January 5, 2023 — Dr. Kelly Diehl discusses hemangiosarcoma in dogs with a team of experts from the University of Minnesota. The group talk about new data regarding this deadly cancer of dogs, the latest research findings and how new ways of approaching the disease could save lives.
Resources:
Hemangiosarcoma Initiative
Referenced Publications:
https://pubmed.ncbi.nlm.nih.gov/31570656/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137578/
https://www.sciencedirect.com/science/article/pii/S0301472X06002621
https://pubmed.ncbi.nlm.nih.gov/21062482/
https://www.mdpi.com/2306-7381/2/4/388
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969990/
https://aacrjournals.org/mct/article/16/5/956/92284/Safe-and-Effective-Sarcoma-Therapy-through
https://onlinelibrary.wiley.com/doi/full/10.1002/aac2.12046
https://onlinelibrary.wiley.com/doi/10.1111/vco.12590
https://onlinelibrary.wiley.com/doi/abs/10.1111/vco.12368
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712213/
https://www.mdpi.com/2306-7381/2/3/270
https://vascularcell.com/index.php/vc/article/view/10.1186-2045-824X-6-20
https://doi.org/10.1101/2021.05.21.445198
0:00:10.5 Kelly Diehl: Welcome to Fresh Scoop, Episode 52, New Thoughts on Hemangiosarcoma in Dogs. I'm your host, Dr. Kelly Diehl, Morris Animal Foundation Senior Director of Science Communication. And today we'll talk to doctors Antonella Borgatti, Erin Dickerson, and Jaime Modiano. Dr. Borgatti is a professor of oncology and the director of the Clinical Investigation Center at the University of Minnesota. Dr. Dickerson is an associate professor of oncology. And Dr. Modiano is the Perlman Endowed Chair of Animal Ecology and Director of the Animal Cancer Care and Research Program at the University of Minnesota. So welcome Antonella, Erin, and Jaime. We've got quite a gang here today. Before we get started, I always ask people to say something about themselves, what led them to become a veterinarian, if you're a veterinarian, and or ultimately a cancer researcher.
0:01:09.1 Antonella Borgatti: Thank you, Kelly, for inviting us today. It's a pleasure to be here. I decided to become a veterinarian when I was six years old. And at the time, my ideal being a veterinarian was petting animals all day, making them all feel better. But discovering that the profession is much more complex than I'd ever imagined and filled with infinite opportunities for learning is really what sparked my interest in oncology during my veterinary school training at the University of Torino in Italy, and eventually led me to pursue specialized training in oncology.
0:01:45.2 AB: So, I came to Raleigh, North Carolina in 1999 with a scholarship from the University of Torino that was supposed to be for a year, and here we are 20 years later. And after a few years at NC State, I completed my residency and a master's degree program at Purdue University. And then I joined the faculty at the University of Minnesota in 2008 and receiving an NIH K01 Career Development Award was really a milestone for me that allowed me to devote most of my time to clinical research with hemangiosarcoma being my primary area of focus.
0:02:23.4 KD: Well, that's awesome Antonella. Erin, do you want to go next?
0:02:28.5 Erin Dickerson: Sure. And I also want to say thank you for having the opportunity today. It's nice to be here with my colleagues and with you again discussing hemangiosarcoma. I am not a veterinarian. I just sometimes play one in the college. But I actually wanted to be a veterinarian and I worked for several years in the summers for a local clinic in Southern Oregon, which is where I grew up. And it soon became really apparent to me that I didn't really like being in the room with the clients.
0:02:57.2 ED: I preferred actually to be in the back room looking under the microscope, doing a lot of the blood counts and looking at all the different cells and trying to understand how changes in cell biology actually contributed to the disease. And I also decided about that time, it was my second year in college, to become a biochemist instead of biologist. And my mother really didn't understand that. She said, that's so hard. Why do you want to do that? And so, I did it anyway because that's really where my interest was. And so, I actually got my degree in biochemistry at UC Davis. And then I worked for a year at a small research institute in Ohio studying cancer. And I had actually worked at UC Davis in a laboratory for about a year studying cancer biology and the effect of lipids on breast cancer and metastasis. And I went on to get my PhD at the University of Wisconsin. And I ended up doing a postdoc at the vet school there where I really became more and more interested in cancer research. And that's my introduction to hemangiosarcoma. And that's also where I started interacting with Jaime and he pretty much kept telling me, this is what you need to do as your postdoc and I said, Okay.
0:04:13.6 ED: So, he gave me some leadership there. And then I wandered on down to the Institute at Georgia Tech. And I started working on ovarian cancer there. And there was an opportunity to come up to Minnesota and continue work on hemangiosarcoma and work with Jaime and also with Antonella. And so, this is where I am and where I've been for a while.
0:04:34.9 KD: Oh, that's great. Thanks, Erin. And Jaime and I have known each other for a very long time. But I'll let him talk about himself and how he got to veterinary medicine and oncology.
0:04:51.1 Jaime Modiano: Yeah. Thank you, Kelly, for the invitation. This is great to be here and expanding on my interactions with Morris Animal Foundation. So, I guess how I got here is that I've always been a contrarian. When I was a kid, cancer was a word that was only spoken in hushed tones in the hallway. And I was always curious about why people were so afraid and so unwilling to discuss this disease. And it wasn't so much that I was personally impacted. But I saw friends of my parents and friends of the family and how nobody would acknowledge that this was just part of biology. So, I became really, really interested in trying to figure out what cancer was from a very young age. I also love animals and the environment. And so, my dream was to become a zoologist, which my mother thought was very cute because not many four-year-olds can say zoology. But as they started growing older, they became a lot more nervous about how I was going to ever make a living being a zoologist. Anyway, I came to vet med partly because of those interests in animals, the environment and cancer and partly truly as an accident because it seemed like a fun thing to do as I was going through undergrad.
0:06:13.8 JM: So, I did complete a combined degree program at Penn, worked with Peter Noel for my PhD, and many people may not know Peter Noel, but he really is the father of modern cancer genetics. It was a great experience. After that, I did clinical training for my residency at CSU, which is where when I first met and spent some wonderful time in Colorado, postdoc, the National Jewish in Denver. And then I have jumped around several places. But in 2007, I was invited to apply for the endowed chair in animal oncology here at the U of M. So, I've been here now for about 15 years and I think collectively with Antonella and Erin and Mike Henson and many, many other people with strong support from the comprehensive cancer center and the medical school and the College of Vet Med, we built a great program and we're doing a lot of fun things. So that's where I am.
0:07:16.6 KD: That's great. And I will let everyone know I have to... Well, I actually owe Jaime a bribe because he has this real passion for Reese's peanut butter cups. So yeah, peanut butter cup bribes work. Moving on to more serious, of course, I think a lot of folks listening to the podcast know something about hemangiosarcoma. And we have a pretty wide variety of folks, as you guys know, from veterinarians to just some of our really science-oriented donors and supporters. Can you guys start by talking a bit about the history of this cancer, like when it was first described, the current treatments and sort of where we're at with survival times with this really, really important cancer of dogs?
0:08:07.9 JM: Yeah, so I'll take that one, Kelly. And it's a really interesting question because I think it's a question that's not asked often enough. And I was not a solid tumor researcher in my career development. And I sort of got dragged into this field kicking and screaming by Erin and the group that she was working with, about 20, 24 years ago. And as we started looking at this disease, thinking about how it develops, how it's treated and really the failures of treatment, there was a disconnect because the assumptions that people were making were inconsistent with the data that were going on. And so, when we started looking back at history, we realized that many of those assumptions were probably wrong.
0:09:00.2 JM: The disease first appears in the literature in the late '50s, early '60s, primarily in Europe. As a disease that seems to be common in German shepherds. And most of the early descriptions are from vasoformative or vascular tumors in the spleen. And most of the dogs are described as dying fulminantly from acute bleeding episodes. In the late '60s, there are reports in the literature coming from the US describing the same disease with also sort of a preponderance of German shepherds.
0:09:36.4 JM: And I think it's important to remember that at the time there were reasons why German shepherds were perhaps the most popular breed across most of the Western world. Movies and shows like Rin Tin Tin really influencing the kind of dogs that people wanted. So, there was a lot of German shepherds around. Over time, the disease was described based on its microscopic appearances, a tumor of endothelial cells with endothelial cells being the cells that lie in the inside of blood vessels. And more breeds were added to the list of dogs that got hemangiosarcoma. And those trends of the dogs that are presumed to be at high risk really follow the trends of breed popularity. So, it seems that as breeds became more popular, more of those dogs were noted to be affected with hemangiosarcoma. And so, when we think about breeds, and there's a question later that we'll talk about, I think that there's a tremendous bias in breed popularity and the kinds of dogs that are seen in veterinary hospitals and create these databases to try to figure out whether or not any particular dog is at risk or not.
0:10:46.1 JM: We also went back to look at what the cell of origin is. And the short answer is it is probably not an endothelial cell. And we don't really know what the cell of origin is. But we actually think that the cell of origin is a specialized cell that lives in the bone marrow and other organs that form blood and blood vessels. And there's a group of cells that are called nurse cells. They're cells that support the generation of blood and all the constituents of blood and blood vessels. And we think that those cells are probably the cells of origin and that the different nurse cells might actually curate different subtypes of hemangiosarcoma, as Erin will describe. And that might also become important in the context of how resistant this disease is to treatment because those nurse cells are known to be extremely resistant to toxic insults like chemotherapy and radiation therapy. So that might play a role in that. So how the disease is treated now, it's treated with surgery. And it's a little bit different from other tumors because getting any visible and accessible tumor out will reduce the likelihood of a life-threatening bleed. So even in the presence of metastases, surgery might be indicated as the first line of treatment.
0:12:02.7 JM: And then depending on the location of the tumor treatment recommendations might be to follow with chemotherapy or radiation therapy. We see that the expected survival time is sort of on the order of four to six months with about 10% to 50% of dogs going beyond a year. And some of our research, which Erin might touch into a little bit, tell us that there are multiple different subtypes of hemangiosarcoma. There may be one subtype or perhaps two that really account for all the long-term survival. So, it seems that our treatment might actually benefit only a subset of these dogs and we need better treatments for all the others.
0:12:45.5 KD: Right. So, four to six months with surgery, right?
0:12:48.6 JM: Four to six months with surgery and chemo.
0:12:51.8 KD: And chemo. Okay. And you touched on this. This is really interesting, the breed thing. Because I'm going to confess right here that I, when I get a request for like what picture should we put with this blog about hemangiosarcoma or this article what pops out of my mouth typically is German Shepherd, Portuguese Water Dog, and Golden Retriever because of course we're doing a Golden Retriever lifetime study. But I was really interested, Jaime, because we've talked about this before. Talk about the breed thing and how we might be thinking incorrectly about it.
0:13:32.6 JM: Well, I think that the breed thing is largely driven by looking for the keys that we lost in the parking lot under the lamppost because that's where the light is. Even though that's not where we dropped our keys. We can only work with the data we have and the data we have are biased because the breed popularity means that there's a lot more of those dogs than other dogs. And also breed popularity makes people assign breeds to their dog, which may not really be the right breed. And so, anything that's hairy and yellow might be called a golden retriever. Anything that's got prick ears and this black antennae would be called a German Shepherd, where in fact their ancestry may be very, very different. And so, once you actually sort of like open the hood and start looking at really what drives this disease, there are no good associations beyond these veterinary referral databases that tell you that there's breed specificity. And when we look at sort of the disease progression and the molecular traits and at the outcome and at the mutational profiles and all the other things that we can do to understand the disease better, there are no differences between or among breeds.
0:14:54.1 JM: And so, the molecular pathogenesis of the disease is really similar. And while we must acknowledge that there might be some heritable influence that modulates risk, that influence is probably small. And so, yes, it is possible that Goldens and Portuguese Water Dogs and German Shepherds have slightly elevated risk over other breeds. It is unclear whether that risk would be shared, probably not, because you would expect that if it was a shared risk, more like breeds would be at greater risk. And we really see this through the canine kingdom, including in captive wolves. So, this is a disease of aging and it's been reported in wolves that are kept in captivity that live longer than they would if they were in the wild, that they also are at risk for hemangiosarcoma. So there seems to be something very peculiar about being a dog that makes you susceptible to this disease if you age, which is different from other animals.
0:16:01.9 KD: Okay. Because that... So, let's talk about other animals, because as a person in practice I saw a lot of hemangiosarcoma in 25 years, I think I saw one cat with hemangiosarcoma. And so, talk about, you just talked about wolves, but talk about hemangiosarcoma in other animals. Do we see it? Are there reports of it? And is there an analogous cancer in people?
0:16:30.1 ED: So, I can go ahead and answer some of this just to give Jaime a little bit of a break. You do see it in other animals, but like you mentioned, it does occur in cats and Jaime talked about it occurring in wolves. But in other animals, it's very rare and you just really don't see it. And you may not see it at all in veterinary practice if you're a clinician. We do see an analogous cancer in people, and this is referred to as angiosarcoma. And it's also very rare. It doesn't occur, it occurs maybe in about 300 people a year in the US. And so, if you look at the pathology of this disease and the progression, human angiosarcoma looks very, very similar to canine hemangiosarcoma. They're both very aggressive diseases. They can occur just about anywhere in the body. We think about hemangiosarcoma as occurring mainly in the spleen, in the heart, and in the liver. It can also occur subcutaneously. And in people, you also can have it occur anywhere in the body. It can occur... You can have subcutaneous hemangiosarcoma, you can have a lot of disease in the heart, in people, and also in other organs.
0:17:45.5 ED: And so, we actually have a pretty robust program here at the University of Minnesota where we compare a lot of what we see in canine hemangiosarcoma and we translate that to the human disease. And we also have other programs where we have taken what we've learned in the human disease and we're bringing it back into the clinic and into the laboratory. And so, if you look at basically the survival of people with angiosarcoma with advanced disease, about 35% of those patients will die within the first year of their diagnosis. And so, there are similar treatments, there are similar mutations, and we can talk about that in a little bit. But we really think that these are similar in a lot of ways. However, there's some more recent studies that show that the mutations that you're going to see in angiosarcoma are a little bit different. You also see some of the molecular signatures that we've since identified in canine hemangiosarcoma don't quite match those in the human disease. And so, we're starting to see with some of these tools that we have in terms of RNA sequencing and bioinformatics that we can actually see that there are some differences even though they... If you look at the pathology and the progression and the aggressiveness of these diseases, they are very, very similar.
0:19:05.8 KD: Okay. Well, that's helpful. Yeah, it's interesting how it tends to be in certain species. Let's loop back because I do want to talk about a misperception that I have had and been taught, which is where does hemangiosarcoma start? And I think most of us are taught about, as Jaime alluded to earlier, about endothelial cells. And thanks to Jaime, when I write stuff for Morris, I've started to like soft pedal backwards when we were very definitive about where this started. So, talk to me about that because that's a kind of big change, I think, for a lot of people who may be listening. I don't know who wants to take it. Who wants to do this? Jaime, do you want to do this?
0:19:57.3 AB: I think this is Jaime's.
0:20:01.3 KD: Yeah. Jaime.
0:20:01.7 JM: Is this me? Okay. I thought this was Antonella. Sorry. That's why I was quiet. Okay. So where does hemangiosarcoma start and where does it originate is the question. And so, the answer again is nobody knows. And if anybody tells you otherwise, they're selling something. But we are following the data. And the data tell us that the most likely place where hemangiosarcoma starts is in blood forming organs. So, if you follow the ontogeny or the embryologic origin of blood, it starts in the yolk sac and vertebrates. And from there, it moves to other blood forming organs, depending on what animal you are. That can be the liver, it can be the kidney, it can be the bone marrow. So, if we really focus on mammals, the blood forming organs are primarily the bone marrow, but everywhere where the primordial cells migrate before they get to the bone marrow retains blood forming capacity. So, we think that the cells originate there and that they might seed networks of capillary blood vessels such as those that are found in the spleen and the liver and the lungs and the heart and the kidney and the brain in a very early malignant state or in a pre-malignant state.
0:21:21.4 JM: And that the cells really create their own environment or their own niche in that particular organ. And so, we see metastasis and progression a little bit different in this disease. And I think we'll touch on that a little bit more, but there may be seeding from a blood forming organ to multiple capillary networks within each tumor following its own evolutionary history. So that you might have multiple tumors in the same dog or perhaps even the same human or the same cat in cases of hemangiosarcoma in other than dogs where each of the tumors really is very, very different. And when we think about personalized medicine, each tumor might require its own type of therapy. And so, we're really now talking about personalizing the therapy for every tumor that may be in that particular patient as opposed to the disease as a whole. So that's what we think now. It doesn't mean that as we get more data, we won't change our minds again. But it does seem that this is not just simply a transformation of an endothelial progenitor in a blood vessel. It seems like the transformation event probably takes place in a different environment than that seeds really seed those blood vessel networks.
0:22:45.4 KD: All right, that was really helpful and really different, I think, for most of us. So, Antonella, I think you could answer this question for me, which is the talk about the disease progression. I think many of us who've had patients with hemangiosarcoma or have experienced it in one of our own pets think of it as a very fast-growing cancer. I can tell people from personal experience having ultrasound dogs' abdomens for some reason, right? They come in to me as a gastroenterologist. And next thing I know, they're back like seven weeks later and they're bleeding out their abdomen. There's a tumor there. So, I mean, anecdotally, I can say, well, geez, I thought this dog was clean. Well, last time I looked. But what do we really know about progression?
0:23:36.4 AB: Yes, I'm happy to answer that question. Hemangiosarcoma is, I would say, an insidious cancer that often doesn't cause any obvious pain or discomfort. It can develop without causing any obvious clinical signs until either a large mass is incidentally identified on a physical exam or more frequently what happens is that the tumor mass ruptures leading to life threatening complications. The tumor cells are able to form blood vessels, but the tumor vasculature that characterizes hemangiosarcoma is very different from normal blood vessels.
0:24:17.4 AB: So, these are malformed vessels where blood tends to pool and clot. And eventually these clots obstruct the vessels, preventing the blood, the nutrients, the oxygen from reaching the tumor cells and causing some of these tumor cells to die. And as a result of that, the tumor mass can rupture, releasing blood into the location of the tumor. So, it could be the abdomen, the chest, the subcutaneous space, the heart sac. And while substantial blood loss can eventually lead to pretty obvious clinical signs of anemia, pale gums, lethargy, weakness, collapse, the signs can also be very subtle in the event of a small bleed and they can resolve as the dogs tend to reabsorb the blood components and they make new blood cells. And this is really one reason why hemangiosarcoma almost always goes undetected or undiagnosed until the very late stages of disease. And by the time the cancer then eventually is diagnosed, it almost certainly is present in other areas of the body, even though metastasis may not be readily visible. And eventually the outcome for the majority of our patients is rupture of the tumor with this acute, severe blood loss, shock, collapse, and possibly death.
0:25:46.5 AB: And so surgical intervention is really important at that stage because it can really save the life of the animal in the event of such acute manifestations of disease.
0:25:57.8 KD: Yeah, I think that's something you guys probably hear it because you're in clinic, but I can't tell you how many times you hear people, I had no idea, they were perfectly fine, they're playing ball in the backyard and it collapsed and all of a sudden it's an emergency. And these guys do come in as a clinician, they're healthy, they look great. They're not some of the typical, when I see cancer animals where they've had some cachexia and maybe it took a while to make the diagnosis. And so that was really helpful, Antonella, because it is a horrible disease, I think, for people who have to experience. So, I don't know, maybe Erin, you want to tackle this, the role of genetic mutation, because we talked about it earlier in the discussion, but take a deeper dive for me in the role of genetic mutation in this disease.
0:26:56.1 ED: Yeah, sure, I'd be happy to cover that. So, I want to take a little bit of a step back though, and I want to talk about the different subtypes that have recently been described. And what we did back in 2014 is we actually characterized three different subtypes of hemangiosarcoma, and these are what we would call transcriptional subtypes. And so, we were able to take basically the genetic signatures and identify subtypes that we called angiogenic, inflammatory, and adipogenic.
0:27:29.0 ED: And this was based upon the gene signatures that we saw. So basically, you can think of angiogenic had a very vascular signature, the inflammatory signature had, of course, an immune cell component, and the adipogenic, which was just a small subset of these tumors, actually had a more lipid character to it. And so, this was the first time that we really had seen identified subtypes of hemangiosarcoma, and the hypothesis and the idea behind a lot of this was that these tumors would respond differently to chemotherapy and the current standard of care. And we do have some information now that was done by my colleagues showing that the inflammatory subtype dogs with this subtype actually have a longer overall survival. They seem to have a better response to standard of care, being surgery and doxorubicin chemotherapy. And so, there is this genetic component to these tumors or this heterogeneity, which is going to dictate how a dog, a tumor responds to treatment.
0:28:32.7 ED: And that's something that we know about cancer. That's not something that's unusual. But we really started to take this apart. And in the last probably four or five years, people have really started to look at the different genetic mutations that are associated with these cancers. And so, the common ones show up like P53, PI3 kinase mutations. And these are also found in these different transcriptional or different subtypes that I talked about. They're not mutually exclusive. They overlap. And so again, you have more of these mutations like P53 mutations and PI3 kinase mutations, which are found in the angiogenic subtype. And you actually have a lower overall survival. And so, what we're seeing is typical of cancer is that certain mutations and certain signatures are going to dictate how that tumor responds to treatment, what the overall survival of the dog will be based on those mutations.
0:29:31.3 ED: And so, we're really starting to pick apart how these work, how they respond. And so this gets into precision medicine. Can you identify a genetic mutation or a signature that is going to be responsive to a certain type of treatment or that's going to respond better to chemotherapy?
0:29:49.9 ED: And so, we're really interested actually in some of these dogs that do respond well to doxorubicin and chemotherapy. Who are these dogs? What do their tumors look like? Can we pinpoint those as a starting point? Whereas you have other people who are looking at a lot of the broader spectrum of mutations that occur and trying to identify different drugs that can be used to treat those and seeing if dogs would respond. And so, these mutations, like anything, are going to dictate drug resistance, drug responses, how fast that tumor grows, whether it invades, whether it's going to be metastatic. And so,, it's not really different from other cancers, but I think we've learned just in the last decade, especially that there are different subtypes.
0:30:34.2 ED: And we really need to pay attention to that moving forward and how we're going to design therapies for these different subtypes and how we're going to be able to apply them into the clinic so that we can improve the overall survival for these dogs.
0:30:47.3 KD: Right. And I don't know if you want to keep going, Erin, because I think you're... I'm going to pull on this thread a little bit. But why is this cancer so tough to treat?
0:31:00.4 ED: Yeah, so that just gets back to pretty much everything I just said. This is a very heterogeneous disease. And as Antonella pointed out, this is something which is we think of as an insidious type of tumor where owners really don't know that anything's happening until the later stages of this disease. And so, because we're getting it at late stage and because we have the heterogeneity of these tumors, whoops, and there's someone chiming in right now. But because we have this heterogeneity of this disease, we really don't know how different tumors are going to respond. And we really don't know exactly how to apply the current treatments that we have to make the most of them. So, there's this huge black hole in understanding, well, what does it really mean to have a PI3 kinase mutation in a tumor for hemangiosarcoma? You know, is this going to respond to chemotherapy? Should we be targeting that tumor or that mutation?
0:32:00.9 ED: And what does it mean to have, say, a P53 mutation in an inflammatory subtype versus, say, a P53 mutation in an angiogenic subtype? And you're probably not going to really see a P53 mutation in an inflammatory subtype because we just don't see that in our data.
0:32:15.6 ED: And so, we really need to understand how these different mutations work in terms of these subtypes. And we really need to understand how they work, how they're going to work in the clinic and how we're going to attack them. And so, this is why it's so tough to treat because it's not just one disease. It's many, many diseases.
0:32:33.2 KD: Right. And I think people are starting to get that idea with cancer, right? I think we tend to lump cancer together and it's really lots of different diseases. So, on the treatment side of things, though, I know that you guys have been working with a drug called eBAT and probably there are folks listening who have heard of this. So, tell us about it. Antonella, maybe you want to take this one?
0:32:56.9 AB: Sure, sure. I'd be happy to take this one and tell you a little bit about how we got to eBAT. So certainly, one way to improve the efficacy of cancer treatments while at the same time reducing the potential side effects is to create some smarter or more targeted therapies that target tumor components that are not present or they're present in lower levels in the normal tissues.
0:33:23.7 AB: And so targeted therapies have been very successful in managing a variety of previously untreatable cancers in human patients, but they didn't exist for hemangiosarcoma for a long time. For decades, we have been treating this complex of diseases with the same chemotherapy approaches. And so, through our efforts to try to develop more effective treatments for hemangiosarcoma, we discovered that these tumors have two proteins on the cell surface that could serve as targets for therapy. And these two proteins are the epidermal growth factor receptor or EGFR and the urokinase type plasminogen activator receptor, UPAR. And EGFR and UPAR are not expressed at the same time by normal cells, but they have this abnormal pattern of co-expression on hemangiosarcoma cells that led us to hypothesize that these tumors would be potentially sensitive to a targeted therapy, able to attack these two proteins simultaneously. And so, our approach was not to inhibit or block these receptors, but to use these proteins as essentially as baits to deliver lethal toxin. And so that's essentially how we came to eBAT. eBAT stands for EGF, or epidermal growth factor bispecific angiotoxin. And this is a drug invented and developed at the University of Minnesota by Dan Vallera, who was my primary K01 mentor in his team.
0:35:02.0 AB: And it's a drug that consists of two proteins to simultaneously target EGFR and UPAR. These proteins are linked to genetically engineer lethal bacterial toxin that was genetically modified to reduce immunogenicity in the patient. And the toxin is delivered to the tumor with a high specificity through the two baits that are components of the drug. And a unique property of eBAT is also that it'll disrupt the environment, the tumor microenvironment, making it inhospitable for the cancer cells. So, at this point, we have published the results of two clinical trials using eBAT in conjunction with the standard of care, surgery, and chemotherapy for the treatment of dogs spleen hemangiosarcoma. And we have been able to demonstrate that this drug is safe in dogs with this complex of diseases. And we have also detected signals of activity. And so, we're very excited about continuing to study this drug and how to optimize its clinical applications. And so more to come in the future.
0:36:12.2 KD: Yeah, it's really exciting. It could certainly change the landscape of how we treat this tumor. Next I wanted to talk about an interesting project you guys are working on. And it's called ShineOn.
0:36:25.0 KD: And many folks, again, who are listening may have heard of it. But for those who haven't, can you talk about what it is and what you hope to accomplish and especially how listeners can participate? That's a pretty common question I hear a lot is folks are interested in participating in clinical trials.
0:36:45.7 JM: Yeah, I'll take that one, Kelly. Thank you again for the question. So let me take the second part of the question first. And then I'll tell you more about the study. So right now, ShineOn, the original clinical trial, has completed enrollment. It's in a follow up phase. And so, it is essentially closed to any new enrollment. Participation is limited to people who have enrolled in the past and were following dogs for their lifetime. So, it's not because we want to exclude people, it's because we have to be true to the science and the data. And of course, we are looking to move ShineOn out into the community. And so, if anybody has a few million dollars sitting around doing nothing and they want to discuss how we can get it out to the community faster, we would be happy to listen to them. But in terms of what the project is, so the idea is that we sort of, I will say that serendipitously stumbled upon an idea. And this really was work that started way back when I was working with Erin and Stuart. And so, the idea was that if these cells are growing in intimate... If hemangiosarcoma cells are growing in intimate contact with the blood, it's not unreasonable to think that some of them go for a swim.
0:38:15.0 JM: And that as they're swimming in the bloodstream, if we have some very specific reagents, we might be able to actually find them. So, when we first came up with this idea, we thought it's so obvious somebody must have done it and nobody had. So, at that time, we decided to essentially formulate that hypothesis and test it. And we're able to demonstrate in a paper that we published about 16 years ago now that in fact, we saw some cells that we at the time believed were circulating hemangiosarcoma cells in the blood of dogs that had the disease.
0:38:52.6 JM: They were not present in dogs that had other cancers or no disease. And the number of these cells that we could find seemed to go down after treatment. But as we refined the data and we spent more time thinking about what this means and sort of did a deeper dive into what these cells are, it turns out that we don't think that they are circulating hemangiosarcoma cells at all. And although our test might pick them up if they're there, what we seem to be measuring is cells that are in the bloodstream, they're present at vanishingly small frequencies.
0:39:31.1 JM: So, they represent somewhere in the order of 0.1% or less of all the nucleated cells in the blood. And they seem to be traveling either from organs like the bone marrow to the site of the tumor, or they may actually be recirculating from the tumor to go and recruit other cells. And so, these are essentially like the construction workers that are building the environment where the tumor is going to live. So, if you think of the tumor not as a mass of malignant cells, but really as an ecosystem, we like to call it a subdivision. And the subdivision requires not only the bad people inhabiting the subdivision, but it requires houses and the schools and the post office and the mall and the tennis courts and everything else. And so, you need people who are going to go in and build all those things, and you need to have all those components.
0:40:22.9 JM: And so, we believe that what we are identifying in the blood is all these constituents that form and remodel the tumor environment. And because these constituents need to be mobilized in advance of a tumor, we actually believe that we can pick up the tumor in the earliest stages of formation.
0:40:42.1 JM: So, before it's actually a tumor mass, when essentially the ground is being leveled to build that subdivision. And so, our data tell us that when we use this test, we can assign dogs into a risk profile. It's a low risk or a high risk. And when we assign dogs to a low risk, we actually think that that low risk extends for about a year to a year and a half. And the likelihood that those dogs are going to develop cancer based on our data is extremely small, maybe one or 2%. Whereas if we assign dogs to a high-risk group, the probability that those dogs either have a pre-existing cancer or will develop cancer in the next few months, six months, year or two years is much greater. Sort of progressing onto about 50% of the dogs that have this risk environment eventually developing hemangiosarcoma other life-threatening tumors. So that's a really good thing because it can allow us to assess risk profiles. But at the same time, it's not such a great thing if there is a level of uncertainty. So, will they or won't they? And if we don't have an answer, so what do you do about it?
0:41:55.7 JM: So ShineOn really didn't become a reality until we had some data from eBAT. And eBAT was not really designed as a component of ShineOn. It was an independent project that really created an opportunity. And as Antonella mentioned, one of the characteristics that was very unexpected and very rewarding about eBAT is its safety. After reviewing data from a lot of dogs that got eBAT, and of course, our clinical models, we agreed that eBAT was probably safe enough to give to a healthy dog. And as Antonella also mentioned, eBAT doesn't only kill the cells that form the tumors, it also changes the microenvironment. It makes the microenvironment inhospitable. And so we reasoned that if we could attack that microenvironment at the early stages of formation, maybe we could prevent tumor formation or at least delay tumor formation altogether. And so the answer to having high risk is the potential if you don't have a preexisting tumor to actually get eBAT as a preventative. And so that's essentially what is being tested in the current phase of ShineOn, where we have dogs that have been assigned to the high-risk group. And through a variety of factors, some are essentially being assigned to an intervention arm, where they're getting eBAT in the prevention setting.
0:43:18.1 JM: And some are being assigned to essentially a follow through to see if we see a difference in the dogs that get eBAT versus the ones that don't. So, we're very excited about the project. We're very excited about the data. But as is true with science, the answer will just take a little bit of time to develop and see if in fact, this idea of intercepting tumors at the time that they're forming by attacking the workers that are building a tumor environment and creating that inhospitable environment is going to work. And moreover, whether that's going to be a strategy that we can apply successfully, not only to hemangiosarcoma, but also to other life-threatening tumors as well.
0:44:02.0 KD: Well, it's really exciting, really exciting stuff. And could really change the landscape for all of us as far as treating, as far as pet owners. Well, this has been awesome, but I probably need to wrap it up, even though it's been great talking with you guys. So, each one of you, just tell me what your take home message is for our listeners.
0:44:29.0 AB: My take home message is that hemangiosarcoma is not just one disease, I refer to it as a complex of diseases. And the more we learn about the differences between the subtypes that also Erin described, the greater the knowledge we generate that we can then apply to the development of therapeutic strategies that can be tailored to the individual patient, hopefully resulting in greater efficacy and better outcomes.
0:45:00.5 ED: Yeah, and I just want to follow up on that by saying that hemangiosarcoma doesn't have to be a death sentence. And for a lot of what Antonella just talked about, I mean, we're learning more and more about this disease every year, and I think we've learned more about it in the last 10 years, probably that we've learned in the past several decades. And so, I think the message really needs to get out to a lot of the local clinics across the United States that if a dog comes in with hemangiosarcoma, you don't have to euthanize your dog, that there may be opportunities, there may be other options, and it doesn't have to automatically be a goodbye. And so I think we really need to get that message across. And I think we can get it across more effectively within the next year and within the next five years and 10 years, as we develop better therapies, and we really understand what these different subtypes are doing and how we can target them.
0:45:58.9 ED: And so part of my partnering with Antonella on clinical trials and also with Jaime is that we can take stuff from the bench, and we can go into the clinic, and then we can go back to the bench. And I think it's a really important partnership that we have to have and understanding we need to run these clinical trials to really understand how we can do better and how we can do better each time. So, this doesn't have to be a death sentence, and I think we really need to drive home that idea.
0:46:26.3 KD: And.
0:46:26.9 JM: Yeah, and I'm going to climb really high up on my soapbox. I second everything that Antonella and Erin said, but I do want to remind people that we should be very careful about breed profile. This is a complex disease. It's not a single gene disease. It is not transmitted terribly from one generation to the next. There's a lot of things that have to go wrong, and it takes a lifetime of a dog for the most part for those things to go wrong. And so it is not a disease that is confined to one or a few breeds. It's a disease of dogs, and we see it in little dogs, and we see it in medium dogs, and we see it in big dogs, and we see it in purebreds and mixed breeds.
0:47:07.4 JM: And as I said, we see it in wolves, and we see it in coyotes. So I think it is about time for us to really be more conservative in how we apply information from retrospective databases and really be more objective about the fact that yes, you can have a Papillon and a Chihuahua and a Min Pin that have signs of hemangiosarcoma and that actually do have hemangiosarcoma and that we can have golden retrievers and German Shepherds and Portuguese Water Dogs that might appear as if they had hemangiosarcoma, but the diagnosis is really something else. And so, we just have to sort of remove that bias from our brains.
0:47:49.2 KD: Well, that is, that's really great information. So, I will make sure that I change when I get a photo spec request. I'll add some other stuff in there, and that's really a sea change for me that I have to do in my brain. I'm sure a lot of people listening. So well, that does it for this episode of Fresh Scoop. And once again, thanks to the gang. I think I sent the invite as gang from Minnesota for this thing. So, thanks to doctors Antonella Borgatti, Erin Dickerson, and my old friend Jaime Modiano for joining us. And we'll be back, of course, with another episode next month. We hope you'll find just as informative. We know the science of animal health is ever changing and we need cutting edge research information, whether we're treating patients as veterinary caregivers or as pet parents. And that's why we're here. You can of course find us on iTunes, Spotify, Google podcasts and Stitcher. And if you like today's episode, please, we'd sure appreciate it if you could take a moment to rate us that will help others find our podcast. As always, to learn more about Morris Animal Foundation's work, go to morrisanimalfoundation.org and there you'll see just how we bridge science and resources to advance the health of animals.
0:49:02.1 KD: You can also follow us on Facebook, not Twitter anymore, but LinkedIn and Instagram. And I'm Dr. Kelly Diehl. We'll talk soon.
