchers in the Cancer Center in joint projects, and we have four that are ongoing right now. 

Two of them deal with ALL, acute lymphoblastic leukemia, which is the most common cancer that children get. One is a very sensitive biomarker sort of study where we try to identify relapses early and penetration of the leukemia into the brain, which would require treatment changes early through something called circulating tumor DNA, which means it's a cell free and ultra sensitive way to do this. And that's being worked on now by Dr. Jessica Blackburn and Dr. Tom Badgett. 

Dr. Daret St. Clair leads a big team of researchers, and she's collaborating with Dr. Caryn Sorge in the division to look at something called chemotherapy induced cognitive impairment. And so this is better known as chemo brain. And so it has long been known that there are effects on cognition. People get fuzzy and mentally cloudy with certain kinds of chemotherapy, and Dr. St. Clair is leading this team and understands that it's through a lot of oxidative damage and immune cell activation and actual brain damage, and this can be lasting. 

And this is one of those things I was alluding to earlier where 90% of kids with ALL stand a risk of ALL and they're curable. What if they go on the rest of their lives being mentally cloudy? That's not the best situation. So try and understand how that happens and what we can do to prevent that is a good effort. 

One of the studies that the Kentucky Pediatric Research Cancer Trust Fund is funding is an analysis of those pediatric brain tumors and why they're a little higher in Kentucky than in the United States and particularly in certain areas of Kentucky. I think it's up to like 42% higher in certain areas of Kentucky. We don't understand that. 

And so Dr. Eric Durbin and his team are looking at geospatial factors and genetic factors. He's collaborating with Dr. Adam Resnick from the Children's Hospital Philadelphia who's got an interest in sequencing tumors and understanding causality of tumors based on their sequences. And so this is a very exciting project that we're collaborating with University of Louisville and getting a lot of pediatric brain tumors and sequencing them and trying to understand why we have a higher incidence than the rest of the nation. 

And the last project that's being funded is actually another Ewing sarcoma project. And so this is a collaboration between Dr. Jurgen Rohr and Dr. Mark Leggas at the College of Pharmacy, and they are trying to design drugs that go after that fusion protein that I was mentioning before, that EWS fly fusion protein that we know causes the cancer. Without that protein being active, there is no Ewing sarcoma. 

And so they're working on making derivatives of a fungal product called mithramycin that itself is too toxic to give to patients, but they're working on making it much more selective and less toxic. And so in UK, what this fund has supported, so far are those four projects, and a sibling survival project led by Dr. Sherry Bayliff and Dianna Holtzhauer in our division. And again, mentioning that not just the kid that's diagnosed with cancer suffer, but the siblings have to deal with this as well. Because all of a sudden, their parents are having to be in the hospital, their brother or sister aren't there, and life gets interrupted. 

And so I feel like we're using that money to work on a variety of issues with childhood cancer, and I'm very grateful to the State for appropriating those funds. 

ALLISON PERRY: It's a pretty wide variety of topics that they're funding. I didn't realize that. 

JOHN D'ORAZIO: Yeah. And the effort was led by Jamie Boyd, who is a parent of a cancer survivor herself. And I mean, just takes one or two dedicated people to get something like this started. If it's a good cause, it kind of catches fire. So we're just very grateful for all of that. 

ALLISON PERRY: I don't think I have anything else. Is there anything else that you all didn't get to talk about, either specifically about this grant or more, in general, about your work? 

JOHN D'ORAZIO: You had mentioned the AYA program, that you wanted a little discussion on that. One of the things that we've developed in our service, in our clinical service this past year is an adolescent and young adult program here at the University of Kentucky. Very exciting because this is a collaboration between the division of pediatric oncology and the Market Cancer Center and the clinical services there. 

And we know that cancers in the AYA range, which we are defining as 15 to 29, there's more of those than patients under the age of 15. And less than 20% of these patients will get their care at a comprehensive cancer center or a cancer center that can deliver comprehensive multidisciplinary care. And that's what we have intended to do, and that's the program that we've started. 

And we're very excited about this because Kentucky is number two in cancer incidents in this age range and number four in cancer mortality in the nation. So we have an overrepresentation of AYA patients with cancer in our commonwealth, and we want to offer them the best services that they can get. So we've developed that program, and it's going well. 

We've enrolled over 40 patients so far since it's opened in February, and this is allowing patients to get much more multidisciplinary comprehensive care than they would otherwise normally get. 

KODY KISER: Well, John D'Orazio, Ramon Sun, I want to thank you both very much for being with us. I feel like I should point out that you both were under the assumption this was possibly going to be a video interview. And so you both dressed very nicely for this podcast, so yeah, I felt like that deserved some sort of honorable mention. 

But thank you both very much for being with us. We appreciate all the hard work, and just good luck with all of your endeavors and the research that's going on and all of the clinical work. And thank you so much for your time. 

JOHN D'ORAZIO: Thank you. 

RAMON SUN: Thank you. It's been a pleasure. 

ALLISON PERRY: Thank you for joining us on this edition of Behind the Blue. For more information about this episode or any other episode, visit us online at uky.edu/behindtheblue. You can send questions or comments via email to behindtheblue@uky.edu or tweet your questions using #BehindtheBlue. Behind the Blue is a joint production of University of Kentucky Public Relations and Marketing and UK HealthCare.