Good evening everybody and welcome to tonight's webinar. My name is Bruce Stevenson and I have the honour and privilege of chairing tonight's webinar. For those of you that haven't been with us before, just a little reminder, we do record these sessions and, the recording will be available on the webinar vet's website, within the next 24 to 36 hours.
So if there's any slides that you want to pause that or go back to, the recording will be available for you to fast forward and rewind and look at them as you want to. We will not be able to rewind those slides or go back on slides tonight. If you have any questions for our presenter tonight, usual story, hover your mouse over the screen, click on the Q&A box and type them in there and we will hold those all over to the end.
So it's my great pleasure tonight to welcome Doctor Tam. And he is the Barbara Cox Anthony Professor of Oncology and the director of the clinical research at the Colorado State University, Flint Animal Cancer centre. He has authored over 190 peer reviewed publications, 25 book chapters in veterinary and basic Cancer Research, is the co-editor for the most recent edition of the textbook Withrow and McEwen's Small Animal Clinical Oncology, and he is the editor in chief of the Journal of Veterinary and Comparative Oncology.
Dr. Tam is the president of the Veterinary Cancer Society and 2023 recipient of the Alan Kelly International Prize in Canine Health from the Kennel Club. Doctor Tam, welcome to the webinar vet, and it's over to you.
Thanks so much, Bruce, and, thanks as always for the invitation to speak. It's always a, a great pleasure to get to deliver some content for the webinar. So thank everybody for their attendance.
I do believe I have an email address that is on my very last slide. So please feel free to utilise that if you have any questions about today's lecture that we don't get a chance to answer, or honestly, if you have any questions about cancer and animals at all, I'm always happy to reach out and converse with my veterinary colleagues. So with that, let's go ahead and get started.
This is my conflict of interest. I think for this hour of lecture, I do not have any conflicts, so we can speak freely. And we'll just dive right in here.
So this is an hour of lecture on what are referred to as receptor tyrosine kinases and their importance in veterinary oncology. So I think the first very simple question to ask is what in fact is a receptor tyrosine kinase and why should we in veterinary oncology be so interested in this in this class of molecule. So receptor tyrocine kinase is Are proteins that generally live on the cell surface, and their job is to kind of listen or sense to what's going on in the extracellular micro environment, usually through the presence or absence or concentrations of a variety of growth factor proteins that might be floating around out there, and then take that information and use it internally to influence the behaviour of the cell.
And why do we care so much about this class of proteins? Well, the simple reason is because there's an enormously large number of drugs that are actually approved for the treatment of human cancer that exert their effect through inhibition of signalling of receptor tyrosine kinaes. I have to let you know that I lied slightly on this slide, so this particular slide looks at all protein.
Kinases that that there are inhibitors for not only ones that are receptor protein kinases, but still it's a class of molecule that's very important and very, very druggable and for certain kinds of cancer, really the outcomes in some patients have been revolutionised thanks to this class of molecule. A really just nice example of this is actually shown here in the in the PET CT that you see here from a human patient. Who actually has an enormous gastrointestinal stromal tumour that you can see is very, very glucose avid here on this PET CT.
So this is a scan that actually injects radioactive glucose into the patient and then is able to sort of look at how much of that glucose is taken up by the tumour tissue and you can see just a couple of weeks after starting treatment with this particular. A receptor tyrosine kinase inhibitor, which is called amatinib, you can see a complete shutdown of glucose uptake, e.g., metabolic activity in this tumour, and this actually correlated down the line with a very profound reduction in the size of this tumour that actually lasted for a very long time in this patient.
And sometimes these really remarkable responses are things that we can see in certain patients. So you know, obviously this is an extreme example, but really a wonderful example of the way that this class of drug can benefit certain patients. So this is a very large and complicated group of signalling molecules.
So there are about 50 some odd different receptor tyrosine kinases that are all expressed actually in normal tissues. So every single cell in our body has multiple receptor tyrosine kinaes, and these receptor thyrocine kinases actually help to govern the normal function of cells in our bodies, so they aid in. Growth and survival and differentiation and all the things that normal tissues have to do.
However, they can definitely become in some cases wildly disregulated in a variety of different kinds of tumours. And this is just a few very, very simple examples of some of the receptor thyrosine kineses that have been identified in different canine and feline cancers and shown to actually contribute to the malignant phenotype of these of these cancers. Again, this is by no means a comprehensive list.
These are just a few examples, but just can show you that again there are multiple family members that are represented. And can contribute to the malignant phenotype that we see. And again there are different drugs that actually can be very specific in their ability to target very specific receptor tyrosine kinaes.
So again, if you just say, hey, we're going to give this dog a kinase inhibitor, well, what kinase is it? It could be any one of these 54 kinases that happens to be targeted. So again they can be very specific and again they can have very, very dramatic responses in some patients.
So let's look a little bit more carefully at sort of the molecular mechanisms associated with the way that these kinases are activated and the way that these kinases can be inhibited pharmacologically. Most of these receptor synch chinaes actually sort of sit on our cell membranes. So this is the membrane of the cell here.
Out here is the extracellular space. This is the intracellular component of the cell, and most of the time when when these knases are just kind of hanging out and not doing anything, they exist as monomers on the surface of the cell. But when their individual ligand sort of happens by, Two of these monomers actually dimerize, and when that dimerization occurs, it changes the structure of the of the molecule such that some phosphorylation events occur in the intracellular domain, and that actually leads to signalling through a variety of second messengers, the names of which we're not going to need to go through for today, but that can result in a variety of different kinds of phenotypic changes to the cells, including things like enhanced proliferation.
Enhanced cell survival under circumstances where that same cell might normally die without the input from that receptor tyrosine kinase, enhanced migration or enhanced invasion, enhanced blood vessel development, and you can see from from the list of things that these molecules can do that this can all result in enhanced malignancy or enhanced metastasis. So again, a very important type of signalling in cancer. So how are ways that this normal cell signalling pathway can be deregulated in tumour cells?
There are actually a variety of different ways that this can happen. So one of them, which is very tricky, is that the tumour cells can decide that they're just going to go ahead and make the growth factor ligand for a given receptor that it also expresses. So that sort of gives a constant supply of growth factor that's going to result in constant signalling through the receptor, and that's what's commonly referred to as autocrine receptor activation.
So the tumour cells just decide that they're going to just go ahead and make the growth factor that they need to stimulate that receptor. So a second way that we can see this happen is through overexpression of the receptor. So this could happen through gene duplications.
It can happen through epigenetic deregulation, but you can just have far, far, far more of this growth factor receptor present on the cell surface. And when that happens, either the cells can become exquisitely sensitive even to minute quantities of that growth factor, or in some cases you can see spontaneous dimerization leading to that same activation even without any growth factor presents just due to crowding on the cell surface. So another way that cancer cells can actually take advantage of the presence of these growth factors and activate them.
A third way and the way that we might be most familiar with in veterinary medicine is through the presence of mutations in the genes that code for these growth factors. And if there's an activating mutation, this can actually result in a situation where the receptors don't care if there's any growth factor around anymore. It's just going to be constantly signalling either in the presence or absence of the growth factor.
And again, that's what we will often refer to as constitutive activation. So no matter what's going on outside the cell, these receptors are just going to be signalling all the time, and you can see that that's going to lead to constant signals telling the cell to divide, constant signals telling the cell to survive, classic things that cancer cells are going to do all the time. So how can we as oncologists interfere with this process?
There are two basic sort of ways that we can do this. One is through the use of monoclonal antibodies, and the other is through the use of small molecule drugs generally that can be given orally. So how about small molecules or sorry, how about monoclonal antibodies?
So one sort of group of monoclonal antibodies actually target and bind to the receptors. And there's some great examples of these on the human side. So the very, very first monoclonal antibody that was ever approved for human cancer was a molecule called Herceptin.
That is an antibody that targets a kinese called HER2 that's present on some human breast cancers. And there are others, and the way these generally work is actually through blocking the ability of the growth factor to actually bind to the receptor, leading to again an inability to signal through that receptor. A second way that this can be done is actually rather than targeting and binding up to the growth factor receptor, you can actually bind up the growth factor itself and sort of take that out of the picture so it's no longer available to signal.
And one of the other very first monoclonal antibodies that was approved for cancer is a human monoclonal antibody called Avastin that's approved for colon cancer, and this actually targets. A growth factor called vascular endothelial growth factor that interferes with blood vessel growth. However, two of the monoclonal antibodies that are actually in our arsenal, not for cancer treatment but for pain control, labrella and Calenza, actually both target.
A growth factor called nerve growth factor that actually inhibits signalling through a receptor tyrosine kinase called Trek A. That's very, very important for the conduction of pain signals. So there are some examples of monoclonal antibodies that are actually in our practise already that actually work through this mechanism, although they're not primarily thought to be anti-tumor antibodies.
So the second way that we can actually interfere with this pathway is through small molecules. And these are small molecules that actually are orally available, get inside the cell, and interfere with those phosphorylation events that I mentioned previously. And on the human side, there are multiple drugs like this that are approved.
Again, 2 at the top there are Gleevec and EEA. Gleevec is approved for chronic myelogenous leukaemia and gastrointestinal stromal tumour. AESA is approved for certain kinds of lung cancer and head and neck cancer.
And we have two great examples in our, in our veterinary arsenal as well, both palladia and massivet fall into this category of these what are called small molecule thyrosine kinase inhibitors, and we'll spend a lot more time talking about palladia and massive since these are the drugs that are sort of currently available to us. So I think most of us are probably familiar with the best example of the way that we can use receptor tyrosine kinase inhibitors for the treatment of dog cancer and cat cancer actually, which we'll talk about is through the use of kinase inhibitors that target a kinase called KIt, and kit is actually the receptor for a growth factor called stem cell factor, and stem cell factor is actually very, very important, and its receptor kit are very important in A hematopoietic stem cells in the bone marrow, they're very important in pigment cells. They're very important in certain neuroendocrine cells, so they play a very important role in the maintenance of some normal tissues, but it turns out that all normal and malignant mass cells actually express the kit protein and It actually appears that kit protein is more likely to be highly expressed and expressed where it does not belong on specifically in the cytoplasm of cells instead of in the in the or on the cell membrane in higher grade canine mass cell tumours, and about a third of canine mast cell tumours actually have a mutation in the gene that codes for a kit like we talked about.
That actually leads to that kit protein being constantly on and constantly signalling into the cell, telling it to do all those bad things, and we know that sorry mast cell tumours that haveIT mutations in dogs are more likely to be high grade. They're more likely to have a high mitotic index, and they're much more likely to behave badly and end up killing the patient. So these are kind of our worst canine mast cell tumours are the ones that have this activating kit mutation.
Thankfully, we have drugs that actually work by inhibiting signalling through the kit protein. One of them, again, that I mentioned previously is a drug called Gleevec or imatinib, which is actually approved for treating some human cancers but happens to target kit. And then we have our two canine drugs, tsarinib or palladia and meitinib or masivi.
I'm going back about more than 20 years now, people started actually looking at the ability of these types of drugs to interfere with both cell signalling and growth of canine mass cell tumour cells, and this is the first paper that was published actually, which was an in vitro study where they did something very simple. They took the drug that ended up becoming palladia, which is this molecule called SU-11654. And they dumped it into a petri dish with canine mast cell tumour cells that had this activating kid mutation, and they found that the more drug they added, the better the cells' growth were inhibited, and the longer the the drugs and the cells were in the dish together, the more of the cells died.
So that's great. We love to see that, but there's an awful lot of drugs that look like they work great in a dish that actually don't turn into good cancer drugs. I could duplicate these results with Formalin or ethanol or tap water, and none of those are necessarily good cancer drugs.
So thankfully Dr. Cheryl London, who did this in vitro work, very shortly thereafter actually published data from a clinical trial in dogs demonstrating that this drug actually did have anti-tumor activity at doses that were tolerated. In fact, around 50% of canine mast cell tumours actually experienced meaningful shrinkage after treatment with the sarinib.
And several of those responses were actually complete responses. And interesting, a fact that we'll get back to is that in this initial study dogs whose tumours possessed those activating mutations mutations in the in the CIt gene were twice as likely to experience tumour shrinkage than those dogs that did not. However, there was no report on how long those tumours stayed small for, and we'll get back to that.
And they did see some activity in some tumours other than mast cell disease, and we'll get back to that too. One of the really neat things that Dr. London had an opportunity to do was actually in some of these patients she actually got a biopsy of the tumour, gave a single dose of sarinib or P Paladia, and then 8 hours later got another little biopsy of the tumour and she was actually able to measure in the tumour whether the kit protein was on or off.
And again, all you've got to look at in this complicated figure is the very top here which says peak kit. That stands for phosphorylated kit, so that's the activated form of kit. So in these five tumours you see here on the left, you can actually see that just 8 hours after the very first dose of palladia, there was a significant reduction, so less blackness in kit phosphorylation, suggesting that the drug was doing exactly what it was designed to do.
So when you give the drug, you actually inhibit kit signalling, and that is what's responsible for at least some of the anti-tumor effects that are observed. So subsequent to that, the drug was acquired by what at the time was Pfizer Animal Health, which is now Zoetas, and they performed a randomised placebo controlled trial in order to get approval by the US Food and Drug Administration. So this is a randomised placebo controlled trial.
Dogs either got Palaia or placebo and then were followed for 6 weeks. After 6 weeks they broke the code, and those dogs that were getting placebo could actually roll on to getting active palladium. The overall response rate was around the same, about 40% or so, and once again they saw this, this interesting fact that the mutant tumours seemed to be more likely to respond than the wild type tumours.
However, once again they made no comment on how long those tumours stayed small for or how long those tumours stayed controlled for, just whether they shrink or grew. So median time to progression in those dogs that were receiving palladia was about 18 weeks or so. There was no difference in the incidence of severe adverse events, but there were some adverse events observed, and we'll talk about that, coming up.
Around about, oh, let, let's talk a little bit more about this whole thing with, does kit mutation status actually inform how likely a dog is to actually benefit from from palladium. So about 10 years ago now, a little less 5 years, 5 and change years ago, we actually performed a study that was funded by the American Kennel Club looking at whether things like kit mutation status were able to predict dogs who might benefit from ladia versus dogs who might benefit from more conventional chemotherapy. And the take home message in this was that actually kit mutation status was not able to tell us who was going to benefit from palladia, and in fact the results were the opposite when we're looking at progression free interval instead of tumour response.
So instead of asking a short term question of whether the tumour shrank or grew, we asked how long were we able to control the tumour for, and actually what we observed was that tumour control was longer in the dogs with wild type C kit than it was in the dogs with mutant CIt. So the reason that this, I think is important is that it does not appear that we can use CIT mutation status to determine who's going to benefit from palladia. And the reason that this is important is because I'm going to tell you a completely different story about Mass event, which I think is very different.
So around the same time that Palaia was being developed, the group at AB Science out of Paris was actually working on another CI inhibitor for the veterinary market, and this was meitinib, what went on to be called Nasy that in the EU. So they were also sort of gearing up to perform a randomised placebo controlled trial. One of the things that was different about this study though is that the primary endpoint, so the endpoint that led to whether this drug was going to get improved or not, was not.
Whether the tumour shrank or grew, it was how long was the drug able to control the disease for, so keep the disease at least stable for, so a little bit different there. And I'm just going to blow up this complicated little table and show you one thing here. So overall it did appear that the dogs that received mesitinib did a little bit better than the dogs that received placebo did.
So that was great, but when you sort of divided them up by whether their their tumour had a kit mutation or not, the difference was profound. So what you can see is all of the benefit was really in those dogs whose tumours had a mutation in CIT. So if your tumour had a mutation in CIT, you did almost 8 times better if you got meittinib than if you got placebo.
If your tumour was wild type for CIT, there was no benefit to the use of meitinib. So that is what led to The EU package inserts saying that the label indication for massive vet is for the treatment of dogs with non-resectable mast cell tumours with a confirmed mutated CIt gene, because that is where all the benefit is. So what is the deal with this?
Why is it that we have two drugs that are both inhibitors of kit signalling, and in one of them, it seems like actually checking for a kit mutation makes a huge difference in the outcome. And in the other, it makes no difference, or maybe the kit mutant dogs even do worse. So here's the reason.
So from the very, very beginning, Massive that was actually designed to be an inhibitor of mutant kit. So they were looking for a drug that would specifically inhibit. The mutated kit protein paladia was actually not even designed to be a kid inhibitor.
It was actually designed to be an inhibitor of a completely different kinase called vascular endothelial growth factor receptor 2, or eja receptor 2 that just happened to also inhibit kit. So that's a very, there's a very simple reason why those results are so different, and that's why I think it's very reasonable to contemplate if you're in the EU where you have access to massy that. Potentially see it sequencing, and if your dog has a mutation in kit, reach for mass see that.
If your dog has doesn't have a mutation in kit, but you want to use a kinase inhibitor, potentially reach for Polaia. So very, very different, and it just goes to show you two drugs, even that target the same kinase, there's potentially different tests that you can use to figure out if it's worth considering. So despite the fact that these are pills, despite the fact that these are not conventional cytotoxic chemotherapy drugs, these drugs are not necessarily benign, and we definitely can see side effects from this class of agent.
So with both of these drugs, we can definitely see gastrointestinal disturbance. Diarrhoea and hyperexia are probably more common than vomiting. But we can see some vomiting too.
I would say we see a little bit more of this with our palladia than we do with our massive, but can't see it with both. We can see changes in blood cells. We can see protein losing nephropathy.
We can see hypertension. With palladia specifically, we seem to occasionally see muscle cramping or depigmentation, and then we can see unusual things like hepatotoxicity, we can see hemolytic anaemia. We can occasionally see epistaxis and maybe that's blood pressure related.
It's unclear, but again, the short version is there are a lot of different sort of adverse events that we can see from this class of drugs, although again with careful monitoring and potentially some dosage adjustments and tweaking, we can almost always find a dose that will work for an individual patient. Again, we do have to be very careful in our monitoring of these patients, especially during the initial period of treatment when we're using them. And again, here's a sample.
Kind of a monitoring schedule we tend to use here at Colorado State, and again this is sort of for us it has to be specific for Palladia because we don't have access to Massive vet, but I would probably do something fairly similar with Massive vet based on what the kinds of adverse events that we're looking for. So again, I'm not going to read everything off to you here, but again, during that initial period of time we recheck these dogs fairly frequently and we're primarily interested in in taking a careful look at. Are they eating OK?
How are their stools? Are they losing any weight? And again, checking the CBC with special attention paid to our neutrophils cause we can see some neutropenia sometimes from, especially from palladium, anaemia more so with massy.
And then once we get through that 1st 6 weeks, often we can diminish the frequency of our rechecks, but we actually end up checking more stuff because sort of with more longer term use, that's, I think, when we can start to see some liver enzyme elevations, that's when we can start to see some protein loss, that's when we can start to see some hypertension that we might need to treat. So one of the things that we know now that's actually very, very important is that the labelled dose of palladia is more palladia than we need to give. So the label dose is 3.25 milligrammes per kilo every other day.
There's some very nice pharmacokinetic studies that were done. Subsequent to the registration trial that have actually determined that a dose in the range of 2.4 to 2.75 milligrammes per kilo probably results in adequate blood levels of tocerinib to do the job that it needs to do, and it tends to be associated with better tolerability.
So nobody, at least in the US, uses the label dose of palladia anymore. So again, we use this lower dose. One might ask, well, why can't Zoetists just change the dose that's on the label so everybody knows that they can't.
So the regulatory agencies will not let them change the dose unless they go back and repeat their gigantic registration trial to support that that change. So they can't. Reflect that on the label, they can't even tell you about that dose reduction unless you ask them, at least in the United States.
So they're prevented by law from talking about stuff that's not on the label unless you ask them specifically. So don't bla blame Zoettes for having the wrong information on the label. Don't blame your Zoetists rep for not telling you this, but this is a very, very important thing.
So we definitely use these lower doses of Pladia when we use it. The label dose of meitini tends to be appropriate. So despite the fact that Pella has been around for almost 15 years and Mitinib has been around around the same amount of time, there are lots of things we still don't know about this drug, but we're starting to learn more about.
So let's go through some of these. So can we use these drugs in combinations with some of the other tools that we have in our toolbox? So these drugs work very differently from conventional chemo.
They work very different than radiation. They obviously work differently than surgery. Can we use these in combination?
Maybe, maybe they would be great if we used them together. So the answer is, at least on the palladia side, we've actually looked at a lot of combinations. We, the veterinary community, have looked at a lot of combinations between palladia and chemotherapy.
So it's been looked at with blastine. It's been looked at with low mustine. It's been looked at with carboplatin.
It's been looked at with doxorubicin. It's been looked at with the nonsteroidals, and with all of the conventional cytotoxic agents, yes, you can give them together, but you have to do in some cases very substantial reductions of the of the dose. Of your cytotoxic chemotherapeutic agent.
So in the case of blastin, perhaps this is most profound, where you have to go from when you're using blastin by itself, you can get something like 2.5 milligrammes per metre square per week. When you give it with Taarinib, you've got to give 1.6 milligrammes per metre squared every other week.
So that's like a 2/3 dose reduction in your blast and dose intensity. So despite that, you can actually see really quite substantial anti-tumor activity with this combination. So again, with the other drugs that I mentioned, I'm not going to go through all the details there, but again, similarly, dose reductions need to be employed of your cytotoxic agent, and neutropenia is dose limiting.
So yep, you can definitely do those combinations, but use caution, look at the literature, make sure you know how much to give if you're going to do that. We did a study here looking at a combination of toucerinib with metronomic cyclophosphamide, which is something that's been used for a long time both for its immunomodulatory activity and potentially for its, you know, antiangiogenic or activity against blood vessels. And what we found was that actually the combination was very, very well tolerated, so you could give Full dose of metronomics like ophosphamide, full dose of tocerinib, and actually really not see any additive adverse effects.
And one of the things that we saw that was quite interesting was that by itself toserinib actually reduced regulatory T cells in the blood. Regulatory T cells are a special kind of lymphocyte that actually have immunosuppressive properties, and if you can reduce them, you might actually sort of wake up the immune system and have that immune system recognise the tumour better. Cooperatively we saw further reduction in T.
Regs when we added metronomic cyclophosphamide, so that was great, and there was some evidence that we could see enhancement of the immune response in the blood, at least based on the secretion of one particular cytokine called interferon gamma. So here's an example where the combination actually appears to be very tolerable at full doses of both drugs, and maybe we have a little bit of cooperative immunomodulatory activity. How about radiation?
So can we give it together with radiation? The answer here is yes. So we did a study here and at a couple of other sites looking at a combination of palladia with palliative radiation therapy.
This was, you know, once a week radiation, very well tolerated, all outpatient, doesn't require any fancy CT-based computer setups or anything else like that. And actually our overall response rate was about 75%. Most of the responses were complete responses.
Here's what's called a waterfall plot just demonstrating that most of these dogs had complete responses. Medn progression for interval was about 10.5 months.
So this is actually our go to protocol now for what we refer to as locally advanced mast cell tumours, so a combination of palladia plus just once weekly palliative radiation therapy, very effective treatment. There were no additive adverse events in most dogs. The one exception is dogs that were receiving abdominal radiation.
So in those dogs where there was a lot of abdominal contents in the radiation field, we did tend to see an exacerbation of the GI effects. Anywhere else on the body, we did not see any worsening of any of the adverse effects from radiation therapy, so a very well tolerated. A very well tolerated combination which looks like it may have additive benefit.
So here's just one of our little patients. This was a dog that had a really obviously locally extensive mast cell tumour in that sort of periocular region that had a brilliant response to that combination of latia and palliative radiation therapy that lasted for more than a year actually. So what about other tumour types?
So I did mention to you that in the case of both of these drugs, other kinases are actually targeted besides just kit. So Tarinib hits some kinaes like platelet drive growth factor receptor and vege receptor 2 that are very, very important in blood vessel growth. Meitinib hits another group of kinases that can be important in metastasis, important in signalling in other kinds of cancer.
So what do we know about utilising these drugs for other tumours? So palladia, there's actually quite a bit of evidence now available, and again I'm not going to go into all of the papers that would take me the whole hour, but quite a bit of data suggesting that it can work for other kinds of cancer. This was a very early paper that just kind of gave us some inklings of other tumour types where we might see benefit, and we could see there appeared to be some evidence of clinical benefit in dogs with anal sac tumours, maybe in dogs with osteo osteosarcoma metastasis.
Although subsequent studies really sort of failed to demonstrate that palladia works by itself for osteo, although it may be effective when we combine it with some other drugs, maybe have some activity in thyroid, maybe have some activity in squamous cell carcinoma, and some other tumours again that I just don't have time to talk about right now, but again, you can find some really interesting data out there on the interwebs about some of those other indications. This is an example of an individual dog with metastatic osteosarcoma that actually had very nice tumour shrinkage with palladia. Here's a dog with massive sublumbar lymphadenopathy from a metastatic anal sac tumour that had very nice tumour shrinkage with palladia, and again, that was enough to palliate the dog's signs of obstipation, which was a really nice benefit as well.
So overall, for reasons that aren't completely understood, it appears that this is a drug that has more activity. In carcinomas, especially neuroendocrine carcinomas or cells with like a neuroendocrine-like phenotype, so anal sac, thyroid, insulinoma, maybe adrenal gland than it does for like sarcomas or hematopoietic tumours. But other than that cell that is.
But very interesting observations I'd encourage you to look at the literature more to really determine all the different things where where it's been looked at. How about mesitinib? So we know less about sort of off-label or off target uses of meitinib, but there's some very interesting data looking at mesitinib for cutaneous T cell lymphoma.
And this is just a brilliant case that was reported at ESFANC actually quite a while ago now looking at a little dachund here with with really quite diffuse cutaneous T cell lymphoma that had a brilliant response to response to meitinib after just a few weeks. And in this particular case they actually did some very elegant immunohistochemical work showing that it appears that this particular tumour had really, really substantial activation of platelet derived growth factor receptor, and that was probably responsible for why the drug works. So it didn't have anything to do with kit, but it actually had to do with the innovation of platelet derived growth factor receptor.
So again, there are probably some other tumours out there that might rely on platelet drive growth factor receptor signalling also. We just kind of need to do the legwork to identify them, in which case mesitinib could be very, very beneficial for those tumours as well. How about cats, can we use these drugs in cats?
So there's some nice tolerability and pharmacokinetic studies suggesting that imatinib, the human drug, appears to be tolerable in cats and may have some activity in cats with mast cell disease. There's also some pharmacokinetic studies that have been performed looking at the sitinib that suggests that it's safe. And there are actually quite a few studies that have been performed in cats with sarinib as well.
And really the only tumour type where there's unequivocal evidence of benefit is mast cell disease. So in cats with mast cell disease, it looks like the response rates are in the neighbourhood of maybe 2/3, so 60 to 70% of cats appear to experience meaningful improvement with with doserinib. And actually it's very well tolerated in cats as well, maybe better tolerated in cats than in dogs, so definitely worth considering there.
It's been looked at some other tumour types, no great evidence of efficacy, but one study I did want to mention is a retrospective study that looked at it in cats with oral squamous cell carcinoma because we all know that as a profession we're very interested in looking for other things that we can try for this horrible disease in kitties. So this is a study that actually looked at a palladia in cats with oral squamous cell carcinoma, and it appeared to show that there was an advantage. In cats receiving palladia compared to cats that did not receive palladia, again, there's a little bit of anti-tumor activity, but you can see that the cats that received palladia did about 3 times better.
However, there are two very, very big caveats to this, and one is that the palladia cats were also much more likely to be treated with non-steroidal anti-inflammatory drugs, and it's hard to know whether it was the nonsteroidal anti-inflammatory drugs that were doing the good or whether it was the palladia. And the other thing was there's an enormous case selection bias here. So if you have a cat with a bad oral squamous cell carcinoma, it might be very hard to get palladia into that cat.
So you might be selecting for the cats that are more debilitated and having a much harder time eating and drinking if you're selecting for the cats that were that whose owners were able to give them palladia. So for both of those reasons, I really take this data with a grain of salt. I am not convinced that the Paidia was really responsible for what we're seeing here, but if I've got an owner who really wants to do something more than just an NSAID, something more than just a feeding tube, maybe, yeah, I mean, it is something that I will have the owners consider as, you know, one step beyond.
Is it a cure? No. Could it be better than just an NSAID?
Sure, possibly. So what about the use of these drugs postoperatively, right? So it's a really attractive concept to give a drug like this after surgery to see if we could delay tumour spread, to see if we could delay tumour recurrence, whether it's with mass cell disease or whether it's with some other tumour type.
So I will tell you that we don't have any data with either of these drugs about how well they work postoperatively for mast cell tumours. I'm not saying they don't work. I'm just saying we don't have any statistics or percentages that we're able to quote about how well they work.
And the other sort of practical issue that we have with these drugs when we're using them postoperatively is we don't know when to quit. Do we give them for a month? Do we give them for 6 months?
Do we give them for the rest of the dog's life? We do not know. For those reasons, I tend to not be a fan of using them postoperatively.
Other people are. I have no problem with that. I can't begin to say that they're doing the wrong thing, but I kind of like to save those drugs in my back pocket for when I have something to measure, you know, at the time of relapse, when I sort of have a better sense about whether I know that they're working or not.
Like I said, no problem if you choose to use them postoperatively. Just can't tell an owner how well they work or how long to use them for. Do we have any data on any other kinds of tumours about whether drugs like Palladium might work?
We do, and unfortunately it's negative data. So we did a study trying to use palladia as maintenance therapy after the completion of regular chemo in dogs with splenic hero sarcoma, and we actually found no benefit. So the outcomes in these dogs was effectively exactly what we would have expected if we just gave them doxorubicin, unfortunately.
We also did a prospective study looking at toserinib maintenance with or without cyclophosphamide following completion of carboplatin chemotherapy in dogs with osteosarcoma. And again, this was actually a randomised study and there was no benefit. So in both of these tumour types.
There did not appear to be any benefit from the addition of palladium maintenance after the completion of standard of care chemotherapy, unfortunately. So, you know, that doesn't mean that it couldn't potentially be useful for other tumour types, but at least in these particular two tumour types there did not appear to be any advantage. So still lots more to know and lots more to learn about palladia and meitinib, but I just told you there's like 50 something different kinase inhibitors that are approved in humans.
Do we know about any other kinase inhibitors and their potential utility in dogs and cats? So let's talk very briefly at the end here just about a couple of, you know, really encouraging studies that have looked at targeting another receptor, tyrosine kinase, in this case in canine tumours. And what we'll start with is talking about targeting a kinase called HER2, which I mentioned previously because it's very commonly targeted in human breast cancer using a drug called patinib, and lipatinib is a small molecule inhibitor of HER2 and a related receptortirocin kinase called EGFR, and lipatinib is actually approved for the treatment of certain kinds of breast cancer in humans.
So there's some very nice work that's been done by some researchers in Japan that have demonstrated that most canine bladder cancers, urothelial carcinomas, express HER2, and that inhibition of HER2 signalling with lapatinib in a dish seems to be associated with reduced proliferation and enhanced cell death and things like that, which really paved the way for a clinical trial that was performed. Of lapatinib in dogs with with transitional cell carcinoma of the urinary bladder, and in this case dogs received lepatinib at the dose you see there 20 to 30 milligrammes per kilo data co-treated with peroxicam, and they were compared to another cohort of dogs, not randomised, not placebo controlled, that were treated with paroxicam alone. And in this study, let's just look at panel B here.
So this is what's referred to as a waterfall plot where the dogs that have experienced the most benefit sort of have the, these bars that have decreased the most, and then those dogs whose tumours have grown are actually on the on the positive side of this little bar graph. So what you can see is, yeah, there are some dogs that had really quite dramatic tumour shrinkage. And it's those dogs in green who received the combination of paroxicam and lapainin that were much more likely to have significant tumour shrinkage than those dogs that received paroxicam alone.
So the objective response rates were higher, and this is just another way to look at the same data looking at a stacked bar graph. So green are those dogs that have partial responses, and you could see, you know, half of the dogs that received the combination actually had a partial response versus maybe 15% of dogs that were treated with peroxicam alone. So very encouraging data.
And then when you looked at progression free intervals, so how long were we able to keep the tube, we, the veterinary profession, they able to keep the tumours at least stable for, you can see it's about twice as long in those dogs that received the combination than in dogs that received paroxicam alone. When you looked at overall survival time, same thing. Those dogs that received the patii and paroxicam survived about twice as long as those dogs that received paroxicam by itself.
And one step beyond that. They actually looked for biomarkers to try and determine if they could predict which dogs were going to benefit the most from a patented, and they did this through a really cool way. So what they did is they just took urine cytospins, so they got some urine, spun it down, looked at the cells, and then stained those cells for HER2 protein.
And the more robust HER2 expressors, so those tumours that expressed a lot of HER2, these are the ones that are in red here, actually did better than those tumours that expressed lower amounts of HER2, and this was translated into higher response rates as well as again longer progression free intervals and overall survivals. So here is a biomarker that we could hypothetically use to actually select patients who might be most likely to benefit from lapatinib. So very cool preliminary data.
So keep in mind lopatinib is a human receptor tyrosine kinase inhibitor. There is no veterinary version of lopatinib here in the United States. We are actually able to access this drug through what are referred to as compounding pharmacies.
So there are pharmacies that will source lepatinib. Usually from chemical supply houses in China and India and places like that, stuff capsules with it, and then those can actually be sold to veterinary practitioners here in the states. I know that can be very challenging, at least in some parts of the EU, to access these compounding pharmacies, but it's conceivable that this could be an option at least in some, some parts of Europe.
So very, very interesting, . Another group has actually demonstrated very interestingly that there's at least a subset of canine lung cancers that have an activating mutation in the gene that codes for HER2 that makes HER2 constitutively active. So the analogue of that same mutation that I described in dogs with mast cell tumours, they're mutation in CIT.
So this is a mutation in HER2 that actually confers sensitivity to drugs like lapatinib. So hypothetically there's at least a subset of dogs with primary lung tumours who could also benefit quite substantially from lapatinib. So again, this is data in a petri dish to suggest that some of these HER2 mutant lung cancer cells are very, very, very sensitive to lapatinib.
We don't have clinical trial data yet sort of demonstrating anti-tumor effects, but I think it's a very logical target to go after and this again is the kind of thing that I think we're going to see more and more of as we continue to sort of look at DNA mutations and more and more canine tumours. I think we're going to find more tumours where there may be already existing human drugs that we might be able to repurpose to really improve the outcome in some of our canine patients. And that additional information is really eagerly awaited.
Stay tuned in this space. I think we're going to see more examples like this in the future, so more very cool and appropriate ways to use our existing drugs like palladia and meitinib, and again more of these other receptor tyrosine kinase inhibitors that we're able to poach from the human space and potentially repurpose in our patients as well. And with that, I thank you very much for your attention.
I do notice that I do not have my email actually on this this last slide. So while we're sort of entering into the Q&A section, I'm more than happy to actually stick my email in the chat, and I will do that right now. Thanks so much for your attention and looking forward to addressing any questions that you might have.
Douglas, wow. What do I say besides wow. That was fantastic and thank you so much for your time.
I, I'm sure I'm not the only one who is sitting here with smoke coming out of my ears thinking. This is so much more complex than than what, you know, certainly what I believe, but it looks like it's one of those situations where you go looking for one thing and if you pay attention to what you stumble over, you find 6 others. Absolutely true.
You know, it's so interesting that when these drugs were initially designed, they were designed to be super targeted and super specific, and over time we've learned that many of them are much more less targeted than we thought, but that actually can actually be a good thing because yeah, we're we're really discovering new uses for them on a yearly basis, which is very, very exciting. Yeah, absolutely. And, you know, finding, finding the use of existing drugs obviously works out to be a lot quicker because the companies don't have to go through quite as extensive production.
It's just a question of off-license use until you can prove it, kind of thing. Absolutely. It's, you know, developing these drugs for, for specifically veterinary use is incredibly expensive and time-consuming.
And if we're able to repurpose something that's already out there, it's, there are enormous savings in time and costs just as you said. Yeah. Yeah, that's fantastic.
And it's lovely to see that you've got, such a nice big team there as well who are dedicated to looking at all of these things, just in one place, regardless of all the other people, around the world that are doing the same thing. Oh absolutely. And again, this particular, this particular group here really comprises imaging specialists, surgeons, medical oncologists, radiation oncologists, and a variety of basic scientists.
Pathologists are in this picture as well, and a variety of basic scientists who are really, so you know, we're trying to sort of address this from all angles, so the molecular underpinnings of the tumour, how these drugs work in the laboratory and trying to translate that actually into our clinical practise. As quickly as we can. Yeah, fantastic, real team effort.
That's wonderful to hear. Douglas, we don't have any questions coming through. I see that Beck has just, put your, your email address up into the, the general domain of the chat so that people can email you.
I'm sure once the shell shock that I'm feeling passes, I'll have questions as well. So, the other thing is, of course, there's a lot of people watch these on recording, and, so you may well find that you, get quite a few questions coming through. Absolutely.
Well, again, to everyone out there, please do not hesitate to reach out. I, I say this with 100% sincerity, actually my favourite part of my job as, you know, being a faculty member is actually getting to communicate with my veterinary colleagues all over the world and help them, help them through their cases. So please do not hesitate to reach out if you have any questions about this or anything else having to do with cancer.
I'm always happy to help. Douglas, thank you. That is very kind of you, and thank you for giving up your time today.
And, to everybody that has attended and those of you that are watching going forward, I hope you have enjoyed this insight that Douglas has brought to us. And, don't forget that the recording will be up on the webinar vet website in the next 24 hours or so. Douglas, thank you for your time once again.
To everybody that attended, thank you, and to Beck my controller in the background for making everything run smoothly. Thank you. From Stevenson, it's goodnight.
Cheers.