Dr. Nolan: It's sort of a provocative idea. That's not an area that a lot of people are researching. And that's sort of my mantra is pick the low hanging fruit, pick the niche that nobody else is in and tackle it so that you're not playing in the sandbox where all the other experts are.
Dr. Venable: Welcome to the Veterinary Cancer Pioneers Podcast, the show where we delve into the groundbreaking work of veterinary professionals who are dedicated to advancing the field of veterinary oncology. I'm your host, Dr. Rachel Venable, and I'm thrilled to embark on this journey with you. This episode is produced and brought to you by ImpriMed, pioneers in an AI-driven precision medicine for veterinary oncology. ImpriMed’s Personalized Prediction Profile helps you make confident treatment decisions for canine lymphoma and leukemia patients by predicting how your patient will respond to multiple chemotherapy protocol options. Learn more at imprimedicine.com. That is imprimedicine.com.
Dr. Venable: Well, welcome to the Veterinary Cancer Pioneers podcast. I'm your host, Dr. Rachel Venable, and I am so excited. Today we have Dr. Michael Nolan on with us. And if you've been listening to some of our shows, he's actually been mentioned by several different guests as a good guest. So I'm so excited that he is here with us today.
And Dr. Nolan is the Randall B Terry Junior Distinguished Professor of Oncology at North Carolina State University College of Veterinary Medicine. He holds a DVM and a PhD in radiation and cancer biology. He got both of those from Colorado State, and he's led North Carolina's radiation oncology service since 2013. His research focuses on understanding and reducing radiation associated pain and normal tissue injury, and he's led multiple clinical trials developing cancer therapies for animals and people.
Dr. Venable: So Dr. Nolan, thank you so much for being on the show today.
Dr. Nolan: Oh, thanks for having me. I'm really excited to do this with you.
Dr. Venable: Well, and it's interesting because you have both a PhD and a DVM, so you're a double doctor. A lot of us don't actually have that. So what got you interested. And doing both of those. What kind of drew you down that path I guess even just to going to veterinary medicine.
Dr. Nolan: Yeah, it's a long and meandering story. I'll try to spare you the details, but as a kid, I was allergic to everything and anything furry. And so aside from fish, we really never had pets at home. And I had no exposure to veterinary medicine. So I guess what I'm telling you is that I definitely wasn't one of those kids that crawled out of the womb that I wanted to be a veterinarian, but I was interested in science, and in college I was a chemistry major.
And at some point I also became interested in aquaculture and fisheries management, and that eventually evolved into an interest in aquatic animal health. And I figured the best way to make a career of that would be to become an aquatic animal veterinarian, through a long and twisted series of events that morphed into an interest in pathology and eventually, oncology. Definitely not a straight line there, but I did an internship, applied for residency, and that's what landed me at Colorado State University.
Dr. Venable: You know, it's funny you mentioned aquaculture because, you know, it's not a very big part of veterinary medicine, right? Like it's a small section. But Dr. Thamm, he almost went into that as well. So it is kind of interesting that both of you guys were thinking fish but somehow ended up in oncology.
Dr. Nolan: Great minds think alike.
Dr. Venable: Exactly, exactly. And what got you into the PhD?
Dr. Nolan: Well, you know, when I was in vet school, I was in a dual DVM PhD program. And the PhD portion of that never finished a long series of events. I won't get into the details, but as you know, when we were residents at Colorado State University, we had to do a master's degree. And so kind of adding up the research I was doing as a master's student, which kind of exploded and was more than maybe the typical master's degree. Adding in that, plus the coursework I had done way back when as a PhD student, I kind of had all the pieces needed to cobble together a PhD, so it definitely wasn't like the most traditional route for getting graduate education. But, you know, I guess I enjoyed research enough that I was able to put the pieces together and make it happen.
Dr. Venable: Yeah, no, that's awesome, because I always feel bad when people take classes and end up wasting those credits. So that's great. You were able to piece it all together.
Dr. Nolan: Yeah.
Dr. Venable: And you know, radiation, it is a really interesting specialty and very interesting technology. What do you think pulled you towards radiation oncology versus more of a medical oncology?
Dr. Nolan: I wish I had a better story, but it really just quite literally was a coin toss. So the year that you and I both applied for residencies was the first year the match was online. So as you'll remember, when we applied for rotating internships, it was paper applications. And you put your CV together and you wrote a letter that was kind of individualized to each internship program. And you said, well, I want to go to this hospital for an internship or reason X, Y, and Z. You made up some nonsense to tell them, and I anticipated doing the same thing for residencies, and I wasn't sure whether I wanted to do medical or radiation oncology, and I figured I'd just write a letter depending on which program I was applying to.
Dr. Nolan: But then they switched it up and turned it online. You could only submit one letter of intent and it just went to the system rather than to individual hospital, so I had to pick between the two. And honestly, I didn't know enough about different aspects of oncology to know which I wanted to do as a career. I thought maybe at some point I'd want to do both, but I also felt like that wouldn't be the strongest way to approach a residency program director. Like, I'm so indecisive that I'll do either. That didn't seem convincing, so I just tossed a coin. It landed on radiation, and I went for it. That's how I wrote my letter, and it became a little bit of a problem, because I didn't take the next step ahead in thinking through things. So when I got to interviews for residencies, I didn't have much better answer. And I guess whatever answer I came up with on the fly was good enough.
Dr. Venable: That's hilarious. Yeah, probably telling them, you know, I just flipped a coin and here I am. Like, that might not have been a great interview.
Dr. Nolan: Yeah. Probably not the winning solution.
Dr. Venable: That's hilarious. Well, you went from flipping a coin to pick radiation to really building back up the radiation program at North Carolina State. What has that been like? I'm sure that's been quite an endeavor because you guys have a quite the program.
Dr. Nolan: Yeah. It's interesting. I don't think when I applied for this job, I had a really good sense about what it meant to be in academia, but I knew I was being given a really cool opportunity. NC state has a long-standing legacy of leadership in veterinary radiation oncology and comparative oncology. There was a decades long collaboration between Mark Dewhirst over at Duke and Don Thrall here at NC State, and their work really helped to establish companion animal cancer patients as powerful models for studying tumor physiology, hyperthermia, radiation responses, and translational therapy development.
Dr. Nolan: But by 2013, when I was recruited here, the program was really at a turning point the major collaborative research grant funding that Mark Dewhirst and Don Thrall had from the NIH had dried up. Don Thrall was retiring, and the clinical program here really needed to be renewed. At the same time, there was a real vision from college leadership to rebuild in a serious way. The dean here at the time was Paul Lunn, who you and I interacted with as department head at Colorado State University. And he reached out to me and said, “Hey, I'm really committed to rebuilding radiation oncology, rebuilding oncology as a whole.” He invested in a new state of the art linear accelerator and hired two radiation oncology faculty, and I was one of them.
And at the time, I was intrigued by that because very few veterinary radiation oncology programs were investing at that level. So it felt like a rare chance to build something meaningful. We had the opportunity to create a modern, high quality clinical service, expand training, and reestablish NC state as a leader. And importantly, I'm saying we because it wasn't something I did by myself.
Tracy Geiger was hired at the same time, and I think that made a huge difference. I was fresh out of training at CSU, had been exposed to really modern radiation oncology technologies, had a sense of what a contemporary facility and workflow might look like. And Tracy brought this extraordinary depth of clinical experience. For those that don't know, she's triple boarded in internal medicine, medical oncology and radiation oncology, and we got together and started working here.
She had tremendous perspective on patient care, oncology practice and resident training. So I think we really made a complementary team, brought different strengths to the table, brought very different personalities to the table. But we shared the same goal. And honestly, like looking back on the last 13 or 14 years, our partnership was one of the most rewarding parts of the experience here.
Dr. Venable: That's awesome. And would you say it was rewarding? Because just the way you guys were different, able to complement and you know, how is the program now, like how many residents or how are you guys doing?
Dr. Nolan: Yeah. So we're in another inflection point. Tracy recently left here and joined the faculty at Cornell, which is an amazing opportunity for her. She's a real cat connoisseur, and they have the feline health program up at Cornell. They are at a point where we were a decade plus ago, where they are reinvesting in radiation oncology, building a new faculty, investing in new technologies.
And so it was an opportunity for her to try it again to rebuild something even bigger and better. So she left. And we're kind of in a rebuilding process here. But at the time she left, we were up to three radiation oncologist on faculty. We had three residents. We had hired dosimetry as part time staff to help with some of the technical aspects of treatment planning.
And we've built a really robust clinical practice that also incorporates clinical trials routinely into our workflow. So I think that's what I mean by rewarding is, is we've been able to take two very different personalities and perspectives and backgrounds and build something that sustained itself quite well, and now is lending itself towards attracting new faculty and kind of re-envisioning what the next decade will look like for this university.
Dr. Venable: It's really cool. And I do like just hearing, you know, how everyone can work together with their different strengths. And I think that's really cool. And building it up. I mean, it's a lot. You know, you mentioned dosimetry and I think a lot of people don't even really understand what all is involved with radiation. You know, if you're not in the medical field, you really don't know.
Dr. Venable: Like I mean, I didn't even realize how many pieces of the puzzle there really are involved. Like, what would you say, especially now with a lot of the newer machines? Like, how do you kind of describe that radiation process to people?
Dr. Nolan: It's really interesting. Look, what it looks like today looks very different than 20, 30 years ago, like 20 or 30 years ago. I think radiation oncologist really worked in the background. The workflow was often the medical oncologist would see a patient decide if it needed radiation therapy. They'd take it to see the radiation oncologist, and after treatment, the patient would then bounce back to the medical oncologist for long term management and restaging.
Dr. Nolan: In many ways, this might be offensive to some of my colleagues, but I think the veterinary radiation oncologist sort of served like a radiation pharmacist. And that's changed. It changed a lot, and I think it's changed for the better. These days, the job of the radiation oncologist looks very much like that of a medical oncologist. If radiation therapy is opted for, the radiation, oncologist can work with the symmetries and a therapist to get a treatment planned and delivered.
Dr. Nolan: But the routine involvement of those professionals has really allowed us to step away from the technical aspects of radiation therapy and instead focus on the clinical aspects of radiation oncology. And so these days, I think most radiation oncologist spend the bulk of their time in exam rooms, talking to to clients, doing consultations, doing recheck evaluations. And the main difference is maybe, you know, a small difference in the types of cases we see.
Dr. Nolan: But the big difference just being the tool we have, the hammer we have for for treating cancer instead of chemotherapy, we're prescribing radiation therapy. And obviously there are a lot of technical aspects to how you get radiation into a tumor. Maybe that the simplest example is just implanting a radioactive material into a tumor or injecting radioactive iodine into a patient.
Dr. Nolan: But probably the workhorse of veterinary radiation oncology is these machines that deliver external beams of radiation, where we can column eight beams and kind of focus the beam almost like a spotlight onto a tumor. And so there's all sorts of technologies that make that more precise and less toxic than it used to, and allows for treatment courses to be shorter and more succinct, more efficient, and in some cases more effective.
Dr. Nolan: So, yeah, I think I think that's how I would kind of describe what a radiation oncologist is and what the role of radiation therapy is.
Dr. Venable: And I think the technology over the last few years has been really fascinating with radiation. And I think even for myself, I've had to make sure I keep up with things in the sense that in the past there were different tumors that I thought, oh, radiation, the side effects are going to be too much. But now, like you were saying, we can be more precise than just how we're able to treat, you know, we're able to treat tumors that, you know, ten, 15 years ago, I would have been like, like, we're not doing that, but now it's like urinary bladder.
Dr. Venable: And I know you've done quite a bit of research with the urinary bladder tumors. And that was one. You know, with the older machines we really wouldn't recommend it.
Dr. Nolan: Yeah, I think that's exactly right. Like now you can see the tumor. You can basically take a paintbrush and paint radiation dose onto the tumor or the area that might be affected by tumor and have shield the surrounding tissues quite literally, from getting high dose radiation exposure and reduced toxicity in that way. Similarly, like a lot of abdominal pelvic targets are now accessible to radiation.
Dr. Nolan: So things that we used to think of as not great tumors to try to tackle with radiation are much more accessible. Liver tumors. Adrenal tumors, deeply seeded tumors within the body, even things that can move around with respiratory motion. GI motion can be targeted in relatively safe and in some cases, really effective ways.
Dr. Venable: Yeah, I haven't really thought as much about some of the internal, especially intestines. Is that is that something more on the human side, or are you guys looking at radiation like intestinal or.
Dr. Nolan: Oh yeah, I guess I was meaning that we can kind of avoid the intestinal tract and treat things that are adjacent to it. It is really hard to do things that are primarily GI in humans. It's more common because colorectal cancers are more common, very distal kind of, you know, these tumors that are tethered to the retroperitoneal and tethered and don't anatomically move a whole lot.
Dr. Nolan: Rectal, anal tumors. And we don't see a lot of that in vet med. So we don't treat a lot of primary GI but things that are GI adjacent.
Dr. Venable: Yeah. Yeah I was going to say I'm like wow, that's new to me.
Dr. Nolan: Yeah. No. You know, I think now at least in North America, most veterinary radiation oncologists have ready access to all the fancy toys. Right. Like the things that made a CSU or Florida unique a decade ago because they could do stereotactic radiation, image guided, intensity modulated radiation. Everyone has access to those things now. So I've almost flipped the script in my head, and I think some of the most intriguing and exciting ways to think about radiation, or how we can best deploy these technologies to treat other things, to use radiation in non-conventional ways, like how do we how do we optimally apply radiation therapy for non malignant disease?
Dr. Nolan: Or how do we use ionizing radiation therapy to prime a tumor for subsequent immunotherapy. So maybe moving away from using linear accelerators just to blast the heck out of a tumor and kill the primary tumor, but also manage other diseases or other aspects of the tour microenvironment. But I think that's kind of the next nut to crack.
Dr. Venable: Yeah, that's really interesting. And you mentioned immunotherapy. And I don't know if your group is you know, the thing that made me think of was Gilbert mad. And I know there are some clinical trials and forgive me, I don't know if you guys are one of them, but that didn't make me think about it. And I know there is kind of some chatter, but I haven't ever I haven't really heard, like, should we give a couple doses of Gilbert Mab and then do radiation, or should we do radiation first and then immunotherapy is that I don't know if you can answer that question or if that's what you guys are trying to tease out.
Dr. Nolan: It's a really good question. I do think that there's a strong potential that that radiation can be used to make the tumor microenvironment more amenable to immune checkpoint inhibition, maybe even certain cell based therapies. We have not been involved here at NC state with any research, primarily with Gilvetmab, but we have worked with Nikki Mason's group to evaluate, in conjunction with Missouri, the team there to look at their anti for molecule in oral melanoma in combination with radiation.
Dr. Nolan: And I think the timing probably depends on which molecule you're inhibiting right. Like maybe anti-CTLA molecules should be given before radiation PD1 inhibitors after. And there may also be opportunities for thinking about how to deliver the radiation within the tumor. Different doses of radiation can have different immune effects. And so there's this idea or concept that maybe you can kind of turn a tumor into a checkerboard and deliver really high doses to portions of a tumor, and really low doses to other portions of the tumor, create gradients of radiation dose across lesions, so that you can engender different immune responses that might differently interact with these immune therapies to optimize outcomes.
And all of that is research and progress, both in preclinical rodent models, veterinary clinical trials, human clinical trials. So I imagine in the next ten years we'll learn a lot, because I think that's a major part of the wave of the future, is how to combine these things.
Dr. Venable: Yeah, that's really interesting that you can even treat a tumor like a checkerboard. I mean, that really is so precise. I don't think a lot of people understand. I mean, most of these tumors aren't really that big and even still like how you can, even if it's big, being able to use radiation like that, like, that's incredible. That's really cool.
Dr. Nolan: Yeah. There's this really old school technology called grid therapy, which is literally just taking a giant thick piece of brass and poking holes in it. And then you put that in the path of the beam. And so it just, it kind of turns the tumor into a grid where radiation shines through these holes in the collimator and delivers really high dose regions. And then the part that's shielded by the brass gets a really low dose. And the more modern approaches to that are things like lattice radiation therapy, where we use intensity modulation image guidance to create little tiny balls of very high dose radiation that you can put into different portions of the tumor.
Dr. Nolan: And kind of version 1.0 of lattice radiation is to just randomly place the balls of high dose. Version 2.0 is to think about how you can biologically target those. Could you do a PET CT to identify metabolically active areas, or an MRI to identify hypoxic areas, and intentionally put the high doses in those areas that might be most radio resistant and put the lower doses in kind of more active portions of a well oxygenated, metabolically active tumor.
Dr. Venable: Well that's fascinating. So are you guys doing any clinical trials on that right now, or is it still more kind of the rodent level?
Dr. Nolan: Yeah, I know we are. So we are involved in very early stage work in this kind of a pilot clinical trial level in canine osteosarcoma. And at the moment we're just trying to figure out how do we actually measure the biological effects of these treatments. And we're not even at the point of trying to combine them actively with immunotherapies, but just trying to figure out, if you give this radiation, how do you know it's doing something that is actively immunomodulatory? And so we're currently doing these treat and resect clinical trials where we take a dog that has, for example, a distal radial osteosarcoma. And we scheduled it for an amputation both between the consult and the amputation we put a giant dose of lattice radiation. And then we can look pathologically at that entire resected limb, the resected lymph nodes, and see what the radiation did spatially within the tumor, but then also immunologically how it altered the regional training lymph nodes.
Dr. Nolan: And then really the goal there is to kind of take what we learned from this pilot clinical trial and use that to design the next phase of clinical trials, which would be combining this lattice radiation with immunotherapies. Right now, we're still trying to optimize the treatment protocols and optimize the time points and biological endpoints that we're looking at.
Dr. Venable: Yeah, that is really fascinating. And you know, we've heard also that you with Dr. Lascelles' that you guys are doing research with pain. And part of that was looking at radiation because, you know, sometimes certainly can be painful, especially if you get a burn or like people have reported things. So what you know, you mentioned looking at radiation in different ways. What are you guys finding with your pain research?
Dr. Nolan: Yeah. It's fascinating. I remember as a vet student doesn't seem like that long ago. But I remember as a vet student, one of my pathology professors teaching us that tumors really didn't have a nervous supply to them. And really, what we know now is that that's nonsense. Nerves play a key part of the tumor microenvironment. So just like we think about blood vessels and immune cells as part of the tumor microenvironment, nerves are right there. And it turns out that they probably play a pretty big role in modifying tumor biology, and also how a tumor can respond to different therapies. So when I first, you know, the history of this research is that when I first joined the faculty here, my graduate research had been using dogs as a model. And these were purpose bred dogs as a model for studying radiation induced erectile dysfunction. And it was interesting work and it was impactful, hopefully. But I kind of got here to the vet school at NC state, and I wanted to transform that research and maybe setting a problem that was more relevant to our own patient population. You know, in however many years I've been a veterinarian, I've never had a client complained to me that their pet is impotent. But I certainly had clients described that their pets with cancer are suffering pain. And certainly I have caused patients with cancer to endure pain as a complication of the cancer treatments that we prescribe. And so I kind of repurposed the information I had in my head and the knowledge I had gained in graduate school about how radiation causes peripheral neuropathy is to be able to study pain as a complication of cancer treatment.
Dr. Nolan: And so some of that work has been done in dogs and cats with cancer that are undergoing treatment in the clinic, where we've focused on trying to develop methods to measure the pain that's caused by cancer treatment. And some of this work has been done in preclinical models in the laboratory, where we can, at a more molecular level, dissect and manipulate nerve biology.
Dr. Nolan: The bulk of our research is funded by the NIH with the idea that, for example, radiation, chemo, radiation often causes a lot of acute pain as a complication of treatment. Most of our models and interest in the lab focus around head and neck cancer. So head, neck cancer and people is depending on how you count the six or seventh most common cancer globally, somewhere around 60,000 Americans that are diagnosed each year with head and neck cancer.
And in some patients, it's a highly curable disease. But almost every one of those will endure surgery and or intensive courses of chemo radiation and ultimately be prescribed opioids for intense treatment associated with pain. Those opioids don't necessarily work all that well, but patients kind of get hooked on those drugs long term. And so the management of cancer treatment induced pain is contributing to the massive opioid epidemic that we have in this country.
And we have kind of similar situations in vet med, right. Like very often do post-operative radiation for anal sac tumors. But when I think about the patients I've treated with that sort of radiation therapy, I think about dogs getting really intense perineal dermatitis and chasing their tails and literally having to sedate them so that they can wait for acute radiation side effects to heal.
Because the analgesics we have available don't work particularly well. And so we developed this research program. Dr. Lascelles and I developed this research program, along with some other collaborators here, to try to understand better the molecular mechanisms and cellular mechanisms of pain that are activated by cancer treatments, primarily radiation, chemo, radiation, and along the way, the goal there is to identify pathways that we can target and new molecules that we can develop as analgesics.
But along the way, we've also found that some of the proteins and factors that induce and promote pain also have effects on tumor biology. And so we developed a series of experiments where we started manipulating pain modifying molecules in the setting of cancer. And we found that there are actually some strategies where you can simultaneously reduce pain.
And this is all in preclinical models. We've not shown this in patient populations. That would be the next step. But you can simultaneously reduce cancer treatment induced pain while improving local tumor control, potentially even reducing metastatic disease burden, which is kind of a fascinating idea that the local tumor innovation may play such a strong role in kind of global tumor biology within the body.
It's sort of a provocative idea, and it's not an area that a lot of people are researching. And, you know, that's sort of my mantra is pick the low hanging fruit, pick the niche that nobody else is in and tackle it so that you're not playing in the sandbox where all the other experts are.
Dr. Venable: I certainly like that idea of the low hanging fruit, but it really is fascinating. So not only are and correct me if I'm not understanding this right, but so it sounds like, you know, trying to help just pain in and of itself because nobody likes pain. But what you're also finding is that if that pain is bad, like it seems to affect the cancer itself. Is that right?
Dr. Nolan: Yeah. So I'll explain kind of what we've seen in mouse models and maybe try to help explain corollaries in patients. In mice, when we induce radiation induced oral mucositis, one of the major players in that pain signaling is called TRPV1. TRPV1 is the receptor for capsaicin. So when you eat spicy food, it burns your mouth because you're activating the TRPV1 receptor. And it turns out that spicy food makes you sweat because TRPV1 is also the receptor for heat. So heat and chili peppers have the same neuronal receptor, and you can do this easily in a patient population. But in mice you sure can. You can delete sensory neurons and express TRPV1. And if you do that you massively reduce the amount of pain those animals experience when they have oral mucositis.
To some degree, you actually reduce the mucositis itself, which suggests that those neurons have some sort of trophic effect on the mucosa. But then you can also simultaneously reduce tumor growth. You get a radiation sensitizing effect that delays primary tumor growth and also seems to delay metastasis. A lot of that is done in highly contrived mouse models. And so we desperately need validation in patient populations.
And that's kind of the next step is figuring out pharmacologic strategies that you can deploy in patient populations safely versus what we can do an analysis. You know, I can I can literally use a molecular scalpel and delete out or oblate every sensory neuron in the body that expresses TRPV1. And you couldn't easily or safely do that in a human or a dog or a cat.
So we've got to develop the tools pharmacologically for doing that in a way that can be clinically deployed. But, you know, we're working. I got a postdoc in the lab right now that's looking retrospectively at some data from dogs with hemangioma sarcoma that have undergone a splenectomy and adjuvant doxorubicin chemotherapy. And this is unpublished. And hopefully we'll get this out in the literature sooner than later anyway.
But it actually looks like dogs that receive post-operative outpatient opioids. So dogs that are sent home with a fentanyl patch develop metastases earlier than dogs that don't. So if you use a non-opioid analgesic post-operative and a dog that's had a splenectomy and later on goes on to get doxorubicin, the opioid may actually allow for metastatic escape sooner.
So allowing that patient to be treated with certain analgesics may modify their long-term prognosis. And again these are you know this is data from a retrospective cohort of patients. It I don't want anyone listening to think that they should stop using fentanyl in their cancer patients for management of perioperative pain. But I do think it's an interesting hypothesis to put out there that by modifying the pain experience a patient goes through, and maybe having more carefully think about the analgesics that we choose to modify a patient's comfort, we may be able to actually modify their long term prognosis in terms of metastatic risk and long term survival.
Dr. Venable: So that is fascinating. So it sounds like with the mice if you take away the actual receptor so they're not feeling pain. That can be helpful. But in dogs at least again I know it's very early on, but it's not just the matter of taking away the pain because that's not necessarily affecting the receptor in the same way.
Dr. Venable: So that's why maybe fentanyl is maybe not helpful because like, maybe the dog has less pain, but that doesn't mean it's helping to treat the cancer in a way. Is that right? Yeah.
Dr. Nolan: Yeah. I mean, I think like everything else in biology and in oncology, there's multiple factors at play. But for example, opioids themselves can be immunosuppressive. And so, you know, maybe there's undoubtedly a dog that has a splenectomy needs some form of analgesia. But maybe a strong opioid is not the best way to go about doing that, because maybe that opioid is causing enough immunosuppression that in that period soon after surgery, it allows tumor cells that are circulating to home in on a metastatic site. That could become problematic in the future. And maybe an alternative analgesic might be more advantageous in terms of thinking about the long-term outcome for that patient. So whether that is, you know, thinking about using NSAIDs or maybe some of these growth factor inhibitors that have become available, I don't think we're at a point yet where we know what analgesics have exactly what effect or which ones we should be picking, but I think that these data all suggests that more research is needed, more thought needs to go into it, and eventually we may be able to tailor our analgesic protocols not to cure cancer, but to at least have a measurable impact on patients.
Dr. Venable: That is really fascinating, and it does make us, at least me. It makes me realize how much the immune system is affected by things that you don't really think about. Like, I wouldn't really think about the opioids in that setting affecting the immune system, or it reminds me of, you know, I heard some talks. This has been a couple of years ago about the microbiome and how different antibiotics could actually end up affecting the microbiome that affects the cancer. Like just it's kind of crazy how many things are at play. It would be nice if it was just A to B to C.
Dr. Nolan: I agree, especially because I'm not an immunologist and immunology is hard.
Dr. Venable: It is. It's really confusing, especially in cancer, because it's almost like a broken car, right? Like it's not working. Right. Or the cancer wouldn't be there. So or at least I mean, that's a very simple way to look at it. But I feel like to some level it's not even the normal, which is already confusing.
Dr. Nolan: 100%.
Dr. Venable: That's really interesting. It also makes me think about NSAIDs, because we know some insects can have some tumor effect, but it would be nice for just something like hemangiosarcoma, you know, because I don't necessarily think about NSAIDs with that cancer. But if you're seeing it with something as simple as fentanyl, I bet there is, you know, who knows different drugs that could be affecting it.
Dr. Nolan: Yeah. These are tough questions. But you know, like I said, we're just at the beginning of this. I'm just trying to throw ideas out there. And ultimately it's going to take a lot of work to kind of sort through this and figure out how clinically meaningful these ideas actually are. But before we get some clarity with more research.
Dr. Venable: Yeah, that's really interesting. Now in this project with pain, that's when you're also looking at, like you were saying, with people like that's one that you're doing both, and you guys are in a pretty unique setting where you're located to work on human research as well. Is that right?
Dr. Nolan: Yeah. The Research Triangle Park here is a unique geographical setting. The vet school is in Raleigh. 40 minutes down the road is UNC Chapel Hill. They have the Lion Burger Cancer Center 30 minutes. The other direction is the Duke Cancer Institute in Durham. And then kind of in between all of that is this huge area called the RT, Research Triangle, where there's a lot of industry from a big pharma, small pharma, biotech software. They're headquartered here. Siemens, the imaging company, is now here in RTP. So there's just a huge amount of interest in biomedical research from the biology side, from the drug development side, from the technology and engineering side. So it's a really rich environment to be in. I've been really fortunate to have amazing collaborators at the medical schools on this pain front. I work with this amazing physician scientist that she used to be at Duke. She's now moved up to the University of Pittsburgh. Her name is Yvonne Mowery. She's a physician radiation oncologist who sees patients with head and neck cancer. And that's been a really fun, rewarding collaboration. Just kind of getting together and sharing ideas and me helping with some of her research and vice versa, that kind of that conversation that goes back and forth between veterinarians and physicians can be really fun and informative.
Dr. Venable: And that's so cool that you guys have so much right there. Like, I'm sure it's really fascinating, just all this stuff coming down the pipeline just in that one small area, right. Like how it's all close together. That is really exciting.
Dr. Nolan: Yeah. Yvonne and I, so I mentioned she's a head and neck physician and her research lab uses mouse models to study head, neck cancer. She also in the clinic runs clinical trials for head and neck cancer. And she's interested in the combination of radiation and immunotherapy, forehead and neck cancer. And then she adds into the mix. These drugs that are developed to modify how radiation interacts with DNA, basically drugs that inhibit DNA damage repair. So it makes radiation more lethal. And she was sharing with me that, you know, she's got these mouse models highly contrived. She can ask certain questions about her radiation plus immunotherapy, plus DNA damage response inhibition and mouse models. She can answer other questions in human clinical trials, but in the humans like for her to get FDA approval for a trial, it's these patients that have very refractory disease and stage disease. There's a very limited ability to ask questions in a useful manner in those patient populations. And so she asks, you know, is there something that we could do in dogs or cats is kind of intermediate. And so we've had this really fun collaboration over the last few years taking one of these DNA damage response inhibitors. It's a small and a small molecule inhibitor of a molecule called ATR. So we took this ATR inhibitor and teamed up with a guy that is at Hopkins who's a pharmacist and pharmacologist, originally trained as a pharmacist, and then went on to get a PhD in pharmacology. And so Jan Beumer at Hopkins helped us to take this ATR inhibitor called conservative, that Ivan had been working with in mice, had visions of running human clinical trials with.
He helped us formulate it for cats. So we developed it into an injectable drug for cats. And then he has PK assays so he can measure drug levels in cats. And so we just finished some pilot clinical trials where we've put this drug camonsertib. Started into cats with oral squamous cell carcinomas with or without radiation therapy.
And this collaboration. So it involves Ivan up at Pittsburgh now. Jan at John and Hopkins a team of people. Here is Jen Luff is a pathologist Kyle Mathews a surgeon. I've got a really talented veterinarian Effie Palyvou who's a clinical research fellow in my lab. And then we've been working with Maciej Parys, who's a cancer geneticist in Edinburgh with CanCan Diagnostics.
Dr. Nolan: And this team of people we've been running this feline clinical trial. And honestly, it's the first time in 15 years of doing this that I've seen cats seemingly cured of their oral squamous cell carcinomas. Really inspiring. Fun story. I've got a colleague here who's an equine internist, and she has a cat who she brought to me a couple of years ago with a sublingual, I guess, on its epiglottis, a squamous cell carcinoma.
And this is when we were just starting this clinical trial with camonsertib. But we weren't ready to put that drug into cats yet. And so we enrolled her cat into the radiation only arm of the clinical trial. And the tumor melted away but recurred within three weeks. So like this. You know, the typical sad story of a cat with an oral or fringy cell carcinoma, but with radiation, it shrinks back, it gets short term palliation, and then it comes back.
And I said to her, well, you know, I don't really know what to do other than we had just gotten back some safety data about camonsertib in healthy cats, and it looked manageable. And the PK looked pretty exciting. I said, you know, we could try re-radiating your cat. It's only been three weeks, but we could try re-radiating with this drug commands or Tib. And this is an early phase clinical trial really focused on safety. I have no idea if it's going to help. This was 18 months ago. The cat's now 18 and still disease free, and he comes in to see me so that she can show how happy and healthy he is now. And he's become the poster child for this exciting research project. It's amazing, you know, because it's this fun story about how I was able to help a colleague, help a patient. It's family. We took a little bit of risk, but now it's become the poster child for our research program evaluating this ATR inhibitor and radiation and really kind of being a nice example of how we can develop these comparative oncology models to fill gaps between rodents and humans and help pets and their families along the way. And really fun to be able to do that to help one of our colleagues.
Dr. Venable: That's amazing. Yeah. No, I, I hope it still continues to look good so we can all get that drug because that is such a terrible cancer. I mean, it's like you said, you radiate it and it just keeps crawling and none of the medical stuff works. So that would be amazing. That is so fun. And I love also how much research you're doing on this. Like, you guys are really getting all the important pieces. I mean, I know that's expensive. It takes a lot of time and money, but that's awesome that we're getting all the needed data and you have such a cool team that you've got working on this, and you're looking even at the genomic part of it. You know, you said with CanCan with Maciej, that's really cool that you guys are looking at all those different pieces, and I'm really excited about that one. You're going to have to keep me posted on how that one goes, because certainly everyone's going to want that in the clinic.
Dr. Nolan: Yeah, it's been phenomenal. I mean we kind of piece this together started a few years ago. We had a bit of funding. We were really fortunate to get a small grant from the Every Cat Feline Health Foundation. We got matching funds from the NC State College of Veterinary Medicine, and we just cobbled things together. Everyone just volunteered a lot of time and worked really hard, and we've been able to make a huge amount of progress.
We're just getting ready to put all this data together for publication, and it's a really small initial kind of early phase clinical trial, but it's exciting. I think that the biggest trick will be figuring out how to make this drug that's been developed for human oncology accessible at a price point that pet owners can afford, and that'll be a challenge.
So maybe it can be like the next palladia story where we just change like one very small bit of its chemistry and can sell it as a veterinary drug that'll be more cost accessible. I'm not sure that's going to be an interesting challenge to think through, but it's definitely been exciting.
Dr. Venable: Yeah, no, I love it. And I like honestly that it's an injection because so many cats, it's just impossible to give them oral med, especially with the tumor in the mouth. So the injection part to me also sounds really good.
Dr. Nolan: Yeah, I'm not a cat whisperer, and the idea of having to pill a bunch of cats that are in the clinical trial, especially cats that have oral tumors, you know, their mouth already hurts. They have these fragile mouths, and I didn't want to hurt them. I mean, fortunately, the clinical research fellow that I hired, Effie is a real cat whisperer.
And so I think she'd be able to get anything into a cat. But if I had been left in charge, it would have never happened. So yeah, being able to do injectables was important to me. And, you know, we send home diabetic cats with insulin to be injected and pet owners are able to manage that. So, you know, even if this were to be used as a standalone drug or something like a chemo sensitizer in the future, hopefully it would be accessible in that manner.
Dr. Venable: Yeah, yeah. No you're right. Owners do insulin all the time. I think as long as you know, it's not like a big needle. Like something more like insulin. That seems really doable. So I agree and I think there's probably some owners that would prefer injections over pills for various things with their cat. Right. It's just going to be more manageable.
Dr. Venable: For sure. Well, this is really exciting. I love that story. I think it's a great place to kind of wrap up our conversation of learned so much just about you, but the different research and everything you've going on really excited about the pain and certainly the oral tumors, that is really exciting stuff. And so as we kind of wrap things up, I always like to ask people, who would you recommend as another guest on this show?
Dr. Nolan: Yeah, it's a great question. So we've talked a lot about comparative oncology and something that has always really fascinated me, possibly because I thought about doing it myself at one point is when folks pursue both veterinary and medical degrees. So with that in mind, my suggestion would be Felicia Lew. Dr. Lew is a veterinary medical oncologist. She trained at Tufts and then worked in private practice for a number of years, went back to medical school to become a physician, and now she's in her second year of radiation oncology residency at the University of Washington. I had a chance to meet her at a conference recently, and just her career trajectory is really, really interesting. I think it'd be great for your audience to hear more about how she made those decisions and what her goals are.
Dr. Venable: Right? Right. And just the comparison. Like there's a lot of similarities, but then there's a lot of differences. So that is really fascinating. Yeah, I think I've thought about med school at one point, but I'm like, I've, I don't know. So that's really cool that she actually went for it and is doing it.
Dr. Nolan: Yeah. Rachel, it's never too late.
Dr. Venable: No, I'm good. I'm quite happy where I am, so I'm all good. It's one of those sometimes, I think you're in school for so long it feels weird to stop. So it's like, well, what else could I learn? Maybe I'll just get this other degree. But now I've been out of school long enough that I'm good.
Dr. Nolan: I agree.
Dr. Venable: Well, Dr. Nolan, thank you so much again. It's just been amazing to chat with you.
Dr. Nolan: It's been great to chat with you. Thanks so much for the opportunity.
Dr. Venable: Well, that's it for this episode of the Veterinary Cancer Pioneers podcast. If you enjoyed this episode and gained valuable insight, we would be so grateful if you could share our podcast with your friends and colleagues. And it would be even more wonderful if you want to give us a five-star rating, positive review, or any kind of feedback on Apple Podcasts or wherever you listen. The Veterinary Cancer Pioneers Podcast is presented to you by ImpriMed.