Ash Tewari MBBS, MCh, FRCS (Hon.) , System Chair of Urology at Mount Sinai, and Gregg Semenza, MD, PhD, 2019 Nobel Laureate in Physiology or Medicine, engage in a compelling conversation exploring pioneering breakthroughs in genetics, epigenetics, and how cellular responses to low oxygen levels influence disease treatment and cancer biology. Dr. Semenza shares insights on the evolution of genome sequencing, the dynamic interplay between genetics and environment, and key discoveries that are transforming personalized medicine and cancer research.
Chapters (Click to go to chapter start)
Early Inspiration & Journey: How a high school teacher sparked a lifelong passion for genetics and medicine. From Research to Translational Medicine: Balancing lab work, patient care, and bringing discoveries back to the clinic. Genetics: Why It Matters: Explaining the power of genetics in understanding and treating disease. Oxygen, Epigenetics & Cancer: How oxygen levels, DNA folding, and epigenetics influence cell behavior Evolution & Oxygen’s Role in Life: From photosynthesis to mitochondria: how oxygen shaped multicellular life. Hypoxia, Tumor Growth & Escape: Why low oxygen drives cancer’s blood vessel growth and spread. Prevention, Lifestyle & Nerve Connections: How exercise, healthy habits, and nerve-cancer crosstalk affect prostate cancer. Nerves & Cancer’s Secret Pact: How nerves grow toward cancer cells, fueling invasion and spread. Evolving & Outsmarting Treatment: Clonal evolution: how tumors diversify, adapt, and resist therapy. Unlocking the Immune System: Why the immune system is powerful — and how cancer hides from it. Hot vs. Cold Tumors: Understanding prostate cancer’s “cold” status and priming it for immune attack. Hypoxia & Immune Checkpoints: How low oxygen helps tumors evade immunity — and ways to reverse it. Rethinking Lymph Nodes & Immunity: Surgical questions: do we help or harm immune surveillance by removing nodes? New Hope: Broad-Spectrum Strategies: Targeting tumor environments to boost all therapies and reshape prostate cancer care.
So my first question to you is, tell us a little bit about your background. Where did you grow up, your childhood, early part of your journey. What happened? How did you get inspired? Who was the driver? Yeah, I, um. I grew up in uh Tarrytown in Westchester County, so just north of the city, uh, and I had a, a high school biology teacher, Doctor Rose Nelson, who was, you know, my inspiration, so she really was able to um. In part the sort of the thrill of scientific discovery, uh, and she had a PhD, had done a postdoc, so she had done research and so she really understood the process and was able to explain, you know, uh, that there were people making these discoveries, you know, it wasn't just facts on a page, uh, and that, uh, that really made it exciting for me and, uh, uh. Yeah, I was interested, uh, really from that time, particularly in genetics, which I, which I found particularly interesting and um. So after college, uh, where I, you know, my majored in biology and did research at Children's Hospital in Boston in the pediatric genetics unit there, um, I decided to do a PhD in genetics and an MD at University of Pennsylvania, uh, and, um. Uh, and then after that did uh pediatrics residency, uh, at Duke and then went to Hopkins for my medical genetics fellowship, uh, and never left there, um, and you know for the first half of my career I was doing both, uh, medical genetics, uh, seeing patients, uh, and, and also working, uh, in the research lab and of course teaching. Um, but the second half I focused more on the lab, um. But at the same time our efforts have been translational right? we're we're trying to take what we've learned and hopefully bring it back to the clinic in terms of uh new treatments. So you're understanding about the genes and the genetics in the last 1020 years. A lot has happened. Oh, it's amazing. Tell me what inspired you in that. Can you tell for lay people as to what why genetics is important in understanding the medicine. Yeah, so, um, you know, always, uh, the, the way I was taught is, you know, why did this particular patient get this particular disease at this particular time in their life, right? So that, that captures the individuality, the effect of genetics, but also the effects of the environment, right? um, and these are all the things that we're trying to understand so that we can treat that patient most effectively. Right, um, because we know, you know, for most diseases, um, you know, it's not one size fits all. You can't just take, you know, one pill, give it to the patient. You you've, you've treated their disease, uh, so, uh, you know, that's been a real advance that we can, we can now, you know, sequence the entire genome of patients. When I was a graduate student, we were studying an inherited, um, a blood disorder called thalassemia in a particular family, uh, and this was one of the, uh the first diseases that was studied at the molecular level because the mutations were in a gene. Uh, called beta globin, which is one of the major proteins in red blood cells, and so, uh, I isolated DNA from these, uh, affected individuals, sequenced the beta globin gene which was only about 4000 base pairs, but you know this took me 2 years. Now that can be done in minutes if not seconds, you know, um, and we can see. On the whole genome of a of a patient in a few in a few days, so it's been a tremendous advance. So people talk about it. There is a lot of length of DNA folded within a human body, and then we were talking about 15 trillion cells versus 37 trillion cells. There is a lot of DNA which if we unfold it, it possibly can go from here to moon and sun and come back a couple of times. Yeah, it's a good trick right to fold into, you know, one tiny cell and And, and so you know that's, that's part of the, um, that's not part of the information, right? How is it folded? what part of it is accessible that can actually the DNA can be read in a particular cell um so we know for example that uh. Uh, when cells are exposed to low oxygen, they respond, but every cell responds differently. Why is that? Because some cells, uh, have particular genes that are already being expressed, um, and those genes, you know. Their expression can be modulated if if a gene is, is, you know, tightly wound up and not accessible, um, there's not going to be any response to that gene no matter what what the stimulus is. So genes are the scriptures which are written inside our DNA. But sometimes they are folded in a way that it is not obvious to the translational mechanism, what we call epigenetics or how the histones and other molecules are hiding it, right? So it seems like not everything which we go through is driven only by the genes. No, that's right, and you know, particularly for epigenetics, people feel that that may be a way to respond to the environment in particular. And um and so we study that a lot when we're looking at responses to low oxygen and we find that's one of the major category of uh regulators that are brought to genes in response to hypoxia are genes that affect the epigenetic landscape so inflammation can have an impact on the epigenetics, uh, some of the metabolic syndromes can possibly have it so. Our interest is mainly on the cancer side, so just continuing on that thought. Why certain cells start feeling a little threatened that they feel their existence is at risk and how much of a gene has a role to play and how much is an environment and what an environment can have an impact that the cell feels that they will be dying very soon. What what do you think goes on? So it's very interesting, right, because we talk for example about tumor suppressor genes which are supposed to prevent cancer, but yet when they're inactivated by mutation, the patients are only susceptible to certain rare cancers, right, even though those proteins play a role in many types of cancer. So it is very puzzling why a patient with a particular tumor suppressor gene mutation will only get kidney cancer and not lung cancer, right? Fair enough. I mean, I think there are certain tumor suppressors, P53s and RVs and all those things which are known drivers for that disease. But, but of course those, you know, the mutations, those are not under our control for the most part, right? But uh the environmental exposures that lead to cancer, of course, are. I will keep on the genes side a little bit for people to understand. So genes could be only abnormal in what we call in the cancerous cells versus they can be abnormal in the whole circulating cells what we call germline versus the somatic, right? And so in most people, um, there's no germline mutation, right, that would be passed on. The mutations are just occurring in the cancer cells and it's the accumulation of mutations. That's thought to get to put the cell over the tipping point where the growth and divide the division of the cell is no longer regulated, uh, the cells proliferate in an uncontrolled way, and the normal physiology of the tissue is disrupted. I mean, I think you have devoted your whole life to understanding the cell and distress discussion, but initially we were a unicellular organism. And over millions of years of evolution, that unicellular organism realized that there are certain cells were better in managing oxygen and some cells were better in moving around, so they kind of started becoming a multicellular and in multicellular we decided, OK, you are the muscle, this is the neuron and this is the blood cell and this is the kidney. But these cells have all those capabilities of going back to the original cell for being a unicellular organism in which they kind of focus only on themselves, not in the society, and I think that society harmonics is what is disrupted and in cancer. You want to say something about this whole thought process, please? Yeah, so. You know, when I think about evolution, uh, I think about, um, going way back the, the first cell, um, that was able to capture sunlight and use it to make glucose photosynthesis, right? So that was, that was an amazing thing, right? To, to be able to capture. or energy by a living, uh, by a living organism converted to glucose and oh by the way, there's this side product of the reaction called oxygen. So oxygen was produced as a side product. It accumulated in the atmosphere at first, of course it was toxic. And many of the organisms died because they couldn't, um, they couldn't resist the toxicity of damage. I mean, I think that's right. And but then. Then the turn the tide turned and it we had this other amazing evolutionary adaptation was being able to use oxygen and glucose to make energy. Where does the mitochondria fitting into this discussion and where and so and people think that the mitochondria were actually free free living cells that came into another unicellular. Organism and said well let's let's have a collaboration we'll focus on making energy you take care of everything else um and now there's much more energy being generated and that enabled the formation of multicellular organisms because the coordination of multiple cells requires much more energy so uh you know, photosynthesis. Gave you oxygen oxygen gave you respiration. Respiration gave you multicellular organisms. And then when we think about multicellular organisms, animals in particular, bigger is better, right? Because the little animals get eaten by the bigger ones, but. As animals got larger, so let's think about insects still quite small, but yet oxygen has to get to all the cells, so they just have simple tubes that take the air from the outside and bring it to the interior of the animal that's sufficient. But then when we talk about vertebrates, now you have a backbone that allows you to carry this tremendous amount of weight. Now you need much more sophisticated systems to deliver oxygen to all the cells, hence the. The evolution of the respiratory and the circulatory systems, so you can appreciate that the entire evolution of life on Earth can be viewed from the point of oxygen. There you go. And at the end of the day there is no cell which is far how many millimeters or centimeter from the last capillary, about 100 microns, yeah, 100 microns, so. Let's imagine prostate to be an organ and prostate was supposed to have 10 million or 10 billion of the cells. Suddenly some cells have started getting into a stress mode and they thought that they are at risk and now they are dividing. That same space which was supposed to have 10 amount of cells, now there are 50 times more eggs. So how do they develop blood vessels to grow inside the new cells so that they can survive? Because in order for them to survive, they still need oxygen. Absolutely. So, um, the, the way I look at this with oxygen is it's supply and demand, right? Or consumption and. Right, so the cell senses that there's not enough oxygen because it's being consumed by more cells so the cell can do two things. One, it can switch its metabolism from one that depends on oxygen to one that that doesn't, that will decrease the demand and the other thing is it can produce uh factors that stimulate blood vessel growth to increase supply. And this is all controlled by the hypoxy inducible factors that we discovered, so they're able to balance supply and demand in normal tissue in cancer though it's a different story, right, because you have all these genetic mutations uh that disrupt the normal physiological responses. So now for example we're making much more of the angiogenic growth factors and this turns out not to be a good thing because it stimulates wild blood vessel growth and so even though blood vessels are forming, they're not structurally normal, they're not functionally normal and so. In a in a way it's paradoxical that some of the cancers that seem to have lots of blood vessels are the most hypoxic because those blood vessels are not functioning properly, but they may be giving an access for these cancer cells to escape out of primary site, absolutely because these. are very leaky blood vessels, and these leaky blood vessels let let everything out, and that can include cancer. So instead of bringing good stuff, oxygen back to the cells which can behave normally, it is just giving an egress to get out of to get the cells can get into the blood vessels and then, yeah. So it looks like hypoxia is one of the factors why cancer cells get a little bit crazy. Yeah, so it, it's, it's, it's very interesting that, uh, so not only in, in, in addition to the metabolic and the vascular responses, but somehow the, um, the properties of the cells are altered, um, so from epithelial cells that are rigid, uh, stiff, they're not motile they interact, um, with each other, right? And then what we have is what's called the epithelium mesenchymal transition where those. Epithelial cells now become more like let's say white blood cells in the sense that they're not rigid, they don't associate with each other and they're able to move. So the balance of the cells changes and what you just mentioned about what we call the hallmarks of the cancer. So hallmarks of cancer being that they start multiplying the tumor suppressor genes get suppressed. They don't get picked up by the immune system. They get in hypervascularity, and then the last thing happens that the cells, they lose the basement membrane, the architecture, the organization and become epithelial to as an EMT transition happens. And this is now a dangerous cell which is no longer behaving like the normal cells of that organ, is ready to get out, right. Then inside there are many other mutations going on. What happens? I'm just going to bring you towards the Warburg effect discussion that that is tied to oxygen. Why cancer cells don't use an efficient oxygen processing process rather than use an inefficient but produce more chemicals and more materials which they may be using for some other purpose. Yeah, so it's thought that generating energy by fermentation. The oxygen independent process generates ATP more rapidly. So for rapidly dividing cells, uh uh just fermenting glucose to lactate may be the most efficient way to generate the energy that's needed. Um, and the, um, cancer cells increase the expression of glucose transporters on their surface so they can take in more glucose, right, because they are no longer acting in a cooperative manner, right, where the, the glucose is shared amongst all the cells. Now each one of the cells says I want as much glucose as I can take up. They are the selfish ones, yes, so. You'll see a theme may evolve, and I'm thinking about it, that. This entire story is about a cell in distress. Progeny becomes crazy, and there is a third part. There is a secret love affair which will happen between the nerves and the cancer cells, at least in prostate and pancreatic cancer. So I'm just slowly touching one part of it. So why cell feels. That it is at stress, is it the chemical, radiation, viruses, hypoxia? What drives the first insult to the cancer that they kind of think that I'm not going to survive. I need to do something above and beyond to break the social norms of living in this organ. Tell a little bit about what do you think are the first reasons why cells become malignant. Well, of course in each cancer it's, it's a different story, right? Um, and in each cancer type there are critical genes that are called sort of gatekeepers right? that they play for whatever reason in that particular cell type a particularly important role. And when they became disabled, it's sort of like the, the gates open, right? And now a host of changes occur that because the, the inactivating the gatekeeper is not sufficient, but it's necessary. Uh, and yes, in every cancer it's, it's a different story. So radiation can do some DNA damage. Hypoxia itself could be driving them. Inflammation which is persisting for a long time could be an issue. Sometimes the viral infections can mutate the cancer cells to become malignant. And then after that they start becoming what you call an invasive cancer. That's where the progeny of the cells are now a little bit crazy kind. I mean, I think they don't trust any surrounding controls. They want to just get out of it. Well, again, you can think about this in terms of oxygen is that there's not a lot of oxygen in the tumor. So they're trying to escape that, right? And where do you go? Where's the most oxygen in the blood vessels? What do you think happens between the immune system, the trauma, the tumor microenvironment, and how the scaffolding of the structures around cancer cells, how cancer cells navigate in that little space around and try to get out? Yeah, well, of course, with regards to the immune cells, uh, probably, uh, many times in our lives a cancer cell may develop and be recognized and be killed by the immune system, right? So it's always a battle to see can those cells be eliminated. Before they figure out a way to inactivate the immune system, so it's in multiple hits which are happening up to a point. The immune surveillance can zap down so few runaway cells, but after a point, there's a fine balance of immuno editing that cells grow, die, but they are not growing beyond a certain. Limit, but at some point they just get out of control and then they just become well again we know that the hypoxia within the tumor results in the expression within the cancer cells of proteins that really play a critical role in the cancer being able to evade the immune system. I have got no idea about it. What I'm going to ask, do you think hyperbolic oxygen can have an impact on body's oxygenation that. Right, so the question is, can you, uh, you know, uh, by increasing the external oxygen, uh, pressure, can you, can you drive that into the cancer? Uh, you know, people have been interested in this in this for many years in the context of radiation therapy because Gray recognized a very long time ago, right, that there's hypoxia within tumors and that tumors that are hypoxic are radio resistant. So this was really the first realization, right, that uh hypoxia within a tumor influences the outcome, um, and people have tried many different mechanisms to increase oxygen delivery to tumors, and it really hasn't been successful. I mean, I mean, I was thinking about it from a practical standpoint of late, I work with an exercise physiologist and he has been talking to me about the VO2 max. You exercise in a way that your oxygen carrying capacity goes up. So could indirectly people who exercise, who have a better lungs, better oxygen carrying capacity, their cancer may be a little less nasty than People who are sluggish, yes, there have been some recent studies about exercise and cancer, and of course we know that exercise is one of the best preventive medicines for many diseases, right? And so and we know that prevention is much more effective than therapy. So in prostate cancer, I personally think that there are times when you need to operate, they need to radiate. They need to have chemotherapy hormones and everything, but we have a large pool of patients who we call are on active monitoring, meaning we found some cancer. This cancer is not a crazy kind. They we call it Gleason 6 or an early Gleason 7 cancer. And we kept them in active monitoring for decades and those patients we kind of nudged them to exercise, to eat right, to do the right things. Do you think that makes sense within your innovation and your invention about the hypoxia? I do, yeah, I, I, I do, um, I think, uh, that this is one of the most important things that people can do, uh, is, uh. Is to take care of themselves, have a good diet, exercise, don't drink a lot, don't smoke. Um, these things have a, have a measurable. Whatever the final outcome is, it can only add value to it. That's right. So, so exercise, eating right, getting some sleep and against the things that we can control. they are controllable. I have got a third part of it is that there is a secret love affair going on between cancer cells and the nerves. So prostate is a very unique uh structure. It is located deep inside the male pelvis and it is interposed between the bladder and the urethra. It is surrounded by a capsule and just outside the capsule, there is a plexus of autonomic nerves which are not only responsible for the bladder function for the prosthetic function, they are responsible for the continence and erection orgasm. Somehow, just like pancreatic cancer, prostate cancer, we find that cancer cells are releasing certain chemicals. There is a crosstalk between the nerves around the prostate. They start growing towards what we call exonogenesis, and they grow towards the cancer cells. Cancer cells. Lure them, nerves release the nerve growth factor. That nerve growth factor gives more power to the cancer cells, and ultimately there's a lock in. And then the perineural invasion gives an extra edge to the cancer cells to escape out. So it started with. Secret attraction between the cancer cells and the nerves and then it becomes a force by which cancer escapes out. Do you have any thoughts about what's going on in here? Yeah, so you know, the cancer cells, um, they adopt programs that are already exist for other cell types and of course one of the cell types, um, that is very good at invading into tissue are endothelial cells forming new blood vessels, right? Um, and we also know that, that the, uh, the larger blood vessels often grow alongside nerves, right? So there's a, there's clearly a program that involves communication between those two groups of cells. Yeah, and I think that the, the cancer cell is reactivating that process. Another, let's think about another invasive cell type are the cells of the placenta that invade into the myometrium of the, the, the pregnant female, right? And, and that that's another program of genes that is reactivated in cancer cells. For, for, you know, for their own purposes. So these secret tools of survival, not going into apoptosis, never getting limited by the limit of how many telomerase divisions you can have. And cancer cell is now ready, now it is there, but what do we think about the colonial evolution? Not every cancer cell is the same cell, even though it started as in one cancer cell. Does it evolve into different varieties, different cousins, and one cousin helps the other one while they are developing other mutations? So do point it a little bit, please. Yeah, so part of that is random, right, because the cells that have the greatest growth advantage will take over, right? And we know that there are mutations occurring at an increased rate in the cancer cells, um, so you have this selection that's going on. Uh, just in terms of, um, which cells can divide most rapidly and adapt to the environment that they're in, and then of course they also have to adapt to the therapy, right? So we give a therapy, maybe it's a, uh, a chemotherapy or a targeted therapy. Um, that kills certain cells, but, but what we do unfortunately is select for resistant cells, right? And now the therapy no longer works and we have to come up with another, uh, another approach. I mean, in prostate we luckily know that initially most cancer cells are very dependent on androgens, so it's an androgen receptor mediated uh mechanism, but. To the surprise of everyone else, I mean, there are AKT pathways, there are wind pathways, there are some inflammatory markers, there are DNA repair pathways. They all contribute to the prostate cancer genesis and ultimately, if they recur, they become what you call neuroendocrine. That's where my concern is that when the cancer becomes resistant to almost everything, it is deifferentiating becoming like a nerve cell. And nerves still within unlimited power, and that becomes one of the most difficult cancers for us to kind of manage. Any thoughts you have as to what may be the best strategy in fighting cancer and maybe we can focus on the male male cancers discussion because one will work for the brain and one will work for the prostate. Any thoughts, generic thoughts I understand, right, so, so yeah, we've talked a lot about the problems, but of course we have some solutions, right? And the most exciting solution. Uh, has been, uh, the development of drugs that allow the immune system to become active again and destroy the cancer cells because there's nothing more effective at destroying cancer cells than a normally functioning immune system and we know that some patients can be cured of cancer by these new drugs. Problem is that those are a vast minority of the patients who are treated with the drugs and so the question that everyone is asking is what can we do to overcome the resistance to these therapies so we can cure cancer in more individuals? I think you are touching upon a very important topic and basically cancer cells in order for them to become cancerous acquire certain mutations. And that mutations are usually unique to them and not in the normal cells, so existing NK cells and existing T cells and the dendritic cells should be able to pick them up. But cancer cells not only are luring the blood vessels, not only luring the nerves, but they are somehow creating a mechanism so that they don't get recognized, and they are doing it by two different mechanisms one to hide the mutation so that it is not expressed onto the outer wall. And then the second part is. That they may be sending another message to the surrounding cells posing to be that they are the good guys. So that's the reason many tumors have been designated into two categories, hot tumors where there is a lot of infiltration of these activated capable immune cells coming into the tumor versus the cold tumors. Prostate happens to be a cold tumor, and I was so inspired by your. Discovery that your single dose medication, and I want you to develop on it can result in somehow immunogenically activating the system so that the next round of therapies, if we bring in the with the checkpoint or some other form, they might work better after priming the tissue with this discussion with you and it's all starting with a hypoxia. So please, so again, what is the, what is the existing program that the cancer cells are co-opting? We know that if you have an infection, for example, pneumonia, white blood cells will stream into your lungs, right? And they will kill the bacteria, um, but at some point. They will be causing more tissue damage than damage to the bacteria who have been mostly killed, so the immune system has to have a way to shut down the response and say, OK, it's over. We've done our job. We need to go away now. It has to be defined end point, yes, and that's what the program that the cancer cells utilize. So that end point is called a checkpoint. It's a checkpoint that says we're on. We're on a gate here and we, we don't want you going in anymore so we're gonna prevent you from going into this tissue. Yeah, that's it, that's it, right? Uh, and that's what the cancer cell does. It, it expresses that checkpoint and says to the T cells, you can't go into that tumor. I have a special passport. You cannot go beyond this. You cannot go beyond this, right? Uh, and, uh, now if it, if it was that simple, that one checkpoint, we would be fine because we now have these medicines, right, that will overcome that, that one checkpoint. But unfortunately it's not one checkpoint, it's multiple checkpoints, um, and not only that, as you alluded to, it's not just that the T cells that would kill the cancer cells are being denied entry, it's that other immune cells. are allowed entry and those cells then participate in the suppression of the immune derived cells which you were mentioning from the bone marrow, yeah, so there are another messengers coming from the central government telling, you know what, these are very precious cargo. Don't touch them. So how do you undo that? And then you were very, your results and data yesterday were so promising. I was really inspired about developing something for the prostate because you showed it for kidney, you showed it for breast, and you showed it for prostate, right? And, and you might have noticed that we treated prostate cancer without an androgen inhibitor. That's correct in that model. And then you, you, you know, men don't like androgen suppression. I mean, it takes away the libido. It gives them hot flashes. It gives them a breast enlargement, and it gives them the muscle mass loss, and they become a little bit prediabetic. So if we have a method of doing this to an early prostate cancer, think about an interactive monitoring patient whose checkpoint can be activated in a way that the tumor cells are being kept in bay by the immune cells. how interesting that scene could be, and I have a feeling it's possible. Please dwell on it. Yes, so again, you know, we find that the that hypoxia within the tumor is playing such a major role, uh, in the, in the immune evasion process that um when we block the hypoxia signaling. Um, we have a profound effect, uh, on the, uh, this, the populations of immune cells that are present within the tumor, the production of these signals that come from the cells, but also from the tumors themselves, and we can really reverse that process so that now, um, those immunosuppressive cells are no longer attracted to. The tumor and the T cells and the natural killer cells are no longer done either and they enabled they are enabled they are well in combination now with the checkpoint inhibitors, right? So here because the cells must be there in order for the inhibitors to work, right? So now we've, we've brought those cells into the position where the checkpoint inhibitors will have an effect, uh, and the, the, um, the immune system will be able to overcome the tumor. I have a little bit crazy thought and you can vein into it. As a surgeon, many a times in cancers and we go out and take the original organ out. But we take out a lot of lymph nodes out also. Do you think taking lots of lymph nodes out can have an impact on this immune surveillance mechanism which you're talking about? Should we be only taking out those lymph nodes out, which is really disease with the cancer, or should we be doing in more extensive what we call lymphadenectomy? We take the whole regional lymph nodes out and then hope that there may be some cancer cells there. Do you have any points? You don't, you may not have it. Well, I can only um sort of point to the history of breast cancer um and uh uh Halstead and Halstead because he was at Johns Hopkins, right? So we understand this history very well and he was. You know, it was his obsession to remove all of the cancerous tissue and he believed that, you know, the further he went in removing tissue in the area of the, the breast tumor, the better the outcome or the chance that the woman would be cured, um, but we know that that failed because cells have spread systemically um and that all that did was, you know, cause. Uh, disfiguring wounds for women and uh leave them with many other problems so they had lymphedema because the lymphatic system had been had been removed. So, um, we, we know that it's not so simple as to say the more I remove the better the chance will be, right? We know that's true to a point. We want to remove the primary tumor, no doubt about that, right? Um, but beyond that. It's not as clear and, uh, and of course this is why clinical trials are done. We can argue this from either side and make it sound very rational, but that doesn't matter, right? We need the data to say, does this help men survive longer? Does it? Improve their quality of life. We do need a better marker which is an immunologically or image wise, telling us which which lymph nodes have a cancer cell. Even the PSMA PET scan which we use is not a perfect test, but it is better than what we used to have it, and I personally believe that the lymph nodes could be of three different kinds. One lymph node which never dealt with that tumor antigen, it was just in the neighborhood. It never got activated. Nothing happened. They are just the normal lymph nodes, and they are needed in the body for some purpose. There is a third group of lymph nodes which cancer cells are sitting in that lymph node. Somehow they are there. They are what we call infected, diseased malignant. And there is an in-between one in which cancer cells never made it there, but the dendritic cells got some antigens, processed it, activated the lymph nodes. So this is an activated lymph node. So at the least we should not be touching the untouched lymph node, and we have to figure out a better way of not just removing everything, but the targeted lymph nodes which are cancerous because they can be sending the seeding back to the primary organs and all those, but the in-between group. Maybe we can activate it. We can grow in the lab and bring them back again in the future as an activated cells from the same patient, but they will nurtured and grown over time in a lab. And 5 years later when the cancer is coming back, we can bring those lymph nodes back into the patient, not the lymph nodes, but the lymphatic cells grown and expanded into a technology method. So these are the crazy ideas we get sometimes to think about how the cancer treatment may evolve over time, but any thoughts? Well, of course, you know, one of the examples that you're talking about is like the CAR T cell therapy where T cells are taken out of the patient, um, and then in the lab they're trained to respond to a tumor antigen. They're expanded and put back into the patient. This works very well in certain leukemias so far, um, and has not been as, uh, uh, easy to apply to solid tumors yet, but, um. I feel optimistic that that's a matter of time. Will you ever consider getting involved in the solid tumor battle and fighting this along with us to? Well, so as you know, as you know, we've we've developed these small molecule inhibitors of the hypoxy inducible factors, and we've shown that these are very effective anti-tumor agents, particularly when they're combined with immunotherapy. And we're very interested in bringing these uh these drugs to the clinic, uh, uh, to see whether they're going to be useful in patients because again we can do all the experiments we want in the lab with tumor models in mice, uh, but, but we know that that's not. That's not a very accurate predictor. We need to take these. I would love to participate in those clinical trials because we do have enough number of patients and then as a side hustle we also have an immunological program in which we are injecting a double standard RNA known as Hiltenol, which is poly ICLC into the tumor, and that is bringing NK cells and some T cells into that small molecule like what you are mentioning along with some other immune booster, maybe. Promising. I mean, in medicine we have to be a little restrained in terms of what can happen, but it's definitely worth pursuing you, yeah, and so you, you may know there's also a uh a a um a uh activator of the immune system called sting um which uh people have found gets shut off in cancer, um, and, um, and people are developing agonists of, of sting as a way to again reactivate reactivate the immune system. We've identified several mechanisms by which hypoxic cancer cells turn off sting. So if you undo the hypoxia, possibly a sting will get active and combine that with a small molecule which you're developing, it may. Stop the secret handshake which these cancer cells are having with the immune system that don't shut us off, that gives a totally new hope to the patient and here, here's the thing, you know, so. Um, we, we are sort of swimming against the tide in many ways. First of all, the emphasis in cancer now is on mutations. Uh, our emphasis is on, uh, the environment of the, of the cancer. Um, the emphasis is on these, um, you know, targeted therapies, um. But hypoxia is present in such a large percentage of the patients that um maybe this is something that could be given as a broad spectrum agent and then because it affects so many pathways many of these targeted therapies will work better. So it's not just immunotherapy, I don't think, um, but many of the targeted therapies will work better once the hypoxia response has been tamped down. And this may be a mechanism where you have a broad spectrum agent, then you have your targeted agents, and now maybe you have a strategy that's practical, right? Uh, and because we know that one drug is not enough because one drug will simply foster resistance, right? So we'd like to have some combination therapy, but we also know that there are so many combinations that it might be very difficult to do that on a practical basis. Right, so maybe we need something that's broad spectrum, but not in the way of cytotoxic chemotherapy that will, that will kill normal cells, right? um, but that is targeted to cancer. But in a much broader way than any pathway which is usually being affected because of particular mutations, so you are bringing a totally new theme to the cancer fight. We talk about as a chemotherapy, which are the toxic agents we started talking about the immunotherapies we have radiation. And again, immunotherapy is also in the same way a very general right approach that's gonna probably be effective in in many types of cancer if we can um kind of uh remove these barriers, right? So the oxygenation of a tissue or somehow the cancer tissue and the healthy tissue may be a totally complementary approach which can enhance the. Efficacy of all the treatments which we are talking about and possibly reduce the side effects. I think I can understand you are so passionate about the things which you're doing. You never had an idea as to what we'll be talking about it. This is in prostate cancer specific discussion, but your passion. is going to make many more discoveries to the world, and I would really love to collaborate with you in sorting out the cancer which I deal with a lot. That's the prostate cancer. Any final parting words you have for? Yeah, so you know you know this is the again the beauty of the symposium where you bring together clinicians and researchers, right, and look. Those connections because you want to understand the science you want new tools or, you know, we want to be able to apply our science to actually to the treatment of patients and so we need to come together. We need to talk about it and we need to make a plan. And Hopkins is only 2 hours away from New York and your daughter is in Brooklyn. That's right. You can't thank you enough. Thank you, thank you, thank you. My pleasure. Thanks.
