November 10, 2022 — Dr. Kelly Diehl talks with Dr. Barb Kitchell about the latest research using repurposed drugs in veterinary medicine, with a focus on new cancer therapies for pets.
Resources:
Dr. Kelly Hume Cornell University: https://www.vet.cornell.edu/research/awards/202206/helping-more-dogs-supplements-and-drug-repurposing-canine-lymphoma
Losartan and osteosarcoma study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8866227/
Human drug study looking at electronic health records mentioned in podcast: https://ascopubs.org/doi/10.1200/CCI.19.00001
Use of machine learning in cancer drug repurposing in people: https://pubmed.ncbi.nlm.nih.gov/31904426/
0:00:11.3 Dr. Kelly Diehl: Welcome to Fresh Scoop, Episode 50, Repurposed and Translational Drugs: Using old drugs in new ways. I'm your host, Dr. Kelly Diehl, Morris Animal Foundation, Senior Director of Science and Communication. And today we'll talk to Dr. Barbara Kitchell. Dr. Kitchell is a practicing medical oncologist and director of VCA Residency and Specialty internship programs in their hospital system, and past president of the Veterinary Cancer Society. Dr. Kitchell also was on faculty at the University of Illinois and Michigan State University. And welcome, Barb. Thanks for joining us.
0:00:50.8 Dr. Barbara Kitchell: Thanks so much, Kelly. Thanks for asking me.
0:00:54.0 DD: First, I always start out by asking folks, tell us a little bit about yourself and what led you to become a veterinarian and then of course ultimately an oncologist.
0:01:06.4 DK: Well, I have been doing veterinary medicine now for 43 years. I've been an oncologist essentially for 40 of those. And I was a farm girl in Indiana, and it was always my job to wrap the horse legs and take care of all the critters. And so, there was no question I was going to be a veterinarian. But during veterinary school, I fell in love with small animal medicine, and I did a residency in internal medicine at UC Davis. But while there, I just fell in love with oncology. And so, I did another program in oncology. And after practicing for about five years, I realized I did not know anywhere near enough about the science of cancer. So, I went back and got a PhD in comparative pathology with an emphasis in cancer biology. And then that's what led me to the faculty positions. And then about 10 years ago, I decided, oh, I'm going to move into the private sector and see what that's like. So that's what I've been doing. I live here in Albuquerque, New Mexico now, and I'm both a practicing veterinarian, an oncologist at VCA Veterinary Care Referral Center, as well as my corporate position taking care of the residents in the VCA hospitals.
0:02:39.4 DD: Right. So, Barb's very a busy person.
[laughter]
0:02:45.0 DK: Yes, I'm always busy. [laughter]
0:02:46.6 DD: Yeah. And I have to give some props here, because I actually had the pleasure of hearing Barb speak a little bit about this topic on... with FidoCure, which is a company that looks at this kind of topic of using different kinds of therapies for specifically cancer. And so, I arm-twisted Barb to come on this podcast and talk with our audience about this topic. And that is really my segue into what exactly... When we talk about... because I think I hear a lot more about repurposed drugs, and then translational drugs, and what are they and can you give us a example of each?
0:03:38.6 DK: Well, let's start with translational, because there really are very few, in fact only maybe three products that are licensed specifically for veterinary indications in the cancer drug world. Everything else we use and have used for the entirety of my career are human drugs that are translated for use in animal patients. And translational medicine actually is bidirectional, because we will provide clinical trial animal model systems for novel drugs or concepts that can then be translated back to be used in human patients. So translational medicine is that interface between cancer care for animals and cancer care for people. And then what repurposing is, this has caught fire probably in the last maybe five years or so, on the human side.
0:04:52.7 DK: And now we are in veterinary medicine also jumping on the bandwagon. And what repurposing is, is there are compounds or medications in the world that have anti-cancer properties even though their original licensed indication is for other disease processes. And so, there are multiple lines of evidence that have been developed that this strategy can help our cancer patients, both human and animal, to live longer and healthier lives, but even more importantly, it provides an avenue for cost containment. Because developing a new cancer drug can take 10 years and can cost literally over $ 1 billion. And only about 6% of the compounds that are initiated in the cancer treatment realm actually ultimately end up being licensed. So, what repurposing does is it allows us to look at drugs that are already licensed, that we know the pharmacokinetics, we know the toxicology, what their side effects and mechanisms of action are, and then we can figure out how to apply those drugs to our patients with cancer. So, there's just a host of examples of that type of strategy going forward right now.
0:06:33.8 DD: Right. And I think for those of you listening and Barb's already mentioned it, it seems to me the area that we're seeing this type of approach is primarily in cancer therapy, in animals. I don't think I've seen a lot of... I mean, translational forever, right? We've been using drugs to treat a variety of diseases. And I think you bring up that good point for a very long time that are not "technically approved" to be used in animals. But I think the real focus with this approach has been cancer. Am I correct in that, pretty much?
0:07:12.4 DK: Well, I think so, but there's also repurposing in other areas, for example, repurposing of compounds that might have anti-COVID activity. There's a huge flurry of that most recently. And spinoffs from that are looking at drugs that might have an impact on things like pulmonary fibrosis that we've never looked at before. So, there are other areas of medicine where drug repurposing strategies are being explored.
0:07:40.0 DD: Right. And actually, that made me laugh a little bit, Barb, because I'm going to tell everybody here, and we're all adults, one of the unusual areas that we use, for example Viagra in veterinary medicine is for pulmonary hypertension, which of course was part of its original purpose in people. And we've used it for that. And you touched to this a little bit, which was, this may be interest in doing it for cost purposes and why... I guess maybe people who are listening are like, "Why didn't we know this before?" Can you touch on why all of a sudden we're looking at these drugs in new ways from maybe the purpose they were originally developed?
0:08:33.8 DK: Well, I would say that that stems from several lines of evidence. The first would be just simply anecdotal things that have happened to individual patients, and then having scientists go, "That guy with lymphoma took doxycycline and his lymphoma went into remission." So, he took the doxycycline for an infectious disease, but yet it had an anti-cancer effect. And so those one-off, "Wow, that was weird. Why did that happen?" led then to deeper investigation. And the reason we can come at this in a very scientific and robust way is because we have massive computer power now. So, another way that people have investigated this is to do what's called a cohort study where you look at a group of patients, some of them have the problem and have been given a drug for a different indication, and then another group doesn't get that drug and then you compare their outcomes. And for some of these compounds, they find that human patients who were taking the statin or were taking the antihypertensive drug, actually had better survival outcomes than those patients who were not.
0:10:06.6 DK: So that led to medical record data mining. So, looking at the electronic health records, they call them EHRs in people, and we call them EMRs. The electronic health record capture allows scientists, statistical investigators to go into that huge data set and identify features that would be missed otherwise. So, I'll give you a 2020 paper example. There were about 50,000 patients at Vanderbilt human hospital who had a variety of different cancers. And they looked at all of the concurrent medications that these patients were taking, not for their cancer. And these patients who were on one of these compounds for a specific length of time, and then they looked at their outcomes. In doing that, they identified about 23 compounds that actually seemed to benefit the patients who took them. Then what they did is they got 100,000 patients from the Mayo Clinic database and they cross referenced these populations. In doing that, they winnowed it down to about nine compounds that showed benefit. So that gets us off to the races, right? Here are nine compounds in real world settings that appear to have impacted the outcomes of cancer patients. So now let's go back. So that type of approach is one of the in-silico sort of on the chip evaluation.
0:12:01.1 DK: And now let's go back in cell culture and let's go back and see why these compounds might have made a difference. And then let's do... We don't have to do a phase one clinical trial. Let's take a select population of patients with a given cancer and do a phase two and do it prospectively so we can really validate this and then go on to a phase three trial where we really get the robust statistical assessment. And then to make it even worse or better, [laughter] there are now machine learning and artificial intelligence strategies where the computational scientists will take protein structural databases like four known cancer associated proteins, and that will encompass things like what are the mutations, what is the amino acid sequence, what is the charge, what is the hydrophilicity or hydrophobicity and races and all that associated with that particular molecule? And now we have that information, we're going to partner that with a deep dive into crystal chemical structures, to say, "I can screen 50,000 drugs or compounds, which one fits this mutation the best?" And then they are able to validate that approach. And through all of these various approaches, we are learning that certain non-cancer compounds, non-antineoplastics, actually can have benefit in a cancer setting. So, it's super, super exciting stuff.
0:14:05.4 DD: Right. And I think you mentioned it, Barb, and for those of you who are listening and didn't catch it, Barb's talking about how we can skip what's called phase one, which is usually your toxicity studies because we already know this stuff. And that cuts down... It cuts down time too, as well as finances.
0:14:26.4 DK: Yeah. And side effects, because we know what the side effects are, so we know how to partner these drugs with other drugs that have known side effects. So, we know how to make it safe for patients without having to do those preliminary safety trials.
0:14:43.7 DD: Right. Can you give us a... I'm going to put you on the spot. Give us a couple of examples of drugs, and they can be repurposed or translational that are just really exciting to you right now as you treat cancer, see and treat cancer patients.
0:14:58.8 DK: Oh, there's a ton that's going on right now in veterinary medicine. There was a paper published in February of 2022 out of Steve Dow's lab at Colorado State University, where they combined an antihypertensive drug called Losartan with an anti-cancer drug, which is licensed for veterinary use, called Palladia. And working with these in combination, they discovered that it had an impact on tumor metastasis. And it's an immuno-modulating approach, so it affects the macrophages, the immune cells that help clean up dead tissue and remodel injuries and things like that. And by combining these drugs, they were able to show that osteosarcoma cells in culture were actually impaired. And better yet, in their first study of dogs who had metastatic pulmonary osteosarcoma, so the bone cancer had spread to the lungs, we know that historically the best that the Palladia drug, which is the anti-cancer drug, the best the Palladia drug can accomplish in that setting is about a 10% benefit to patients. But combining the Losartan with the Palladia, they had about a 50% rate of improvement in the patients as a consequence of that combination. So that's very, very powerful. And that's just one example, there are many others.
0:16:55.7 DK: There's a drug called sirolimus, which is a very old drug derived from a fungus, from Rapa Nui, which is Easter Islands, and it's (also) called rapamycin. And it was discovered that mice that take this drug can live twice as long as mice who do not. So that prompted this interest in the gerontology community about, well, if this makes really old mice, maybe it could make really old people and in between there, let's look at a population of dogs to see if it will extend their longevity. So, it's... I just heard this term, it's a gerostatic [laughter], it stops your geriatric progression. But... So, there's probably about 3000 dogs now in the Pacific Northwest that are on that compound doing a long trial, it'll take seven or eight years for the results to be available because you take a middle-aged dog, you start some of them on a placebo, and then your control group, you start some of them on the sirolimus, and you see who lives the longest statistically. But in the cancer world, we understand that sirolimus works through a specific cell signaling pathway, and that pathway is often broken in cancer cells. So, it's the PI3 kinase/AKT/mTOR pathway.
0:18:44.0 DK: And there's normally a break on that signaling, which is a molecule called P10. So, there's tons and tons of patients who have P10 mutations that mean they lose the breaks. So those cells are constantly signaling through that pathway. And what sirolimus does is it restores the breaks by blocking the mTOR molecule, which is downstream of the broken break up above. So, we have been using sirolimus for a variety of indications in cancer care. And if we get a gene profile from, say, FidoCure or from Vidium, the other company that does genomics for dog tumors, and it says we have a P10 or PAI3 kinase or something in that pathway that's aberrant, that's an indication to specifically use this drug. So, in that case, it's personalized. It's personalized, repurposed, and translational.
[laughter]
0:19:56.3 DK: So, it does all the things.
0:20:00.7 DD: Right. So yeah, that's pretty exciting. I actually have to... Full disclosure here, the study that Barb is alluding to with the rapamycin for aging is part of the Dog Aging Project. And my dog is actually in the TRIAD arm, which is, she has cleared some hurdles and she's getting some mystery drugs.
[laughter]
0:20:22.2 DD: Because of course I'm blinded. I don't know what I'm giving my dog. And actually, the person... People who are checking her at CSU, they don't know which drug I have, which is the gold standard. So, I'm hoping she lives longer. I hope she's not on placebo, but we'll find out. She's going to be gone, I mean realistically before we ever sort all this out, but I'm really excited that my dog could be contributing to this thing. Because rapamycin is kind of an interesting medication as you said, Barb. I think we're just scratching the surface of that. What other things are you seeing out there or you're using or doing in your practice?
0:21:05.9 DK: Oh, there's a lot now. I had a client bring this to me, but it turns out that certain of the anti-parasitic agents have the potential for anti-cancer activity. And the one that she was interested in using in her particular dog was fenbendazole. So, the things in that class of chemicals, albendazole, fenbendazole, mebendazole, there's several types in that family. But they actually can act as what's called mitotic spindle poisons. So, some of our traditional chemotherapeutics, like vincristine, vinblastine, Taxol, those anti-cancer drugs act as mitotic spindle poisons. So, it's known that one of the mechanisms of action of these drugs is that in the parasite, they kill the parasite by breaking down this mechanism in the parasite. So, the concept here was, if we keep them on this continuously, it might be additive to the anti-cancer drug strategy. So, we're kind of tentatively looking at that for our lymphoma patients. Very, very early days. But I will tell you that this individual's dog with the prognosis at the outset, when we first met this dog, I would have said four months survival even with chemotherapy. And that dog's out over two years.
0:23:00.2 DD: Wow.
0:23:00.9 DK: So, you go, "Well, that's an anecdote." Right? So that carries no statistical weight whatsoever, but it's certainly provocative and it makes you start to wonder. Another agent that we're looking at is atorvastatin or Lipitor. And it turns out that in human medicine, patients who take Lipitor, it's one of those compounds that has a positive benefit in a variety of different cancer outcomes for people. But just incidentally, by the way, you're taking Lipitor because you have high cholesterol, oh, and by the way, it's helping you live longer with your cancer. So, people are exploring the mechanisms whereby that can be biologically beneficial. And one of our most common mutations in any cancer is a mutation in a gene called P53. That's a master regulatory gene that controls a variety of pathways, several pathways in the cell in health. And when your P53 system breaks down so that P53 can no longer do its normal job, it allows cancer to go very fast and to be resistant to chemotherapy.
0:24:29.0 DK: And it turns out, in certain types of P53 mutation, not all, but in certain types, being on atorvastatin can actually be of benefit to you. So, Lipitor, dirt cheap, generic... I think one of the things that we have to remember is that these compounds, these repurposed compounds, are not directly anti-cancer, they're complimentary to other things most of the time. So, we are kind of gently embarking on this. You have a P53 mutation, let's explore that and see if you might benefit from atorvastatin.
0:25:13.6 DD: Okay. Yeah, and actually that brings me to something that I was thinking about, which is, what are the biggest... What are misperceptions that you hear in your practice? Because this is pretty radical stuff. Sometimes it's new, it sometimes seems a little weird. What do you counsel people who come to you? Because we can hear all different kinds of things on the internet, and what do you hear? And actually, that was my next question was... That you reminded me was, what are some of the dangers maybe in this approach?
0:25:53.7 DK: Well, I think again, that these are going to be supplemental to primary chemotherapeutics, not stand-alone. So, when people say, "All I want to do is put my dog on IV vitamin C," for example, that's a strategy that is unlikely to work, although we know that vitamin C is beneficial for certain cancers because it alters the energetics inside the cancer cell. So, you can have people who are so convinced that this strategy they read about on the internet is so good that they don't need to do anything else. And that results in a shortened life expectancy and a worse outcome for that patient. The other thing, one of the drugs we have recently started to see used a fair bit in conjunction with a drug called doxorubicin are tried and true. Probably number one solid tumor drug in veterinary medicine is a drug called propranolol. So that's a beta-blocker. So, you can put patients on propranolol concurrent with doxorubicin, and theoretically enhance the benefit that the doxorubicin provides. So that work was initiated by Erin Dickerson's lab at University of Minnesota, following on from human studies in a similar vein.
0:27:29.0 DK: And it's a hemangiosarcoma combination in particular and is being investigated as such in multi-center clinical trials in dogs. But, propranolol is a beta-blocker, so you can have patients who become hypotensive because they're taking this drug when it's not their primary disease that you're treating. So, you can see those types of side effects that you would expect naturally from the drug you're using, and they can actually make your patient feel worse. So, I would say we have a variety of different potential landmines that we have to avoid as we go forward with these strategies.
0:28:21.1 DD: Yeah. And you know Barb, you're probably plugged into this better than I am, but what are you hearing out there? Like where are some... You mentioned some, but where are some other avenues of research that you're hearing about people are doing in, especially cancer obviously, and in animals that you find very exciting?
0:28:41.8 DK: Oh, I find all this repurposing to be exciting. Obviously, any new drug that comes into our hands we're excited to receive it, because we need better tools. It's finally... As I say, I've been doing this for 40 years, it's finally at the point where you can say, "I have more than these 12 drugs I had when I started this business." So, any way of advancing the field through combinations of medications, through understanding better indications to apply drugs, like, "Look, this is the genome... These are the genetic injuries we can find in this cancer, and these are the drugs that work best in this setting." It allows us to improve outcomes and to reduce the risk of side effects because you don't have to expose a patient to a drug that's not going to benefit them and has side effects. So, all of it is super exciting. I love being able to profile the tumors so that we understand what's wrong with the cell. And I love being able to say, "This drug is probably better than that drug for this particular indication," although all of these studies are ongoing. And we have to have lots and lots of validation studies before we can say, "This is the truth."
0:30:20.2 DD: Right. And yeah, it is an exciting time because I think we always say... And you can correct me if I'm wrong, it seems like sometimes scientific advancements make big gains and then they plateau for a while. And...
0:30:33.5 DK: Yes.
0:30:33.5 DD: I would definitely say, being of the same era pretty much of you as far as practicing is, I can remember when I was a young veterinarian in vet school and in my internship and residency, we saw this big surge of anti-cancer drugs, and then we flat-lined for like 30 years... You know, 25 years. Right?
0:30:54.1 DK: Yeah, that's absolutely true. [laughter]
0:30:55.3 DD: Where we just don't see very much. And it seems like I'm hoping we are on another cusp of really giving people more tools and for people too, right? Because...
0:31:04.9 DK: Yeah, absolutely.
0:31:06.0 DD: A lot of what we find is there.
0:31:07.6 DK: Absolutely.
0:31:08.9 DD: So, if people are interested, Barb, is there a place they can go for more information, whether... We have a lot of veterinarians and veterinary techs who listen, but we also have some pet owners. Where are some good places for good information?
0:31:22.3 DK: For repurposing? I would say, first, you'd talk to a veterinary oncologist who keep abreast of what's going on in the field and learn these things as we all do, as we go along. I would say the veterinary colleges like Colorado State, UC Davis... Cornell has a repurposing program with Dr. Kelly Hume, there are a lot of programs right now... I'm probably leaving out some of my friends and I'll feel bad like... I'll feel bad afterwards, like the Academy Award ceremony.
[laughter]
0:32:00.4 DK: But yeah, contacting a university that has an active cancer research program. And they will probably be able to give you really up-to-the-minute information.
0:32:15.1 DD: Okay, that's great. And you know what, we will post these in the show notes, so that gives Barb a chance to complete her Academy Award speech...
[laughter]
0:32:22.3 DD: If she's forgotten anyone... You can email me... Email me later. And I think... You bring up a really good point, and I'm not a veterinary oncologist, but I'm a veterinary internist, and I think it's really important... I just know that I say this even at Morris Animal Foundation, we have people call us about some of our research, and I always tell people, it's probably worth it talking to a veterinary oncologist, because not all of us can keep plugged in to all of this all the time. And...
0:32:50.3 DK: Oh boy. Yeah.
0:32:52.6 DD: They're a really great resource for your veterinarian to call or whatever. And don't forget that they're there to help. So, as we wrap this up, Barb, what's your take home message for our listeners?
0:33:09.2 DK: I would say my take home message is, it is an exciting time in veterinary oncology as well as human oncology, as these new tools are developed. And in our world where we don't have really deep pockets and third-party pay very often for medications, turning to a licensed medication that we can use in this setting can save people money and allow them to treat their animal where the similar treatment profile for a human patient might cost thousands of dollars a month, and we can do it for hundreds. And so that affordability piece for me is really heart-warming. Because everybody wants their dog to live and be happy and not suffer. And these new approaches can help us to achieve that ultimate goal.
0:34:15.3 DD: Yeah, absolutely. So, thanks so much. That does it for another episode of Fresh Scoop. And once again, thanks to the wonderful Dr. Barbara Kitchell for joining us. We will be back, of course, with another episode next month that we hope you'll find just as informative. The science of animal health, of course, is ever-changing as we just learned today. And that's awesome, and we need cutting-edge research information for our patients and for those of us that are pet owners and caregivers for our beloved animals. And that's why, of course, we're here.
0:34:51.6 DD: You can find us on iTunes, Spotify, Google Podcasts and Stitcher. And if you liked today's episode we'd sure appreciate it if you could take a moment to rate us because we want others to 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. You can also follow us on Facebook, Twitter and Instagram. And I'm Dr. Kelly Diehl and we'll talk soon.
