There are two major challenges to cancer patient survivorship: metastasis and therapy resistance. By applying an ecological framework to study how individual cells move and respond to stress, we have identified a Keystone Cancer Cell that underlies both processes. Dr. Amend presents background information on the Keystone Cancer Cell, and reviews our current efforts to design treatment strategies that target the unique vulnerabilities of these cells, a theory called evolutionary double bind.
Well, good afternoon, everyone, and thank you all for joining us for our inaugural presentation of urology speaks. My name is Alan Partner, and I serve is the director of the Brady Urological Institute and the urologist in chief for Johns Hopkins Medicine. In just a few minutes, I will be introducing our speaker for today's session, Dr Sarah Amond, who will be leading our talk entitled Ecology Meets Cancer Biology, Defining the Keystone Cancer cell species to develop a cure. I cannot think of a more engaging topic to kick off this web Siri's than the subject of curing metastatic cancers. This work encompasses the entirety of the Bradys tripartite mission of excellence in research, education, patient care through the pursuit of our groundbreaking discoveries, The metastatic cancer is no stranger to the global public health arena. In fact, it has been a top concern for medical care teams, basic science, research and community community leaders around the world for decades. This topic is truly frightening, humbling but also profoundly motivating. I'm often reminded how the findings and treatments we developed here at the Brady Laboratories make a positive impact on even the most far reaching communities across the world. What Dr Amon will soon share with you is an incredible example of how the curiosity and tenacity of our investigators, doctors, nurses, basic scientists and staff take seed ideas and developing in a groundbreaking discoveries that have the potential to change the way we understand and treat urologic disease. Normally, we would hope to be able to share these exciting highlights with you in person. After all, as a patient, donor, friend and advocate. You are an integral member of our team, but we're adapting to the Times and delighted that we live in a world with the technology to bring our amazing people and stories of discovery to your home or wherever you may be. A. To this moment ID Like Thio, Make a comment about philanthropy. 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And we did not want to let a pandemic keep us from recognizing the impact that you have on our institute and ultimately the future of medicine. So please accept my thanks on behalf of our speakers, faculty, resident staff and patients now and into the future. Today we're honored to have this opportunity to connect with all of you so that you could hear directly from our experts and ask them and me your questions. Now a few quick notes before we get started with Dr Ammons presentation. This afternoon's webinar is being recorded, so we will be able to share it with friends who are unable to join us. If you are interested in receiving a link to the recording. Please let us know as we invite you to pass it along to any friends in your family who might have an interest in watching it. After Dr Men finishes her presentation, she and I will take your questions. Please use the Q and A button at the bottom of your zoom screen to ask a question during the program, and we will try our best to answer as many as we can. And now I probably introduce you to our speaker for this afternoon. Dr. Sarah Amun is an assistant professor of urology and oncology who joined the Brady faculties in 2000 and 18. She works closely with Dr Kim Piento, medical oncologist and director of research here, the Brady to study the Ecology of Cancer. She completed a post doctoral fellowship and Dr PNC's Lab, received her undergraduate degree from North Carolina State University and biological Sciences and received her PhD from Washington University in ST Louis. Dr. Amon has been an invaluable asset to our institute, bringing a novel and game changing perspective to cancer research. Dr. Amon, I'm delighted to turn this session over to you. Thank you, doctor. Pardon? I'm really excited to be with you all today. Um, I come from the cancer question, and it's a little bit of a different perspective. As Dr Partner mentioned my background, I actually started in broad biological sciences and my first research experiences were actually in plant pathology. When I went to graduate school, I started focusing on the role of the host micro environment, which has become more and more a part of how we think about cancer. When I came to the Brady as a post doctoral fellow, I sought to bridge these two ideas. So bringing the ideas of evolutionary ecology in the background in micro environment and how interacting cells in their environment can drive cancer. I'm gonna walk you through this journey that we that we have created over the last several years. It's really an exciting one. We believe we found the Keystone cancer cell species that really critical cell type that may open the door to a true cancer cure. Now I'm a basic scientist, and so I think it is especially important because I don't see patients face to face, but instead and this step back from them here in the lab to consider our ongoing health crisis of cancer. Worldwide, cancer kills 10 million people per year and then the United States alone. That represents that represents 600,000 people per year. Now those numbers air pretty big, at least for me to think about in real terms. What that means is that one person is dying every minute of cancer in the U. S. That's 60 people lost in the hour that will spend together today. Now, when cancer is truly localized, when, for example, we way study prostate cancer when it's truly localized to the prostate. If that tumor can be completely removed, like during radical prostatectomy, survival rates are very high near 100%. So what accounts for those cancer related deaths there to central challenges to cancer survivorship? The first is metastases. So when cancer leaves that primary site and it spreads to all parts of the body, can prostate cancer most commonly the bone? That's what's known as metastases, and the problem with metastases is that we cannot cure cancer with systemic therapy. All cancer becomes resistant to any standard of care therapy, and that includes hormone therapy, chemotherapy and what's really fascinating about this question from a basic science perspective is that cancer is resistant to all forms of known systemic treatment even before it's been exposed to it. Classically, these two challenges to survivorship, metastases and resistance are considered separate silos. They're both considered. They're both attributed to tumor cell heterogeneity. So within the tumor, their diverse types of cancer cells with different genetic variation and some of those variants may by chance be resistant have a resistance mechanism to a particular drug, while other cells by chance may escape the primary tumor and established in the secondary site. What's really interesting to me, though, is that these are kept separate their research separately. Very little actually crosses the divide to consider both of these challenges to survivorship and from an ecological perspective and evolutionary perspective that's really non intuitive. Both metastases and therapy resistance requires a high degree of resiliency. Those cells must survive chemotherapeutic assault. Therefore, we would then hypothesize that they would have the same what we call co adaptations, that they would have the same traits needed to survive. We're going to start within the tasks of space because from the ecology point of view, it's studied a lot, so why move? This is true of human beings. This is true of bacteria. In addition, it's true of cancer cells. Just because you can move doesn't mean you do move. Movement is incredibly high risk in its high energy. You could be you have to use of energy stores that you could use fewer cancer, self for proliferation and you're exposing yourselves. Thio yourselves to new risk. One of the most common step stimulants to move is scarcity of resource is or an abundance of toxins. Now, if we were in person at this point, I would invite you to think about a coffee break. If you had a late night last night and really need a lot of coffee, you would be more willing to take increased risk to get to get to that coffee cart. So even if somebody you really didn't want to talk to a standing there giving a cup for themselves, you would still go and get some. Sure, on the other hand, maybe you didn't need that much coffee, but they have really great pastries. So something else that would pull you into that site that what we just described that that give and pull between what you want your positive goods of resource is and the cost associated with it, as well as your ability to get up and go to the coffee cart is all described under optimal foraging theory. The O of T optimal foraging theory is well described in the field of ecology, and it predicts how an organism will behave when searching for resource is and responding toe hazards. Essentially, it balances ability, costs and benefits to maximize fitness to maximize survival. Okay, so why do organisms moves and why, as we found to cancer, cells move to move toward good in away from bad. If we think about factors in the environment in this case, the tumor micro environment, there are many goods. There's oxygen. There's glucose, their sugars and carbohydrates and fats to survive and proliferate and drive the metabolism of the cell. There's also Babs, though, for example, chemotherapy, a toxin in the micro environment. All of this ability to move, though, is hinged on the on the individual's capacity to actually move Now. This is a problem for cancer cells because cancer cells come from an epithelial cell that is programmed to stay in place. It's how our bodies work. It's how our tissues air separated. So how does it overcome this? We can once again turn to ecology, where there's a really beautiful example of what's known as a transmogrification from a proliferated from a reproductive, more to a dispersal. More so you can see here a picture of a grasshopper. They're very small, very short, just a couple of inches long. And these air known in ecology as a stay at home Worf Really beautiful language and grasshoppers. Stay at home. Stay in a local habitat when there's high resource is when there is plenty of food for everyone. If, however, there's overcrowding and reduced resource is as a grasshopper develops, it will transmogrified instead into a dispersal locust. Of course, locust plagues were in the news over the last few months. But what's really important about this is that these Locusts they can't reproduce is quickly, but they can travel hundreds of thousands of miles. They're much larger than within a grasshopper. They need longer wings to fly. What's really fascinating about the story of our grasshoppers and locust is that these two pictures are actually siblings they're twins. They have identical genetics. It's on Lee, a change in their circumstances, a change in their gene expression on their phenotype. So how their body plan is organized and what they're able to do well is all due to their environment. This led us to the question. What about cancer? Does it have a grass hopper and locust? More? To answer this question, we turn to a prostate cancer cell line model called PC three, and we put we used a micro fluid X device so it's very small. It's about the size of a dime, and these cells are labeled green and red, and this micro flu ticks device allows us to place ingredient. So in this case, we are testing the ability of cancer cells to respond toe high dose dose of taxes, which is a common chemotherapy and prostate cancer toe low doses of dose of taxol. And then we tracked these cells and I'll be showing you a movie here in a moment over several weeks. So we're gonna let this play, and the first thing I want you to notice is that we have die off of the cells under the high dose dose of tax ill. It's really good. That means our drug is working. This is why dose of tax will works in patients. So, as you can see first, that the that the drug works and the cells die. What becomes immediately apparent are these very large cells here in green. The red ones do it too, um, that are moving around rapidly even in the high dose dose attacks ill. And then eventually, as we see here, they see what we can consider an in future recurrence. So small cells then re populate that space. So this was frightening to us because we were watching the acquisition of therapy resistance in real time. But it was exciting because it also meant that we made a critical discovery and what I was telling you a little bit later, perhaps more of a rediscovery, what we call the poly and employed cancer cell. So this is a poly and deployed cancer cell you can see on the right this very large green cell, typical sells its parental cells. You can see in these red images here so you can see there's a big difference in size. In addition, as I'll be showing you they have an increase in DNA content. What we could observe from this movie is that these cells are highly motile. They're highly resistant, and they see recurrence. Interestingly, thes multi new created polyp Lloyd cells. So again, that means increased DNA content have been reported in the literature for decades. They've been described after therapeutic intervention and multiple cancer cell types, and those interventions include different types of chemotherapy, radiotherapy and even hypoxia. So low oxygen and the two are micro environment. What's interesting, though, is that it was long assumed that these cells couldn't survive. They were too disorganized, they couldn't proliferate to form to smaller cells. And so, therefore, must I do to what's known as my topic catastrophe. So we had to prove to the field and to ourselves that this wasn't just simply an artifact of in vitro cell culture. We asked the question. Do these packs exist in human tumors? It's often said that a day in the library will save weeks in the lab, so we hit the books on. As it turns out, the first description of one of these cells was actually in 18 58 by the father of cellular pathology. Rudolph, very cow. And he looked at tumor slices. So he took tumors, um, after autopsy and slice them. And then look, Thumann looked at them under some of the very early microscopes, and right away he observed these various polymorphous cancer cells and you can see his beautiful illustrations here on the right that clearly show very similar types of cells that we saw and our micro fluid ICS device. What about in our animal models? Can can we really start to study this? But this is a picture of it's known as an H and E stain. The dark blue is nucleus of DNA, and the pink is cytoplasm. It's the rest of the cell body, and these are human prostate cancer cell lines that are grown in the back of an immuno compromised mouse. What you can see in these circled regions are that we were very quickly once we need to look able to pick out packs even in these tumors. Okay, What about in human tumors? This is an example of a metastatic lesion, and this time the blue again is DNA, But we included a cell border stain to make sure we were actually looking at DNA all within one cell. And what you can see very clearly in the slide indicated by the arrows are a number of Polly Anna Floyd cancer cells. So now we know that very have found them in a primary tumor. We found them in a metastases. Well, are they getting there? Are they the cells that are leaving the primary tumor and going to the metastatic site? The answers may be this time we took peripheral blood from a patient with metastatic prostate cancer. Um smeared it on a slide and then stained to in order to see various markers. So what we can see here in the middle is a cancer cell on these air normal white blood cells. But what I hope you can appreciate right away is that here is a cell cancer cell with three distinct nuclei. We have another one on this side. Um, that has multiple nuclei as well. Now, this was a bit humbling, to be honest, because most computer algorithms for all this time that we've been studying rare cells are trained to exclude cells that have funny looking nuclei. So we've been missing these critically important sells the whole time we next One is to know whether this was a prostate cancer phenomenon or whether it was universal toe all cancer cell types on. I'm not going to go through this data very carefully, but this is a summary table showing you that we have found packs of both cell lines and pathology from breast, colon, ovarian, lung, glioblastoma and bladder cell lines. And right now, in our incubators across the hall, we have headed next cell lines growing. We're planning to check those in the coming weeks. So now we know that packs are relevant to human cancer and not just cells grown in a lab in vitro. So what have we learned about packs? What you're looking at here is a rotating view of a three dimensional image that we now can take due to con focal microscopy of a normal PC three parental cell and a pack on the right. And what? I hope you can appreciate it again. The blue, in this case again, is DNA is that in the normal cell, it's nicely organized and packed into this nice tight nucleus with clear margins versus the packs on the right that have clearly disordered nuclei, their morphological very different. In addition, these two images as they rotate er on the same scales. So we right away appreciated that these packs are much larger, not just in two D, where we sort of saw them flat on a piece of plastic, but also in three dimensions. Now we did put some numbers on this, which is important not to just to take a qualitative you. So we looked at cell volume and again, this is the parental cell versus the pack, and we found that on average pax, you're about 5 to 7 times larger in volume than their parents. We also looked at DNA content known as employees. So how many copies of their complete genomes do these cells have? The parental cells have a peek at what we know is to in so their regular amount of DNA, and then right before cells divide, they double their DNA in order to make two cells. There's a smaller peak there. What's incredibly striking about the packs is that there's an accumulation in this at least four in peak, so they're pushed over to a higher degree of DNA content. We also found that more packs air formed after treatment and that this is doesn't matter what type of treatment or type of cancer cell line, thes images on the left or no are what is known as phase contrast. And this is our control, and I'm going to outline these cells here on the left. You can see that they're quite small. In contrast, after only 72 hours with chemotherapy, all the cells that survived were these giant packs that I'm highlighting on the right and really interestingly, whether we treated cells with dosa, Taxol atop aside or CIS platinum that all work in different ways. And no matter what cell line we checked, we saw an increase with the increasing amount of dosage. Now, one of the first questions we get is this. Just the small cells all dying off because we know that there is at least one in this picture. Big sell remaining Well, actually, there's a dramatic increase in the total number of packs 10 and sometimes 15 fold, so we see the cells when we see the million cells. There's about 30,000 packs there just at baseline. After only three days in treatment, there, then at least 30,000 packs. There's this dramatic enrichment off this novel cell type. How two packs form. I talked to you a little bit about how one cell doubles its DNA and then divides into two equal cells. But then how do you get one big sell? One way this might happen is by undergoing late Indo mitosis. So what that means is that the cell starts to go through its normal cell cycle, it doubles its DNA and then it fails to divide. So we'll walk through this video here. We're gonna be looking here. Cell starts to divide it balls up, Do you have to cells? And then they seem to bounce back together again. Now, this cell is now a pack, and conventional wisdom would tell us that that cell can no longer survive. But in fact, we track the self for weeks and it survived. What? I hope you can see from this movie right away is that contrary to what we thought that so that these cells, air dying and are, are sort of still on the plate and not doing much. They actually have remarkable motility and morphological differences. Ah, great graduate student here. Starting to put numbers on this here again are movies. We have a PC, three parental cell line and then a pack population. Andi, I hope you can see it in the movies. But if you can't, we quantitative it here in the graph on the left and you can see that packs have the striking increase in motility. So how we missed these cells for so long there. Cow described them more than a century ago. Why hasn't this been the focus of all cancer biology research? Well, for one, it has to do with our training and our bias. So again, I I introduced this picture before that this is a standard cell culture, a cell line and what I was taught as a cell biologist. And indeed what I taught others until the until we made this discovery was that that cell was unimportant. It would die. We don't need to worry about it anymore. Alternatively, we've become overly reliant as a as a field on these plate based essays. So instead of looking at the cells through the microscope, we put chemicals on them so we can tell whether a cell is metabolizing something in a particular way or whether it's doubling its DNA in a particular way. And so this this picture of themselves very much alive on the plate was actually taken at what we would typically consider about 20% viability. So we've stopped looking at our cultures as a field. Yeah. Now this brings us a little bit back to the question about whether paxar artifact. So even if we found them in patients, even if they move more, do they actually actually disease? Ah, most scientists assume that their evolutionary dead ends, they're destined to die. And if it's true, it would imply that packs maybe a biomarker of stress or cancer progression, but that they are not actually contributing to the process itself. So far in this story, we've learned that packs are resilient cells, that former response to stress that can survive anti cancer therapy, and they're highly motile. So that means that we definitely have a Locust Morphin hand. The question is, can this locus more switch back to a grasshopper more? Can these packs actually see the recurrence and form a recurrent tumor following therapy failure or at a metastatic site? To our surprise that answer is yes. Packs can give rise to this recurrence of typical size cells. So this is packs back to normal. Normal cancer cells not packs into packs. Here we have packs that were induced with this Platon and you can see that this is ah, whole plate full of those very large cells. We stuck these cells in the incubator and largely ignored them. So we get We gave them normal media, so it doesn't have any chemotherapy, Plenty of nutrients. We left them there for 75 days. And when we came back, this the culture flask was full of these very small cells. Of course, some of these packs remain, but by and large, recurrence isn't made up of big cells. If you go, if you remember back to those slides of tumor samples that I showed you, the majority of the cells weren't those big cells. It's a minority population. It's a very critical minority population. And here in the back, I just show you this picture to prove to you that I didn't just cherry pick this smaller image here where you can really see the cell borders. This was the whole flask. Was now back to normal. So we talked before about the importance of size. But what about the importance of DNA employees? You've already seen these first two graphs. We have DNA content across the horizontal access, and we have parental cells that have normal amounts of DNA and cells undergoing cell division that have a little bit more DNA. When we added treatment and got packs, this number increased. So most of the cells had more DNA than usual after a recovery period. However, of those 75 days, the DNA content distribution goes back to normal, where most of the cells of a normal amount of DNA again. One of the reasons why this is interesting is that it may be a point of therapeutic intervention. So if we can keep cells, keep these packs just in their pack form and they never start to divide again, then that means that we could stop recurrence. Now, packs may re populate through a number of different mechanisms. One is by neo sister budding. So this is a still image of a pack and another cell maybe blubbing off here. The other is by asymmetric division. We have a pack in the middle of the screen here and in a moment and started dividing into two. It's actually get a divide into three viable happy cells that go on to live for weeks. So what we know about PACs they're found in human cancer there increased in size and DNA content, and that may be important for their function. More formed in response to treatment, they have high motility, and they conceded recurrence. So all of these components are really coming together and lead us to our hypothesis that packs are the keystone species of the lethal tumor ecosystem. I think one of the most common keystone species are the wolves of Yosemite of Excuse Me of Yellowstone, and this is a beautiful story where they took away the wolves and the ecosystem started to collapse. Different populations were mawr and greater and even the vegetation changed. They re introduced the the Wolves, and within just a couple of years, that ecosystem found its equilibrium in equilibrium again. So a keystone species is one that plays a critical role in maintaining the ecosystem with a very large effect, despite a very few number of cells, and it actually gets its name from the architectural keystone itself, and a keystone supports two arches to walls of an arch or the dome structures of some of the amazing cathedrals. This led us to a paradigm shift. For a cancer biologist, this is a really big deal. Instead of considering metastases and therapy resistance as distinct siloed fields, we instead began to think of them as both supported by the poly and employed cancer cell. By this pack, what we now identify as the Keystone Cancer Cell elimination of the Keystone Cancer Cell may then be the answer to a cancer cure. If the keystone. If the pack is the keystone species and we eliminate the pack, then the lethal functions of metastases and therapy resistance are no longer supported, which would lead to collapse of the cancer cells and the tumor itself. So how can we do that? I already talked to you about how standard chemotherapy forms packs, but the important part about this is that it does reduce total tumor burden. That's that's why it works so well in patients, so it reduces the total tumor burden but enriches for packs, which provides us a window of action. What we propose is an evolutionary double buying treatment strategy, so double bind is sort of out of the out of out of the frying pan into the fire. So if we treat with the side of toxic therapy to kill the majority of the cancer cells and induce these Keystone cancer cells, then we come and treat with a therapy that will specifically eradicate these cells directly. This begs the question. What is unique and potentially target herbal about these Keystone cancer cells? To begin to answer this question, we took a global approach, So what you're looking at here is what's called a heat map. It's called the heat map, because the orange or the warmer colors mean high in the cooler colors mean low. And this is for RNA and in in ourselves, RNA. It comes from DNA RNA that encodes all the proteins needed for life. So we have these parental sells. Those were the same parental cells we've been talking about this entire time, and then the three write columns are all packs that air induced by three different therapies, and now it doesn't really matter the details of this. But what's important is that if you step back and take a look at this that the control population is quite different from the packs. That means they have unique vulnerabilities. Highlighted in yellow are areas where we're already starting work now to try and identify what specific pathways or specific proteins to go up against. Ah, few vignettes, though one is that we found that Keystone cancer cells may survive by going into a hibernation state similar to bears in the wintertime. So this state of dormancy or quiet essence is when the cell stalls and cell cycles from the steps out of cell cycle and protects its DNA. To get this image, we engineered cells with a special cell cycle reporter called a food she sell Reporter that turns red when cells enter this quiescent state. We're working on this now with even newer reporters and even more sophisticated methods to see if all packs go into hibernation and to start to study how they enter in how they exit. We also now know that Keystone cancer cells have increased fat stores Where you're looking at here in green are lipid droplets that are accumulating in these packs. We believe that Keystone cancer cells may use these fat stores to survive. While such stresses present, I, of course, don't have time to go over all of this today. But this is our overview of how we're thinking of attacking Pax. You can see that we're thinking of a number of different mechanisms, including their metabolism, their ability to form recurrence and how they're responding to stress. A really exciting part of this evolutionary double buying strategy is it means that we could repurpose drugs that have already been approved, and these drugs in yellow are those that are already approved for other indications. In summary, we have much to learn about these Keystone cancer cells, and it really takes an ecosystem to do this work. This high level discovery and inquiry requires powerful tools. I've shown you data from our Sprint Nana string machine and images from our conflict called my cross microscope that allows us so. Look at Pax over time and in three dimensions. Coming soon, very soon in the coming weeks is a machine called an Inca site that will allow for very long term cultures over weeks and months with high power imaging. For us to get an idea of what this Kinetics looks like, and we're grateful for federal grants and foundation and private funding to make all of these tools possible. The other thing that is essential about this is truly collaborative and interdisciplinary scientists. We work with scientists from around the world and now was zoom. We can travel around the world in a single day, drawing from expertise so that we could learn from the best. You are a part of our team, a swell and thank you for letting me share the story with you today. All that is left is for me to thank our super Pac on the left here, our current members of our team, including can in our many collaborators, both in Hopkins and beyond and special thanks to all of our funding sources that made this work possible. And with that, I am happy with Dr Pardon to take any questions that you have. Thank you. Thank you so much, Dr Amond. As a reminder, please use the Q and a button at the bottom of your zoom screen toe. Ask a question and I will read them off as they come in. The first question that we have received Dr Amond what has surprised you the most when researching these cells. I think a big surprise to us was just how resilient they were. As I alluded. Thio cell biologists have fought for decades that thes were just dying cells so that cells survive such stress and then gave rise to other cells was absolutely remarkable. And it took a while Onda and a lot of data and careful science in the lab to really convince ourselves of that truth. Thank you very much. There's a question here R p a, C, C S and K C. C s the same thing. And if not, how do they differ? Yes. So we believe that K. C. C s Keystone cancer cells and packs are the same thing that packs is probably any appoint cancer cells is really big cells are the keystone species of the tumor after amond. How does immunotherapy come into play here, if at all, so we're not quite sure yet. We are working to understand very specifically how these packs will respond to immunotherapy. Think it's a really great question and it's something that requires very careful interrogation. Um so we hope Onda all signs point Thio but we still need to test this. That they may be. The T cells might be able thio kill these cells more readily because they look so much different from normal cells and that immunotherapy would help in that space. Dr. Ammons, you spoke in terms of cancer cells, seeking out an ideal environment or increasing movement in response to scarcity. Can this information applied a lifestyle as a way to decrease the risk of recurrence or metastasis, for example, with a low sugar diet? Discourage the movement of cancer cells? Or, alternatively, would Internet would intermittent fasting encourage cell movement? So it's important to recognize that what a cancer cell sees is on Lee. It's very local environment, and by the time the circulation is getting to the cancer cell itself, it's not necessarily going to recognize your high sugar, low sugar or fasting state. Um, so our work does not address any of those lifestyle changes at all because we're only at the cellular level. Do we know if P A. C. C s express PSM A. We think they do. That's actually a question that is actively ongoing in our lab. Right now, we have a really great person who is trying to understand whether packs, like other cancer cells express PSM A. We we know that it's not on Lee PSM expressing cells, though, because this this comes from we see packs in PSM, a non expressing cells as well. But a really great question. Dr Amond as Keystone cancer cells seem to apply across the cancer spectrum. What progress have you and your team made in bringing other researchers from other cancer disciplines aboard to increase the momentum? So we're actually getting a lot in that space. So we are trying to tackle the urological cancers here. Of course, we have collaborations with breast cancer biologists, in particular that cell cycle, beautiful image with the food she cell line on that has work done in a breast cancer space. We have I'm meeting with a past collaborator of history is multiple myeloma. Next month, we have also moved some into the lung space with researchers here in Hopkins. So we are moving with great momentum. New PCC's still need TME to survive or have they become truly autonomous, right? So, um, TME there, I think, refers to the tumor micro environment. Um and we know that packs are formed in the tumor micro environment. But we believe that those packs then can go to another environment and be successful there. So they we believe that it's needed for that initial formation. Um, but not for eventual survival. There's an interesting question about related to active surveillance and maybe doctor Pardon. You'd like to answer this. Do we know if this research has implications across the prostate cancer spectrum, and particularly for patients who are undergoing active surveillance? Might it help to identify patients who are good or poor candidates for treatment? Intervention? I mean, that's a great question. Actually, Melissa, the majority of our patients that we put on actors surveillance are very far to the left of the spectrum when it comes to developing metastases and, uh, resistance to chemotherapy. But I think that if these cells air able to be identified, and actually you could see them on a prostate biopsy at the time of diagnosis, there is a future for this being a prognostic markers. Well, our nano particles a possibility to use to be a systemic treatment for any of this work. Eso nanoparticles are great. And for for those who don't know what a nanoparticle is. It's a, um, small sort of package to put in ah, higher payload of a drug that can theoretically then be specifically delivered to a particular site. So in that respect, yes, if we knew how to deliberate, um, I'm working closely with several is so fu who studies, um nanoparticles. And she's an expert in membrane dynamics and how to deliver those specifically to the cells that we want to kill. So, yes, but not ready for prime time. Yet as you pursue all of your ideas to attack these keystone cancer cells, are there any clinical trials using some of the drugs you suggested going on right now? And if not, how soon? What does the timing look like for clinical intervention? Right. So many of the drugs that were interested in using have gone through clinical trials and are known to be safe and patients for other indications. So, for example, for diabetes or high blood pressure, so we know that the drugs were safe. These drugs have not been specifically tested in cancer unnecessarily, and it's going to be important with our evolutionary double bind strategy to consider the timing so that first you need to be treated with chemotherapy, followed by the second intervention. We're hoping to get those clinical trials up and running in the next two years. I think a list of one point I sit on the porch and drink coffee we can be in a couple of times a week. One of the points that a lot of people may miss is that it may not just be important to kill these cells but actually keep them from dividing. And the timing I think that Sarah keeps mentioning is what the critical aspect is going to be. And I believe Sarah can tell us they may have identified a couple of molecules that might be specific for these cells. Yeah, so So we have, ah, couple on our shortlist. Eso in particular thinking about how those cells divide and we're interested in understanding. It's a protein called Gypsy one, for example. That's really important for that unequal cell division that we saw a movie of, um, but again, that timing is going to be critical. Someone has submitted a question asking if we know if there's a connection between these Keystone cancer cells and BPH I think that's a great question. S o far. We haven't found any evidence of these keystone cancer cells in a be in the BPH setting. I would hypothesize not s o. We know that normal prostate doesn't typically have this type of morphology, even at a single cell level. It's something that we need to go back and test very specifically. And we're working with Angelo de Marzo here, who has done a lot of work in that space, is an excellent pathologist. So look at prostate cancer, sort of a long, different stages of progression long, different leasing grades as well as those, um, states like BPH and normal prostate as well. So we are looking, but we don't think so. After Amon, do we know of hormone therapy might induce the formation of Keystone cancer cells. Short answer to that is yes. Um, hormone therapy will form will induce formation impacts in any of your current research on the keystone cancer cells. Have you been able to eradicate them? So we can in a dish which is a lot different than doing it in an animal or in a patient s o the levels of drugs that we are that we have been successful in so far. Killing the packs directly are much higher than what a patient could see. What we have been able to do is using this evolutionary double buying strategy is keep them in that pack state and not allow them to divide eso again and experiments ongoing. We have stopped them is refrozen them in that pack state, and now we're waiting to see if they ever start dividing again. Um, but we need to wait a long time. Thio Be sure of that. Since variation drives evolution, there's a question about perhaps there are other metastatic drivers in addition to Keystone cancer cells. Have you made of that possibility? Yes. So I think the question is alluding to the genetic heterogeneity and the known genetic drivers on cancer. And it is undoubtable that there are many way many routes to metastases through a genetic and a very specific variation in particular genes. Um, but what has been really compelling about past is that we have found it in every cancer type. We have found it in response to every therapy for any of these drivers that have been identified before. They have been specific either to a particular drug. So if a cell up regulates a particular drug pump, for example, um due to its genetic variation, it then is not we also resistant to another drug. These tax, we found, are true across drugs, and the same holds true across all cancers s Oh, it's not that there's other factors aren't at play, but we believe that the packs are sort of a unifying factor in all of these different cancer types. And across all these different therapies. Keystone Cancer cells have a non co gene or on co jeans or, in other words, genetic heterogeneity. So what's interesting about these parents again is that they arise from all these different types of cancer. Eso We have formed them, for example, from a breast cancer cell line that has its own unique set of genetic variance and, ah, prostate cancer cell line that has a different set of unique variance. When we form packed, they don't seem thio change that genetic material in such a dramatic Why, unlike, for example, person to person variation of breast cancer, where one person may have one gene that really started the cancer and another person may have another gene that really started that cancer here the past. It really seems to be a factor of forming that cell type, versus what in particular is going on with the DNA. Now what goes on afterwards, we're still trying to figure out so whether the cells that come after the packs are somehow genetically different, the ones that came before Dr Amond Is there a thought that if we believe cancer is eradicated in someone, and perhaps there were dead cancer cells that in reality cells could come back to life? So it's not that these cells can come back to life. We know that cells can lie dormant so they could be asleep for a very long time, sometimes decades without then waking back up in starting proliferation, actually forming a tumor that would have an impact on a patient's life. It's not that those cells are dead and then came back to life. It's that they were asleep and woke up from a clinical aspect. We, uh, thanks to Dr Walsh is careful monitoring of his patients. We've seen men that had undetectable P s A values for 16 17 18 years and then suddenly they begin to have a measurable level. So that tends Thio. Make me believe that what we're seeing here has a clinical applications. Well, dormancy. They received a great question for both of you. Has there been any evidence to show that surgical treatment of prostate cancer may induce the development of Keystone cancer cells? And if not, is it something worth studying? You can I could go ahead first. Uh, to my knowledge, there is no evidence that surgery induces the formation of Keystone cells. There is some vague and controversial evidence and suggestion that surgery could release cells from the prostate while you're manipulating the gland. Um, if that were the case, I would expect we would see many, many more men recurring than we do. But it is something that's being investigated. I did my PhD for years studying, uh, in a very crude way compared to what Sarah's doing. Whether or not the surgery released cells into the men's bloodstream on, Thank goodness, we didn't see it very often. There's all cancer treatment increase, Keystone cancer cell activity. Might there be any treatments that show less activity or less impact on Keystone cancer cells? could less treatment perhaps be better for longer survival. So I'm gonna take a each piece of that question at the time. Every therapy that we've tested induces packs eso drawing off of that. I would that to speculate that any other chemotherapies are poisons to the cell would would also induce packs. Um, it's also important to know that we can make them other ways. So, um, if we put them in 0% oxygen, for example, there formed or if we put them in highly alkaline or acidic conditions, change repeats there are also formed, so it seems to be a stress response. The second piece of that question was about Should patients be receiving less chemotherapy to sort of extend the time to create packs? Andi here remember that even a little bit of chemotherapy can induce packs, and chemotherapy works really well. It gets rid of most of the South, um, and it really shrinks down tumor size, and that's really powerful. There is some studies, um, in the evolutionary dynamics of cancer. It's called adaptive therapy about whether the time again, it's timing, though not dosage, so whether the timing off therapy should be changed to control tumor burden for a longer period of time. I think we have time for one more question on you touched on this during your presentation, Doctor Amond. Why were Keystone cancer cells, or P A. C. C s so ignored up until now? And because you really are pioneering a new field, are you meeting resistance and skepticism from within the cancer and research community? We need a lot of resistance in a great deal of skepticism, which is really great in the scientific world to be met with that resistance because it means that we need to prove our point better on. That's one reason why we had so many careful studies to assess these packs and determine whether there really actuators of disease or just something you see in cell culture the reason why we have ignored them for so long. Number one, they're rare. So if you don't see them very frequently, I think it's human bias to think that then it's not very important. The second reason is because they arise again, going back to what I was talking about about the changing pH. They arise under stress, so if you consider cells in culture. We work really hard to keep those cells. We call them happy. We want all the conditions to be right so they will keep growing on plastic, which is sort of amazing in and of itself, that we can grow cells in the lab at all. And so when you see something that is a parent, that's different from what you would usually see, you think it's something wrong You think it's an error and because it didn't happen that often unless you really go and look at for that question. In particular, people just dismissed it. Thank you so much. That's all for the questions. Thanks, Eliza. Want to go ahead and formally close us out for today? Um, first of all, what an amazing presentation. And thank you, Sarah, for joining us this afternoon for presenting your research teams discovery so beautifully and for answering the many excellent questions we had thanks to the audience, I also like to give a special thanks for all of you who participated in this webinar and for your continued support of the Brady and Johns Hopkins Medicine and the dynamic collaborations between our community investigators, clinical staff and patients that gives me so much hope for a brighter and healthier future. If you enjoyed today's session, please consider joining any of the other sessions in the Siri's. You'll see him on your original, um, asks our next one, scheduled for Thursday, November 19th, when two of our star urology residents will present on the prevalence of prostate cancer in the black community and our efforts to further understand the causes of the disparity and develop strategies to better serve these men. Upon completion of this webinar, you're going to be directed to complete a short survey. Please let us know what you thought of today's presentation so that we could refine the futures planned presentations. I also want to thank Lissa Coal and her development staff for making this possible today and overall, thank you again for spending your time with us and stay healthy and well
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