Michael O'Dwyer, MD National University of Ireland Galway Interview Date: August 25, 2017
Why does multiple myeloma become resistant to current treatments? Research has been done showing that sugar molecules can cover the surface of cancerous cells, hiding them from the immune system. The surface sugars, called sialic acids, can mark the cancer cells as “self” cells, giving the immune system the signal to ignore them. The glycosylation process (or the reaction when carbohydrates is attached to other molecules) is a process that produces DNA, RNA and proteins. This normal process is altered in multiple myeloma and could cause changes in cell signaling, adhesion and drug resistance. Dr. O'Dwyer is both an expert in multiple myeloma and in glycosylation and explains how this works and the steps being taken to overcome sugar's effects.
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Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. This is our 102ndshow and I’d like to thank our episode sponsor Takeda Oncology for their support of Myeloma Crowd Radio. Now, I hope you all enjoyed the recent eclipse because we did. The Myeloma Crowd hosted an eclipse camp in Rexburg, Idaho and we raised over $11,000 for the Myeloma Crowd Research Initiative. This means we’ve now raised $488,000 towards our $500,000 goal. We are only $12,000 away from meeting that goal. As you hopefully know by now, the Myeloma Crowd Research Initiative is funding two immunotherapy projects. One is the CAR T cells research project at the University of Wurzburg in Germany targeting CS1 and BCMA, and the second is called MILs or marrow-infiltrating lymphocytes, which is an immunotherapy used with stem cell transplant from John Hopkins. Now, today’s show is a fascinating one which I ran across several months ago. It was an observation that sugar molecules can essentially act as a smokescreen for myeloma cells. And when we posted an article on this, Dr. Michael O’Dwyer and myeloma expert from Ireland retweeted the article on Twitter and noted how key this is for myeloma. I had the wonderful opportunity to meet him in person at the European Hematology meeting in Spain in June and invited him to participate on the show. So welcome, Dr. O’Dwyer.
Dr. O'Dwyer: Thanks very much, Jenny. I’m delighted to be on the show.
Jenny: Well, it was so fun to meet you in person, and it’s wonderful to have you here. So let me just give a brief intro for you, and then we’ll get started with some of our questions. Dr. Michael O’Dwyer is the director and founder of the Science Foundation Ireland and Irish Cancer Society Blood Cancer Network and Chair of the Hematology Lymphoma Subgroup of the Ireland Cooperative Oncology Research Group. He established the multiple myeloma translational research program at the National University of Ireland Galway and was the first to run Phase I clinical trials for blood cancers. Dr. O’Dwyer is a professor of hematology at the NUI Galway and helps research board clinician scientists there as well. He’s a visiting scientist at the Dana-Farber and the Harvard Medical School. Dr. O’Dwyer has six patent applications including a particular marker that you can say and talk about today for multiple myeloma and patents involving natural killer cells. He is co-founder of a company called Onco-Cellular and Onco-Immune, two startup companies focusing on NK cells as anti-cancer therapy. Onco-Immune's research is evaluating how NK cells can be optimized for use in myeloma therapy. Dr. O’Dwyer interestingly treated the first patient worldwide with an E-selectin inhibitor in AML (which is leukemia), which received breakthrough designations from the FDA, and he’ll be sharing a little bit more about that, in myeloma. He’s now running the first clinical trial for E-selectin inhibition in multiple myeloma. So welcome, Dr. O’Dwyer. We’re just thrilled to have you. We know you have intensive experience in immunotherapies and looking forward to understanding the sugar molecules a little bit better.
Dr. O'Dwyer: Thanks, Jenny.
Jenny: Maybe we just want to start by describing siliac acid sugars?
Dr. O'Dwyer: Sure. It’s sialic acid. I guess if we buy something to eat or whatever and we look at what’s on the label and it tells us that there’s carbohydrates, proteins, and fats, basically our body is made up of these different building blocks along with essential minerals and so on. But carbohydrates are, I suppose, a term that encompasses all types of sugars. Some of our sugars are for energy like glucose and so on, and glycogen is the storage form of sugar. But there are other sugars that actually have a different function. Sialic acid in a non-energy type of sugar. It's normally expressed on the surface of many cells in the body and on the surface of cells, it decorates proteins and lipids or fats on the cell surface. And the addition of, in fact, different types of sugars to proteins or lipids is a process that we called glycosylation. It's sometimes referred to as one form of post-translational modification, which means that when your genetic code is made into mRNA which is then made into protein, this is a way of further modifying and making even more complex these different proteins. The sugar coating of proteins and lipids on the surface of cells can greatly influence the function and so on of these proteins. An example would be, for example, erythropoietin or EPO, which some patients with myeloma may sometimes receive to stimulate blood cell production, this protein or growth factor needs to be sugar coated for it to work properly. The same thing with monoclonal antibodies, daratumumab and elotuzumab, for example, of monoclonal antibodies, these are frequently glycosylated or sugar coated as well. Basically, sugars attached to proteins is actually a very, very common thing. Now, if you to actually look down with a very, very powerful microscope such as an electron microscope at the surface of cells, what you would see is that they have a kind of fuzzy outer halo on the outside of the cells, and this is actually composed of sugars. When one cell encounters another cell in the body, the first thing that they sense, in fact, is the sugar coating on the outside of the other cells. The sugar composition on the outside of the cell is very, very important in how cells interact with one another. And all of the different types of sugars that are involved in, if you like, cell to cell communication or how cells adhere or stick to one another, sialic acid is probably one of the most important sugars. Now, in terms of the binding then or the interaction of proteins that are on one cell interacting with sialic acid and proteins that bind to specific type of sugars are referred to as lectins. This terminology I hope is not too complicated, but there are two different type of proteins or lectins that bind to sialic acid. This is relevant for our further discussion because these two main proteins that bind sialic acid are referred to as the siglecs and the selectins. And a lot of my research in this area is based around the understanding how sialic acid on, in this case, myeloma cells, interacts with siglecs expressed on immune cells or selectins that are expressed on blood vessels.
Jenny: Okay. And then what’s the relationship with the sialic acid and the siglecs and selectins with the tumor cells?
Dr. O'Dwyer: So then if we take the siglecs first, the name is a shortened version of sialic acid-binding immunoglobulin-like lectins. There are proteins on the surface of blood cells especially immune cells that have a structure that's similar to immunoglobulins or antibodies. And these siglecs selectively bind sialic acid and particular types of structures that are coated with sialic acid. And the expression of the siglecs appears to be particularly important on the surface of immune cells such as macrophages and natural killer cells. We believe that they play an important role in regulating the immune responsiveness of these cells and, in most cases, the binding to sialic acids stimulates the siglec which dampens down the immune response because siglecs, they’re a little bit analogous or similar to PD-1 receptors, so I think many people are probably familiar with the checkpoint receptor PD-1 that can be expressed on T cells and, in fact, NK cells as well. If you think of sialic acid on, for example, a tumor cell, which could be a myeloma cell, and siglecs on an NK cell, in a way it’s a little bit analogous to PD ligands on a tumor cell interacting with the PD-1 checkpoint receptor on an immune cell. Therefore, I think we can consider that siglecs are somewhat like checkpoint receptors on NK cells, and they also seem to play a similar function on macrophages.
Jenny: So you have the sialic acid on the myeloma cell, and you have this siglec on the immune system cell, and what you’re saying is they’re talking to each other in a certain way depending on how much of each are on each type of cell?
Dr. O'Dwyer: Exactly. Now, an important thing is that sialic acid is expressed on the surface of many different cell types, but what is important is that in cancer this expression of sialic acid sugars seems to be exaggerated. Why this is the case? We’ve done a little bit of work looking at this in myeloma. We have found that myeloma tends to have a very high expression of sialic acid. It doesn’t to appear to be geared to any mutations. It doesn’t appear to be due to increased numbers or copies of the genes. It appears to be more related to increased expression of the genes. What we’ve actually found is that some of the factors within the micro-environment and the tumor micro-environment that we know aren’t a good thing in myeloma such as cytokines or things like interleukin 6, IGF or insulin-like growth factor and low levels of oxygen or hypoxia. All things that we know were bad in myeloma that drive more aggressive disease, all of these things are associated with stimulation of the genes that are code for the enzymes that are involved in generating sialic acid on the surface. These enzymes are referred to as sialyltransferases.
Jenny: Is this true for everybody? What you’re saying is regardless of the generic features that you have for your type of myeloma, that you find that everyone or just some people have this increased level of sialic acid or these sugars on the myeloma cells?
Dr. O'Dwyer: I think that what we find is a variable level of expression. In some cases, it does appear to be much higher than in others. Our own meeting is a little bit serendipitous in a way, but in fact how I got into this area in the very beginning was really quite serendipitous as well because I’m a hematologist. In fact, I started my career initially in CML, in chronic myeloid leukemia. I worked as a fellow and subsequently as a junior faculty on the development of imatinib, which is the first kinase inhibitor for CML with my mentor, Brian Druker, in Oregon back in the early 2000s. When I was resurrecting my academic career in Galway I had a chance encounter with a glycobiologist. Glycobiology is the study of the biology of sugars. Over a cup of coffee, we were sharing experiences with each other and what our respective areas of interest were in terms of, in his case, glycobiology, in my case, blood cancers and leukemia and myeloma. When he started explaining to me what sugars did, immediately I thought very likely that they must play a role in what we call adhesion mediated drug resistant. So when cancer cells stick down on a surface, in the bone marrow or in blood vessels, they often become more resistant to chemotherapy. That’s what stirred my interest originally. My colleague Lokesh Joshi and I decided that we'd put together a project. We had a very bright young hematologist called Siobhan Glavey, who subsequently went to work with Irene Ghobrial at the Dana-Farber. In collaboration with Irene Ghobrial and Gareth Morgan, we had access to more resources than we would have had here in Galway. What we found was that a number of different sugar-related genes were important. But the one that caught our eye as being important in terms of its impact on survival and when we looked at Gareth Morgan's UK days of one of the big myeloma trials that they did in the UK with this gene called ST3GAL6, it’s a sialyltransferase, so one of these enzymes that puts sialic acid on the surface of cells. Now, what we found was that there was a range of expression of this enzyme in patients. But if you looked at those patients who had the higher levels of expression, that they had a much worse overall survival and a shorter time to progression on treatment. And when we looked at the time as other factors that could be responsible for poor prognosis such as genetic factors, stage of disease, and everything, the expression level of this particular gene, this sialyltransferase was, in fact, independent of those other recognized risk factors. So we thought that this was quite important, quite novel because it's the first time really that something like this had been implicated in multiple myeloma.
Jenny: That’s so fascinating. What you’re saying is the more of this expression that you see of that particular gene, then the lower the immune response or the more drug resistant it tends to be?
Dr. O'Dwyer: Well, I suppose more -- I feel I'm on steadier ground when I talk about the drug resistance because our research is at a more advanced stage than our work on the immune side of it. But we have growing data supporting the fact that increased sialylation or expression of sialic acid on the myeloma cells does impair the function of immune cells. We have strong data in the laboratory to support that, but we need to extend that I think a bit further and show in animal models, for example, that that is definitely the case. But we can take parallels from other cancers and some very nice work has been done in other settings such as in kidney cancer or in breast cancer showing that the expression of sialic acid on the surface of tumor cells is associated with reduced responsiveness of natural killer cells, for example. Carolyn Bertozzi from Stanford had a very nice paper in the reps of the journal PNAS back in September I believe where she showed a very interesting approach where they used a monoclonal antibody, Herceptin or trastuzumab, which targets the HER2/neu antigen in breast cancer. With the antibody, what we did was they conjugated or added to the antibody an enzyme known as sialidase. Now, this is an enzyme that actually removes sialic acid, cleaves it all or removes it from the surface of the cell. And when the antibody was combined with this enzyme that removed sialic acid from the cell surface, they saw much greater enhancements of killing of breast cancer cells by the HER2 antibodies in the presence of the natural killer cells. Now, I should explain maybe just in case people aren’t aware of one of the main mechanisms that antibodies use, that monoclonal antibodies use to kill tumor cells is activating natural killer cells. When an antibody binds to its target on the surface of a tumor cell, the natural killer cells are then able to recognize the antibodies because they have receptors for antibodies on their surface. They can then bind to the tumor cell via the antibodies and release their toxic payload of granules into the tumor cells that kills the tumor cells. So basically, in the absence of the sialic acid using this novel antibody to its very significant enhancement of the killing of these breast cancer cells by natural killer cells.
Jenny: So kind of like wiping a clean slate to let the natural killer cells do the job?
Dr. O'Dwyer: Exactly. What we have done in my lab is, first of all, we have seen that myeloma cells -- initially, we just looked at cell lines. We saw all the cell lines that we looked at expressed the types of sialic acid that will bind to siglecs. So we refer to these as siglec ligands. We found that myeloma cells expressed these quite strongly. Then we decided, well, that’s all well and good, but these are only cell line. So we looked at patient’s samples and we found that in patient’s samples that we can also see these sugars that bind to these siglecs are also present on the surface of patient samples. But we also looked at natural killer cells from patients both in the blood and in the bone marrow. And in all the samples that we’ve looked at, we can see that there’s strong expression of siglecs on the patient’s natural killer cells. Now, we then have gone and looked at natural killer cells in the laboratory, and we have shown that when you pre-treat myeloma cells with an inhibitor that removes the sialic acid from the myeloma cell and that in itself isn't in any way toxic to the myeloma cells and combine then or put the myeloma cells in contact with the natural killer cells in what we call a co-culture, that the natural killer cells are much more efficient at killing the myeloma once this cloak of sugars has been removed from the surface of the myeloma cell. We think that this is important way for myeloma cells to evade killing by natural killer cells. Of course, you could argue, well, maybe there’s some other reason why removing the sugars has made the cells more sensitive to killing. So what we also did is we used the genetic approach to actually knock down the expression or reduce the expression of the siglec receptors on the natural killer cells, and we saw something similar that again there’s enhancement of killing of myeloma cells by natural killer cells when you reduce the expression of the siglec receptors. Again, it’s a little bit like if you were to use a PD-1 inhibitor, targeting PD-1 on a T cell or if you were to use a PD-L1 antibody or inhibitor, targeting PD-L1 on the tumor cell, thus you would expect to see an enhanced effect and this is what we’ve seen.
Jenny: A couple of questions. First, how do you measure for this, the thing you call ST3GAL6, how do you -- because you said in different patients, you saw different levels of this. And might that be an indication for a patient to go “Oh, this is why I’m not responding to my drugs or why I am becoming resistant to my drugs. I have too much of this and that’s why?”
Dr. O'Dwyer: Well, I think while, of course, I have a particular interest in this particular gene, this is one of many, many genes that could be playing a role in any individual patient, so I wouldn’t want to overstate the importance of this gene in isolation. But certainly, one way of assessing the level of expression of this gene would be by doing gene expression profiling. Another way is to look at the levels of RNA by a technique known as RNA sequencing. Now, in an individual patient, the value of looking at this is difficult. I think things like gene expression are probably more applicable to, if you like, a population or the whole group of patients than looking at a level among a large group of patients rather than seeing the significance of high versus low, rather than just trying to personalize this. I don’t think we’re some way away from using these technologies on an individual patient basis. But what I can tell you is that the expression of the ST3GAL6 is more important really for the generation of the sialic acid that would bind to selectins rather than to siglecs. Now, selectins, these are proteins that are on the walls of blood vessels, always expressed on the walls of blood vessels or endothelial cells in the bone marrow, but are also expressed in blood vessels and inflamed tissues. Now, myeloma cells express a type of sialic acid linked to another sugar called fucose, and this combination gives rise to something that we call as selectin ligand. It’s a sugar that will stick or bind to E-selectin, which is on the walls of the blood vessels. And basically, what this interaction serves to do is to slow down blood cells as they’re travelling through the circulation or in the tumor cells. In fact, in the small little blood vessels, blood cells are travelling along a couple of hundred miles an hour, literally. For blood cells to get out of the circulation, for example, into the bone marrow, it has to slow down, stop, and then exit. And selectins, by binding to these selectin ligands on the surface of cells, allow the cells to slow down and stop. We think that E-selectins plays an important role in how the myeloma cell exits the circulation and gets into the bone marrow, so it’s functioning as a gateway into the bone marrow. And some years ago, I think we would have thought that myeloma is just little pockets of disease that stay resident in different sites in the bone marrow, but the idea that cells would leave the bone marrow, go into the blood, circulate and end up in another site of the bone marrow wasn’t something that people really considered. But work by people like Irene Ghobrial has shown that, in fact, circulation from one bone marrow site to another is actually a very important feature of myeloma. We think that the E-selectin ligands play an important role in that circulation and certainly in how myeloma cells get back into the bone marrow. And so, this ST3GAL6 by high levels of this will lead to rethink higher levels probably of these E-selectin ligands that participate in this process. And once cells are then in the bone marrow and perhaps in contact as well with the selectin, they can be more resistant to chemotherapy. So this is a drug-resistance behavior that is actually quite separate from the immune resistance. I think collaborating with the company called GlycoMimetics, a small Maryland-based company who, as the name implies, they are in the business of developing small molecule mimics of sugars. What they have actually developed is a small molecule that is sort of a mimic of sialic acid and fucose that basically blocks the binding to E-selectin, so it’s an E-selectin inhibitor. And working with this company, what we were able to show is that when you take myeloma cell lines and if you look at cell lines that we study in the laboratory, they don’t actually express a very high level of these particular selectin ligands, the E-selectin ligands, but it’s possible to purify the cells that are positive for these particular sugars. And when you put those myeloma cells into mice, very interestingly, the myeloma is completely resistant to bortezomib. Now, if then you add in this E-selectin inhibitor, basically you reverse the resistance. The myeloma is now sensitive again to bortezomib. We believe that in this case that this particular E-selectin ligand on the surface of myeloma cells may play a role. It would be a very big leap to say that this is the reason for bortezomib resistance, but may play a role, in some cases, in the resistance to bortezomib. If myeloma cells have lots of these sugars, maybe they’re more likely to stay in the bone marrow where they're more resistant to chemotherapy. But if we can block back to the gateway into the bone marrow when the cells are circulating, then more and more of them accumulate outside the bone marrow, then they’re more vulnerable to treatments like bortezomib. So you mentioned the experience briefly in AML and by getting involved with the company, a few years ago they invited me -- because I have interest in leukemia as well -- to get involved in their first clinical trial in AML. And so, we were lucky enough to treat the very first patient ever treated with an E-selectin inhibitor here in Ireland for the treatment of AML, and that drug basically has shown sufficiently promising activity in AML. And in AML, it’s thought again that expression this sugar selectin ligands of the surface of the AML cells and binding to E-selectin is mediating resistance. There's very good data in AML now that it’s safe to give this drug in combination with standard intensive chemotherapy and that increases the response rate over and above what would have been expected in relapsed AML patients. In fact, it’s extremely well-tolerated as well to the extent that this compound in some way seems to actually provide some protection against the development of a complication know as mucositis which is inflammation of the gut, and anybody who’s had a stem cell transplant for multiple myeloma is probably familiar with mucositis because you had it. It turns out that mucositis a part of the problem is that you get inflammation in the gut from the chemotherapy, and one of the mediators of inflammation are macrophages. Macrophages actually migrate to the size of inflammation. And as I mentioned earlier, the blood vessels in inflamed tissues increase the expression of E-selectin. So you get these inflammatory cells moving to the location of inflammation, and this can be stopped by using the small molecule inhibitor. In a way, it's the best of both worlds that you’re able to enhance the effect of the chemotherapy while at the same time mitigating, to some extent, the side effects of the chemotherapy. So as I said, based on the promising data in AML, the drug now has breakthrough designation in relapsed and refractory AML. We recently initiated a trial with GMI-1271 in multiple myeloma with GlygoMimetics. And what I should say, they have initiated the trial but I’m leading the study. It's very, very early days yet. We’ve only enrolled a few patients so far, but other sites are coming on board outside of Ireland, in Germany, in the UK, and in Denmark. Hopefully, before long, we’ll have greater patient numbers and some data to share.
Jenny: So for that study, how is the study created? You are using this E-selectin inhibitor for relapse, I’m assuming, like relapsed refractory myeloma patients. Are they giving any other treatment with it?
Dr. O’Dwyer: Actually, at the moment, I think because -- which is a great thing -- because of the wealth of different agents available now to test in patients with relapsed multiple myeloma and more and more promising things become available by the day, that how to fit in an agent like this is a challenge. So one of the things I would point out is that this drug, on its own, would not be expected to have any activity in multiple myeloma. What it's doing effectively really is if you like blocking the stickiness of the cells to the blood vessels and desensitizing the cells to treatment, but it's not actually killing any cells on its own. So what we decided to do was to do a study looking at this in patients who had left aggressive relapse. Patients who are in relapses are basically two categories: patients who are in relapse who are responding slowly to a proteasome inhibitor, so less than a VGPR after three cycles of treatments. Now, that could be with a --
Jenny: That’s like a partial response, right? People may not know what a VGPR is.
Dr. O’Dwyer: So VGPR, very good partial response. Anything less than very good partial response within three cycles of proteasome inhibitor-based therapy so it could be bortezomib or Velcade. It could be Kyprolis or carfilzomib. Those patients then are considered eligible or potentially eligible providing they fulfill other sort of standard criteria. So that's one patient population. And then the second patient population are patients who are slowly biochemically relapsing. Somebody maybe who's been on Velcade who has achieved a response but is now slowly starting to lose that response but there's no organ damage, just that their M protein is starting to slip a little bit. Those are the categories of patients and the intention is simply to add in the investigational agent on top of the existing treatment that the patient is already getting. So therefore, if a patient is slowly responding and has, in a way, hit a wall that their M protein just isn’t dropping any further, and now we add in this drug and we continue therapy, their M protein then starts dropping. Well, it’s not definite, but it is a stronger argument that the only change really was the introduction of the new inhibitor. And the same if we see somebody who’s biochemically relapsing and that their M protein sort of turns the corner and starts coming back down again, the only thing we’ve done different is to add in the new E-selectin inhibitor. So it’s a challenging study. I kind of won’t dispute that. It’s going to take I think a while to build up experience with this. With our first few patients, we’ve also started with a somewhat lower dose than was eventually found to be the best dose in AML. It’s a Phase I study, so it’s going to take a little bit of time to learn how best to use this drug. It’s also, at the present time, it’s an intravenous infusion, so it takes about 20 or 30 minutes to give this as a short infusion, and it's delivered the day of and the day after treatment. It could be more convenient I think the development of, for example, subcutaneous formulation. Of course, the holy grail would be an oral drug, but I think for something like this that works in this way, that would probably be challenging. I think probably the best we're likely to get to, in the short term at least, is a subcutaneous formulation. It's likely that this drug will be explored in other settings in myeloma. We have to kind of go with the data, the pre-clinical data that we have for the time being, and the data that we have most strongly justify trying to reverse resistance to proteasome inhibitors.
Jenny: Well, it sounds really exciting. So it sounds like you’re working on two different but kind of complementary approaches, so getting rid of the sialic acid on the cells so the NK cells can do their work, and then this E-selectin inhibitors that basically clear the path so the blood can keep flowing and they don’t have a chance to escape into the bone marrow. I have a prior question about the sialic acid. You said that when you basically clear it off, then the NK cells can kind of do their work. So if you wipe out this sialic acid on all cells, is there any downside to doing that? And then is there anything in clinical trials that is happening on that right now?
Dr. O’Dwyer: That’s a very, very good question. I have been collaborating with investigations from Scripps in San Diego who developed a sialyltransferase inhibitors, so a drug that actually blocks the enzyme activity of the different sialic acid enzymes. And if you give this drug in high doses to mice, it’s very, very effective at removing sialic acid from cells. Sialic acid is present on normal B cells, T cells, but it’s also present on cells, for example, in the brain, in the kidney, in the liver. And the single most important toxic side effect when this drug was delivered to mice was reduction of sialylation in the kidney, and this led to a major leak of protein inflammation and a protein leak, something that we call nephrotic syndrome. Basically, it caused fatal kidney damage to the mice in very high doses. Now, when you give smaller doses, you may not need to give those really high doses, it may be possible and it’s something that we are actively exploring in animal studies. So I have a good collaborator in Maine, Michaela Reagan, who used to work with Irene Ghobrial, and we’re collaborating because she has a lot of experience with animal models, looking at the ability, if you like, if you'd excuse the pun, to find a sweet spot where we can deliver just enough of the drug to get the desired effect without causing any of the unwanted side effects. But, of course, there’s an entirely other approach that can be used as well since we’re dealing with a disease that involves the bone marrow, if we could selectively deliver the drug to the bone marrow and avoid exposure to the kidneys, then there shouldn’t be such a problem. The effect does wear off, so we will get enough of an effect by delivering this to the bone marrow that potentially we could recalibrate the immune system. We could affect drug resistance and maybe if we followed up with a bit of bortezomib, we clear out a lot of the myeloma that is resistant because of binding to E-selectin. But also, by hopefully reactivating the immune system, we are now able to engage the natural killer cells and maybe macrophages as well. We think that this siglec phenomenon is important on macrophages as well. We’re looking, we’re exploring ways in the university here in Galway. We have a large biomaterials group, and I’m actively collaborating with the director of a very large network called Curam, which is the Irish I think for cure, which is all about biomaterials. Professor Abhay Pandit and myself are trying to develop a nanoparticle delivery strategy that could selectively deliver a payload of a sialyltransferase inhibitor into the bone marrow as one possible approach. Another approach though that I alluded to that Carolyn Bertozzi is pursuing in Stanford is to use antibodies as a means of delivering an enzyme like sialidase. You can imagine we have a number of antibodies that work quite well in myeloma as it is, but you can imagine that maybe you could potentiate the effect of those antibodies even more by adding some sialidase or something to them and targeting the myeloma cells directly.
Jenny: Yes, then it would be more targeted. So one question that we haven’t talked about that I know probably everyone thought about when they heard that we were doing a show on sugar molecules is, is a patient's diet relevant at all? A lot of us have heard, well, sugar feeds cancer and maybe that’s why there are more sugar molecules on top of these cells. Do you want to discuss that? Because I think that’s something really important for patients to understand.
Dr. O’Dwyer: As I said at the outset that there are different types of sugars and sugars are a very large family. Yes, sialic acid is a type of sugar, but what is sugar really is, it’s a sort of a compound that’s made up of in a particular structure of carbon, hydrogen and oxygen molecules. There's many different types of sugars. We have what we call monosaccharides, polysaccharides and so on. Glucose is a very specific fructose. People have heard of high fructose corn syrup and so on. These are very, very high energy types of sugar that are specifically there for the purposes of energy. And obviously, too much of these in the diet is what's linked to obesity and everything. Sialic acid isn’t really linked to the diet as far as I’m aware anyway. But in terms of the link between obesity and immunity and cancer, that time we met in Madrid, I had actually attended a session there where I heard quite an interesting talk from a lady from MD Anderson. She was talking about how obesity and a high fat and sugar diet in mice can lead to changes in the immune system. One of the things that she discussed was the development of an increase in myeloid-derived suppressor cells. Now, there’s a lot of literature and a certain increase in literature about myeloid-derived suppressor cells in multiple myeloma. They're one of the bad cells that’s in the microenvironment in the bone marrow in myeloma. And these myeloid-derived suppressor cells, they express PD ligands. They also purge the development of a regular T cells which are the type of T cells you don’t want because they're dampening down your immune response. They’re reducing the number of your active cytotoxic or killer T cells. And they’re also actually dampening the activity of the NK cells. So in that sort of way, not related to sialic acid but certainly obesity and too much sugar and everything and have very detrimental effects on the immune system, that can ultimately promote cancer.
Jenny: So I guess that’s the key point. Regardless of whether it causes more sialic acid or not, it’s still important to just be healthy, little fat, healthy diet and probably exercise.
Dr. O’Dwyer: Yes, I couldn’t agree more.
Jenny: Interesting. Well, I want to open it up for the opportunity for people to ask questions of you. So if you have a question for Dr. O’Dwyer, you can call 347-637-2631. And then I have one follow-up question if everyone is shy. We have a lot of callers on the line, so just press 1 on your keypad if you would like to ask him a question. And then in the meantime, while we’re waiting, I would like to ask about -- I saw on your research that there was some kind of NCI-MATCH signal finding trial, and I just wanted to ask you about that because it looks really, really interesting.
Dr. O’Dwyer: Well, I’m not sure where you saw that, but I’m not personally involved in that. But I do know what it is. It’s where across a number of different cancer types that if people aren’t responding to standard treatments but they're found to have a specific mutation or usually mutation that might be responsive to a number of different investigation or other agents that are out there, then patients can be enrolled on this study. So there’s a large panel of different kinase inhibitors, for example, targeting things like BRAF. There’s a kinase called ALK. Various different things that aren’t necessarily expressed in just one cancer, that can be expressed across a range of different cancer. So for example, everybody is very familiar I think with BRAF as being an important target for malignant melanoma, and people sometimes confuse myeloma with melanoma. But, in fact, small proportion, maybe 5% of patients with multiple myeloma, especially in the high risk in a relapsed phase and particularly enriched I think in patients with extramedullary disease can have a BRAF mutation. So it’s not something that’s exclusive to melanoma. So if, for example, somebody happens to have some sequencing done or had a mutation found and there was a drug on this list that could be useful to them, then they can potentially get on that NCI-MATCH trial. I believe that myeloma is one of the diseases that is on the list.
Jenny: Okay. I have one final question. I think everyone is being very shy. When you talked about the technology to kind of clear up the sialic acid in higher testing and lower doses and things, where does that stand in terms of clinical trials and when do you anticipate that coming to clinical trials?
Dr. O’Dwyer: I think we’re a long way, to be honest, from that. I think if we can show in the research that we’re doing in animal studies that this is something that really does work, then what we would need to do is potentially I suppose patent this or license this technology to a pharmaceutical company who has the deep pockets to actually do the necessary work that would get this all the way to a clinical trial. I think we’re really exploring at this stage more the biology and understanding the importance of sialic acid on myeloma, but we’re a long way I think from actually translating this into a clinical trial. I think there are other approaches and I mentioned the possibility of instead of removing the sialic acid from the surface of the cells, if this turns out to be important in myeloma and, of course, I emphasize we’ve only done work in the test tube and, if you like, in the laboratory, but if it turned out that this was really important, we can actually knock out the receptors on the NK cells.
Jenny: Oh, interesting.
Dr. O'Dwyer: That’s something that can be done in a much faster way, and it could get actually in the clinic much, much faster.
Jenny: That’s really fascinating that you could go from the immune system side and not from the sugar cell side. Interesting. Wow. Well, what you’re working on is just so fascinating. It sounds like the E-selectin inhibitors are little bit closer or a lot closer because now they’re in clinical trials. But we just wanted to thank you so much for joining the show and for your participation and explaining all of this new -- because this represents a completely new drug class for a group of drugs.
Dr. O’Dwyer: I want to thank you for the opportunity, if you like, to share what we’re doing. I do emphasize that it is really relatively early compared probably to most of these speakers you have on your show. Probably, their work is at a much later stage and kind of more accepted. And that we’ve a lot to do I think to really validate this and show that this will ultimately be a value to patients. But we have to start somewhere, and I think for the time being at least we're on the right track.
Jenny: Oh, yeah, it sounds fantastic. And I think this just goes to show how complicated the whole things is -- why some people respond and why some don’t, why some people will become resistant, why some don’t. And so, what you’re doing is really important.
Dr. O’Dwyer: Oh, thank you.
Jenny: Well, we have a caller question go ahead with your question.
Caller: Dr. O’Dwyer, I carry the BRAF mutation. And my question is at what step in the patient’s treatment plan does it make sense given the multitude of other available treatments? Does it make sense to try the agents that are found to help patients who carry the BRAF mutation. At what point is it appropriate to try those inhibitors, et cetera?
Dr. O’Dwyer: Yes, I mean think there are people like Marc Raab and Gareth Morgan who have present experience of using BRAF inhibitors in this situation. And I think I have no personally experience doing this, but I think the general concept is that just because you find a mutation in a patient doesn’t necessarily mean that that’s what’s driving their disease. And I think the clinical context is very important. I think in a patient that got extramedullary disease where they have very explosive disease that’s rapidly progressing and where you find that it looks like a high proportion of the cells are BRAF mutated, then makes perfect sense to use a BRAF inhibitor. And in that situation, very good clinical responses have been seen. But, of course, because of the nature of clonal evolution and everything, it’s inevitable that as you suppress that clone, then in time another clone that's BRAF negative is probably going to take its place and take over again. So responses aren't going to be durable, but you can get a very good response for a period of time. But if it’s just there in a minority of the cells and it’s not what’s actually driving, then it probably doesn’t make much sense. I started my career with imatinimb in what is a fairly homogenous disease where you've got a single kinase that if you targeted sufficiently well, you can get excellent durable responses. I think we all know that myeloma is so complicated genetically that you probably need to be hitting multiple different things at the same time. And the more specific your treatment is, the less likely is it to be successful. So it’s really combinations of things. Probably bringing in immunotherapy, for example, is one aspect but is not the sole aspect. I think the more angles that you hit the disease from, the better.
Caller: Right, and just as a followup, how can one determine whether a particular mutation such as the BRAF is the driving mutation for a patient’s myeloma.
Dr. O’Dwyer: Again, I wouldn’t have personal experience of doing this type of analysis, but I’m sure you can probably look at and identify different clones that are present. You can probably sequence and see what proportion of the disease that’s there is actually positive for that particular mutation. And if it looks like it’s the dominant mutation across all the different cells that you’re looking at, well, then it makes sense to treat that. But if it’s only present in a minority of the cells, probably doesn’t that there are other clones that are probably more important.
Caller: Thank you.
Jenny: Okay, thank you so much for your question. Well, Dr. O’Dwyer, thank you so much for joining us today and we just wish you well in your wonderful work
Dr. O’Dwyer: Thank very much. It’s been a pleasure.
Jenny: Oh, thank you so much. And thank you, our callers, for listening to Myeloma Crowd Radio. Tune in next time to learn more about the latest in myeloma research and what it means for you.
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Feb. 01, 2023
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