Cancer Metabolism: From molecules to medicine

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Hello. Good evening. I'm Gina Vild. I'm the chief communications officer for Harvard Medical School, and I am thrilled to welcome you here tonight. This is the 19th year that we've been offering Harvard Medical School's Mini-Med School to those in Boston, and more recently, to those throughout the world. So to all of you here in the auditorium and to those of you who are watching us on the live stream, thank you for joining us. Over the past two decades, this program has allowed many thousands to learn about science and health issues from Harvard's expert faculty. Think of this as your classroom, and we will think of you as students. So you'll have an opportunity to both learn and ask questions from our expert faculty about the latest research and medical breakthroughs. The people you will be learning from are on the front lines of science and medicine. I'm happy to report that last year, we had more than 120,000 students. 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So now for this evening's seminar-- Cancer Metabolism, from Molecules to Medicine. Did you know that there were 17 million new cases of cancer worldwide in 2018? Worldwide, there will be 27.5 million new cases of cancer each year by 2040. That's astounding. And so this evening, you're going to learn from some of the leading scientists at Harvard Medical School who are working to tackle this devastating disease. By illuminating molecular pathways, researchers have discovered that cancer metabolism actually changes the activities of cells when compared to normal cells. Research is now underway to figure out how metabolism becomes reprogrammed in cancer cells, and then to find new and effective treatments to stop the disease from spreading. I'm delighted to introduce you to our panel of experts who will share their insights with you. Brendan Manning is Professor of Genetics and Complex Diseases and Director of the PhD program in Biological Sciences and Public Health at the Harvard T.H. Chan School of Public Health. Nabeel Bardeesy is Harvard Medical School Associate Professor of Medicine, Assistant Geneticist in the Center for Cancer Research, and the Gallagher Endowed Chair of Gastrointestinal Cancer Research at Massachusetts General Hospital. But first we'll hear from Marcia Haigis. Dr. Haigis is Professor of Cell Biology at the Blavantnik Institute at Harvard Medical School. She is a member of the Paul F. Glenn Center for the Biology of Aging and the Ludwig Center at Harvard Medical School. Her lab continues to work on understanding the role mitochondria plays in human aging and age associated diseases. So thank you for being here with us. We're just thrilled to see so many in attendance. And please welcome our first speaker. Thank you. [APPLAUSE] Thank you very much for coming here today. Thank you for that wonderful introduction. And I am so thrilled to be here and share with you all tonight's program, Cancer Metabolism from Molecules to Medicine. And so 2018, the World Health Organization reported that cancer remains a leading cause of death globally. And, in fact, in 2018 one in six individuals had cancer as the cause of death. So these remarkable statistics really highlight the urgent need to further study cancer biology with a hope to identify improved therapies to improve patient care. So today I'm going to talk about fuel. And these are some of the fuels that I think about when you consider fuels. And fuels are important. They need to be harvested. They are delivered. They need to be processed. But in doing so, burning fuels to generate their energy so that they can do the work that needs to be done also has the side product of generating byproducts. And, in fact, it's become a major and very important dialogue today to consider alternative fuel sources that result in a cleaner, more efficient fuel utilization, maximizing ways to process fuels efficiently, and also generate less byproducts. And think about how do we deal with these byproducts. But you might be asking yourself, what does this have to do with cancer. So I'm going to talk about a different kind of fuel today. And this is a picture of a salad that I had last week in Italy. This is the kind of fuel that our bodies use. And so when we consume foods, these foods are broken down into metabolites. And here's a metabolite cartoon of a sugar and an amino acid. And these metabolites, or metabolites similar, are taken up by cells, and they're also delivered and processed by cells. And as a side reaction of this cellular metabolism, metabolic byproducts are also generated. And understanding how fuel metabolism is processed in cells and how that affects cell biology has really blossomed into this new field of cancer metabolism. And it makes us wonder, is cancer metabolism an Achilles heel that will lead to a new class of therapies. And I think to fully understand this point, we need to discuss a few questions. And so in the field we have several driving questions, and I'm going to talk about mainly the first one. And you'll hear about the second and third points today from Brendan and Nabeel. But we're interested generally in understanding how do tumor cells differ from normal cells in their metabolism of cellular fuels. How do tumor cells integrate growth signals and nutrient metabolism in order to proliferate and survive different environments and promote tumorigenesis? And this coordination, you'll hear, is really critical to tumor cell growth. And what is the metabolic communication between tumor cells and their surrounding environments? And understanding how all of these influences interact. And the bottom line is we want to understand, can we actually exploit the unique metabolic properties and vulnerabilities of cancers in order to improve patient care and therapy. And so what are fuels and why do we care? Why do we care about fuels in cancer biology? So if there are lots of different fuels that our cells can use, and a few are shown here, sugars, fatty acids, amino acids broken down from proteins. And they're taken up by cells and converted and processed in order to make molecules important for providing the cell with energy such as ATP, and also for generating molecules that contribute to the essential building blocks of macromolecules important for cell life. And these macro molecules include DNA, RNA, proteins-- I can't really reach way up there but-- membranes to form lipid bilayers to form membranes around cells. And so you might think how do they actually help contribute to building a cell. So these macromolecules are actually the building blocks that form the physical components of a cell. And so you might imagine that a cell that proliferates a lot needs a lot of these macromolecules. And so it's apparent, so you need genomic information, you need RNA in a cell. Cells are full of proteins. And cell boundaries and organelle boundaries are framed by membrane layers. So all of these components are absolutely critical for cell growth and cell proliferation. Now normal cells need these components, too, and they use fuels to generate energy and maintain homeostasis. That's important to their specialized function. So if you consider the specialized or normal cells in our bodies, our brain cells, our heart, our muscle cells. They need to metabolize fuels. But a lot of the fuels are used to make energy so you can do muscle contraction, or also to provide homeostasis and maintain repair and the health and viability of that cell. But by contrast cancer cells are kind of punctuated by their unique ability to proliferate. And they have unchecked proliferation, in part because of mutations. There are many causes of cancer and mutations and unchecked growth signaling pathways and coordinated upregulation of fuel uptake and metabolism. And the fuels are used in cancer cells not only to make energy, but tumor cells upregulate the fuel usage in order to make more of the macromolecules needed for the building blocks to make the mass and the physical form of the cancer cell. And we see evidence of this in patient care today. So you can put a probe, a label, onto a sugar molecule and administer that to patients, an image where the tumors are through PET imaging. And that basically measures where is the glucose taken up. And so you can see glucose taken up in highly metabolic tissues like the brain and the heart. But you also see it here in this patient with a lung tumor because it's highly metabolic. And so we know that these tumors don't metabolize fuels in isolation. But instead there is this really dynamic competition of fuels for the tumor cells and the normal healthy cells surrounding it and in other tissues. And so what we want to do is know can we actually identify the precise molecular pathway that tumors use in order to exploit metabolic fuel preference to target the tumor cells, and maybe minimize the side effects in healthy cells and also improve patient therapy and care. And so the rationale is really simple. And we know that signaling and cell-cell interactions and immune cells affect tumorigenesis. And we know that this synergizes with altered metabolism, because tumor cells have to take up more fuels in order to make the building blocks for their mass. So standard of care historically has targeted this one arm of signaling and cell interactions to try to block tumor growth. And, of course, there has been therapeutic success. But ultimately in many cases there is emerging resistance. And not every patient responds similarly. So we want to know by targeting the fuel, by targeting the energy pathway and the building blocks, can you synergize with standard of care available in order to actually improve outcome and maybe help to overcome resistance. And so in order to answer those questions, we need to dig deeper. And so far I've told you some of the big picture concepts of fuel usage and how the fuels are taken up and metabolized by tumor cells. But in order to design precise drugs, we actually need to identify the metabolic pathways themselves that are altered between normal cells and tumor cells. And this is showing an overview schematic. And it is simplified of the difference in how a normal cell handles sugar compared to how a proliferating cancer cell might handle sugar. And so in a normal cell, you can see the glucose is taken up and it's converted to these intermediates through a process called glycolysis. And then it's metabolized further in this round organelle called the mitochondria. And in the mitochondria, the glucose metabolites, namely pyruvate metabolites, are further metabolized to generate ATP. Now in a tumor cell, they have more glucose uptake. And in addition to more uptake, the process of the handling of the sugar differs. So you don't just have simple metabolism of glucose through glycolysis to make energy. But instead many of the carbons from the glucose are diverted into pathways that you can see form these critical building blocks important for macromolecules that contribute to the mass and physical properties of a cell. And so in understanding some of those properties, we can also see that burning fuels in cells contributes to metabolic byproduct production. And so here is an example of how healthy cells versus tumor cells metabolize an amino acid called glutamine. And high levels of glutamine breakdown generates this small metabolite called ammonia. And what happens is that ammonia really builds up in the tumor environment, called the tumor microenvironment. And so we wanted to know in our lab, what is the role of this metabolic byproduct in cancer. And so there are two hypotheses. One hypothesis is that it's simply secreted from the tumor cells, detoxified through the urea cycle, and thrown away as cellular waste. But another hypothesis is that a rapidly dividing cell would need those nitrogens to form building blocks and support cell proliferation and growth. So we actually measure the effects of this metabolic byproduct in tumor cell proliferation. And so first of all, ammonia accumulates in a tumor microenvironment. If you use a mouse model of tumorigenesis, you can actually measure the level of ammonia in the bloodstream or in the fluid surrounding the tumor and find that it does accumulate to a high level in the tumor cells, in the fluid around the tumors. Moreover, if you add ammonia to estrogen receptor positive breast cancer cells, it actually stimulates their proliferation. And so this shows that the cancer cells actually use their waste, or metabolic byproduct, to fuel growth. Moreover, if we stop this process by inhibiting or reducing the level of the enzyme that's important for this metabolic waste recycling, called glutamate dehydrogenase, you can slow down cancer growth in vivo, in an animal model of cancer. And so you can see that here, if you look at ER positive tumors that have normal levels of metabolic byproduct recycling, shown in this blue line, compared to the levels of tumor growth in tumors lacking the ability to recycle nitrogen. And so in this simple study, we found a new pathway where ammonia in normal cells is known, as the dogma states, to be produced by cells and secreted by cells. But, paradoxically, tumor cells are able to kind of reharness this additional ability to use this metabolic byproduct which accumulates in that tumor cell environment. And then they kind of start to eat it, and they can use that to make glutamate amino acids that are important for protein production. And so through this pathway, they're able to recycle their nitrogen waste products. So going back to my starting question, is cancer metabolism a new Achilles heel. Well, to really answer this question, we still have more questions that we have to work on solving and starting to address. So what are the metabolic signatures of specific tumor types? We know that different tumors arising from different cells of origin have unique metabolic properties. And so we need to learn more about those in order to better target cancer metabolism. We need to understand with a rational, logical way, what are the best combinations of metabolic inhibitors with approved drugs. We have to understand how does tumor metabolism differ with tumor genotype and signaling, and you'll hear more about this from Brendan Manning. It's really critical to understand which genotypes and which patient populations might be more sensitive to particular metabolic inhibitors and combinations. And so when I think about cancer metabolism, I really think about this as a field that's at the tip of an iceberg. So this field really started decades ago with the studies of Otto Warburg looking at how glucose was handled by cancer cells. But now in the last 10 years or so, it's really had this dramatic and exciting Renaissance that has deepened our understanding of how tumor cells use fuels. But I think also exciting to me is that beyond cancer biology, these lessons we learned from cancer metabolism have taught us simple properties that are critical for tumor cell biology, like understanding mechanisms that let tumor cells survive, proliferate, and progress. Our understanding of cancer cell metabolism has also created an open new field of metabolic research in other biological systems, and these range from immunology to stem cell biology. So these same principles of how fuel use in macromolecule building hold true when you think about immune cell activation in response to an antigen, which triggers massive cell proliferation, as well as in the principle of stem cell biology, proliferation, and differentiation. And so this is just really, really basic science that's kind of been uncovered from these mechanistic studies in cancer biology. And, in addition, studies of cancer metabolism are continually pushing the envelope of technology development, and I find that also extremely exciting. When we're trying to map these precise mechanisms and pathways, it always pushes for further technology development. And that also just supports a lot of other studies. And so I want to thank my lab for doing the work, all the wonderful collaborators that we have at Harvard and beyond. And some of the collaborators involved in the breast cancer study are shown here. These are my lab members who love to draw mitochondria, as you can see. And I thank you all for your attention [APPLAUSE] So I'm pleased to introduce our next speaker Dr. Brendan Manning. [APPLAUSE] Thank you. I'm very honored to participate. I'm very honored to participate in this symposium to bring what we do every day as scientists to the public as well as to those online listening around the world, including my boys, Garrett and Cameron. Hopefully, they don't ask any hard questions during the question and answer period. So I'm going to drill down on an aspect of cellular metabolism that Marcia touched on in her talk, and that's the concept of cell growth. This is something that my lab is very interested in. We have a laboratory across the way at the Harvard T.H. Chan School of Public Health, just in the back corner of the Harvard Medical School quad. And we're very interested in the concept of cellular growth, and in particular the metabolism that underlies cell growth and how that metabolism is controlled in cancer cells. So just as a take home-- let me back up here. So cell growth is really a concept that underlies cell proliferation. A cell must increase its size. It must double its cell size before it divides in order to form two cells of the same size. So this is a simple concept, but it may not be one that's obvious to everyone. If a cell divides without growing, the cells will get smaller with each subsequent division. And this is why cells must increase their mass in order to divide and create more cells. So it's a very simple concept, but how a cell achieves this is actually quite complex. Again, something that Marcia touched on is that cells utilize nutrients and energy. And they consume nutrients and energy in a process of anabolic metabolism in order to drive the building of a new cell. Through the consumption of nutrients and energy, you can produce the macromolecules that underlie cell growth, that underlie that the products that are used to make, to double a cell's mass. So we refer to this as cell biomass. About 2/3 of our cells are made of water, not surprisingly. But when I say cell dry mass or cell biomass, I'm really talking about the dry weight of a cell. So cells are really comprised primarily of these four components here. 55% protein, 25% nucleic acids, 15% lipid, and about 5% complex carbohydrates, give or take on each of these numbers. And so in order to do this seemingly simple process, a cell must take nutrients and energy and build these macromolecules. And it does that by driving anabolic metabolism, by driving metabolic processes. So I think a good analogy of how this functions is really in the concept of building a house. So in building a house, in this case-- excuse me, keep-- the materials to build the house, rather than nutrients, are building materials, everything from shingles and lumber and wires. These materials are utilized by specialized contractors that build different aspects of the house. And you can view the contractors as metabolic pathways. So each of these contractors is using these building blocks to build different aspects of this new house. Just like that new house, metabolites are utilized by metabolic pathways rather than contractors. And these metabolites are util-- and some of these metabolites include glucose and amino acids, the things that Marcia talked about, the fuels that Marcia talked about. These are utilized through metabolic pathways and turned into those macromolecules that underlie cell growth. So these nutrients are turned into the protein, lipid, nucleic acids, and carbohydrates that I talked about on that first slide through these metabolic pathways. So, however, this process is-- it doesn't occur on its own. Cells in our body grow only when they're told. They're very disciplined, and they really only grow when they're told to do so. So they really only grow when they receive a signal from other cells that it's time to grow. And this is really in the form of growth factors, hormones, and cytokines, which are in our blood and circulating and are messages from other cells to a cell that tell it to either grow or not. Sometimes the signal tells it to die. But a growth signal will start this process of cell growth by stimulating the processes, the metabolic processes that I was just referring to. So what distinguishes a normal cell and its controlled growth that's induced by growth factors and a cancer cell is that a cancer cell grows in an uncontrolled manner. It receives this growth signal without the growth signal even being there. So the cancer cell, through a variety of different cancer causing mutations, and Dr. Bardeesy will talk about a key mutation that's very common in human cancers in his talk. These cancer causing mutations drive cell growth by manipulating the cell growth signaling pathways to promote cell growth in an uncontrolled manner. So this cycle doesn't occur just once. It can it occurs continuously in an uncontrolled manner, therefore giving you a tumor. Looking more closely at this, the way that cell signals are propagated, and growth signals are propagated within cells, most of the time initiates at the cell surface by receptors that receive these growth factors signals. Those receptors are then activated to propagate a signal into the cell that tell the cell to grow. And I'm going to tell you about one key growth signaling pathway today. Cancer cells are receiving that growth signal, and generally the mutations that effect cancer cell and cause it to grow uncontrollably affected these same signaling pathways, these lines of communication within the cell, and signal to the cell to grow even in the absence of an exogenous growth signal, so that you have uncontrolled cell growth. So in thinking about what this signal hits in the cell to tell it to grow, it's really useful to think about this growth signal as being a general contractor, if we go back to our house analogy. So these individual pathways or specialists-- the roofer, the carpenter, the electrician-- that helped to build the house are coordinated, often coordinated, if you're going to build a house de novo by a general contractor. Hopefully somebody who is more competent than this general contractor here. If you are a general contractor, I apologize. This is not how I view you. So the general contractor really coordinates the specialized workers that build the house. And this is really what that growth signal hits in ourselves. It hits the general contractor of the cell. And that is a protein called mTOR that my lab and many labs are very interested in. This is a protein called the mechanistic target of rapamycin The title, the name of the protein, is not so important. But it is a key downstream target of growth signaling pathways, and it drives cell growth. And the way that it drives cell growth is by programming the cell to convert nutrients and energy through metabolic pathways into biomass, into the macromolecules to build cells. So it is a coordinator of this variety of metabolic pathways to drive cellular growth. And what happens in cancer cells is that mTOR gets flipped on, and it stays on. So it is receiving that growth signal through cancer causing mutations such as the one that Dr. Bardeesy will talk about. And it, therefore, is being turned on in an aberrant manner. It's receiving a growth signal that's not really there and, therefore, driving cell growth in an uncontrolled manner. It's not surprising, given that mTOR is activated in the majority of human cancers, that there's intense interest in targeting the pathways that lead to mTOR activation as well as mTOR itself in human cancers. And this has shown some promise. It's certainly not a magic bullet, and I'll talk a little bit about why that might be in a few slides. But of course, there's intense interest in targeting the general contractor to stop this entire program. So let's go back to that general contractor analogy. This is the analogy of firing the general contractor. If you fire this contractor, basically work on the house generally stops or at least slows down. So construction is halted. So this is something that would be good if you're trying to stop the building of a cancer cell and stop the building of a tumor. You want to at least slow the growth of the tumor, if not completely stop the growth of the tumor. Another strategy, which may not be as obvious, is instead of firing the general contractor, to fire a single person within this, that is underneath the general contractor that's driving the building of the house. So in this hypothetical, if you fired the carpenter, for instance, without telling the rest of the specialists or the general contractor that the carpenter had stopped working on the house, you could create, in theory, a setting where you have a structural imbalance and the house collapses. And this is really what we want to do to a tumor. We want the tumor to collapse. We want to create an imbalanced setting that causes the tumor to collapse. And this is really a concept that my lab is interested in, and many labs that are studying cancer metabolism are interested in, whether we can create metabolic imbalance in a tumor. And I just want to tell you a little bit about that concept here. So, again, if we go back to our mTOR signaling driving cancer metabolism slide, and we think about the usefulness of targeting mTOR, again, the general contractor in this case of the cancer cell. What will happen, and we do see this in many settings, is that these metabolic pathways will slow their function in the growth of the cell, and the growth of the tumor will slow down. OK? Often, this is frequently accompanied by another pathway being activated, which turns mTOR back on, or other pathways being activated that can then turn on these metabolic pathways. This is frequently what happens, and you get the development of resistance to those targeted therapeutics. Again, going back to our analogy of targeting the individual contractors instead. If we can take out a single metabolic pathway that mTOR controls without telling mTOR, and mTOR stays on and is still driving the activation of these other metabolic pathways, we might be able to create metabolic imbalance such that we ultimately can kill the tumor cell. And this is something that we have examples of in the literature. I'm going to show you just one piece of data from my own lab that demonstrates this concept. This is actually two separate experiments, one done in cell culture, and one done in a mouse tumor model. And I'll take you through these. I'm sorry. Excuse me. In this slide here, on this side here, we have two cells that are basically identical to one another. The only difference between these two cells-- this is a normal cell, which has growth factor control of the mTOR pathway. So you need growth factors in order activate mTOR in this particular cell. This cell has a mutation that leads to uncontrolled mTOR activation, like one of these cancer causing mutations. mTOR is just on, and it's fully on all the time. And what we've done, you can see there's a little bit of a difference between these two cell types. First of all, they're all purple because we stain them purple. There's not something special about the cells. One thing you might notice is that these cells have a different shape and they're bigger, and that really is controlled by this uncontrolled mTOR signaling. But what we've done here is treat either with a control compound or a metabolic pathway inhibitor that inhibits specifically just one of those metabolic pathways I showed on the previous slide that mTOR usually drives to promote cell growth. Just one of those pathways. mTOR is still on, and all the other pathways that mTOR is activating are still on. So one pathway has been eliminated, and we see collapse of those cells. They die. We see the same thing in a tumor. This is a mouse tumor that's caused by uncontrolled mTOR signaling. You can see that the tumor is here in this tissue stain. If we stain mTOR signaling, you could see that the mTOR signaling is very active really exclusively in the tumor. The rest of the normal kidney is pictured out here. And what happens when you treat with the same inhibitor that we did on this slide is that the cells within the tumor all die. Importantly, the remaining cells still have activated mTOR. So mTOR is really still on. And this turns out to be an essential element of this treatment. If you turn mTOR signaling off, they lose sensitivity to this drug. So you need to be driving this program in order to have this antitumor response. So with that, I want to take a step back and just talk a little bit about targeting cancer metabolism in general and the cancer metabolism field. So targeting the key metabolic processes that underlie cancer cell growth is not a new concept. Really the first antimetabolite therapy ever discovered was discovered across the street by this gentleman here, Dr. Sidney Farber. He discovered, working with children that have leukemia, he discovered an antimetabolite that would kill leukemia cells that otherwise were untreatable, thereby sending these leukemias into remission. And what he did was target a pathway necessary for nucleotide synthesis. So nucleotides are one of the pathways that I showed on the previous slide that mTOR drives, drives nucleotide synthesis. Nucleotides are used to make nucleic acids. That's the DNA and the RNA in the cell. This comprises about 25% of our biomass, give or take. Nucleotides are really made from exogenous nutrients. They're made from glucose, amino acids, and vitamin B9, or folate or folic acid. And what Dr. Farber found was that treating these patients with antifolates that blocked the use of folic acid to produce nucleotides could selectively kill the leukemia cells and, therefore, send them into remission. And this is still a therapy, this antimetabolite therapy, is still something that's in use today. So targeting cancer metabolism is not a new concept. But it's been re-energized in the last 15 to 20 years really by modern technology, our improved ability to measure metabolism, metabolites, metabolic flux, as well as improved understanding and a deeper understanding of cancer biology in general. We've really started to unravel many aspects of cancer metabolism that are targetable. And this is really what we're looking for is targetable metabolic vulnerabilities. And the field of cancer metabolism in general is inherently multidisciplinary. It draws on lots of different aspects of biomedical research and also contributes a lot back to various aspects of biomedical research. And so just in closing, I want to say that I've really talked about one small piece of cancer biology today. I've talked about really the early stages of tumor development, how a single cell that acquires a genetic mutation can give rise to a tumor. But we know that cancer really is a complex disease that-- sorry, keep mixing up the pointer. And so that as the tumor grows, we see that various aspects of metabolism kick in. And the tumor undergoes a variety of different metabolic adaptations as it progresses. At some point during its development, the tumor will reach a point where parts of the tumor may be starving for nutrients. And at this stage, the tumor will send out signals that tell the body to grow more blood cells, more blood, more blood vessels going into the tumor, in order to resupply the tumor with food, because the blood is really the source of nutrients for the tumor. So this is a process called angiogenesis, which I'm not going to talk about today. But basically what angiogenesis does is refuel the tumor and provide nutrients back to the tumor. And then finally one of the worst aspects of tumor biology, one of one of the most daunting parts of tumor biology, is the fact that tumor cells will ultimately leave the primary tumor and metastasize and move to another site in our body and set up camp there, and therefore metastasize and form a metastasizing tumor. And in that setting, there are other metabolic challenges that that tumor cell faces as it's entering a new tissue niche and experiencing a different nutrient environment. And so I bring this up because I'm not rooting for the tumor cells except to say that these are all challenges that the tumor cell faces that are targetable and that we can take advantage of as cancer researchers and clinicians to target cancer metabolism and therefore eradicate cancer by targeting these different metabolic pathways. So with that, I want to hand it over to Nabeel Bardeesy, who is going to pick it up from there. [APPLAUSE] So I'd also like to thank everybody for attending here in person and live streaming. It's a real pleasure for us to be able to give a public lecture. We're so used to speaking to each other, and it's a bit of a challenge for us to try to convey things in a more broadly interesting manner, but it's also a lot of fun. Brendan and Marcia, my colleagues, nicely laid out general principles in metabolic reprogramming in cancer. As Marcia noted, individual cancer types use different strategies to rewire metabolism that are often in keeping with their specific environment of that tissue. As an example of this, I'm going to talk about metabolic reprogramming in pancreatic cancer, which is an area that my lab works on in Mass General Hospital. The pancreas is an organ involved in digestion, so producing enzymes to digest food in the intestine, as well as the production of insulin to control blood glucose levels. Unlike many other cancer types, progress has been actually quite limited in the therapies for pancreatic cancer patients. In the graph on the right, pancreatic cancer survival rates over five years, five-year survival rates, and how they've changed over the last 40 years are on the bottom. Whereas much more promising advances have happened in other cancer types, the cancers tend to be detected late and respond very poorly to conventional chemotherapies and radiotherapies. And so we really need to understand much more about the biology if we're going to make clinical headway. The central, or one of the central, bad actors in pancreatic cancer is the gene KRAS, whose normal function is to be coupled very closely to growth signals and to act as a conductor to orchestrate a whole set of events happening at once, regulating cell metabolism, migration, modulate modulating the immune system, but in a very controlled manner. And this is important in the normal development of the organism, or different tissues, as well as in repair in adult tissues. In virtually all pancreatic cancers, and 20% of all cancers throughout the body, KRAS is mutated. And so there's no need for any upstream signal. The protein is always on and always acting in an uncontrolled way to drive all of these processes. Unfortunately, in one of the great, let's say, unmet needs in oncology is a specific and effective KRAS inhibitor. In the absence of such an inhibitor, and yet despite decades of attempts to develop one, many scientists around the world are trying to investigate what KRAS is specifically doing within the cancer cell in order to curtail what we call the downstream effects of KRAS. And one particularly promising area is in understanding and exploiting KRAS mediated alterations in cell metabolism. All cancers undergo a gradual evolution, which is driven both by-- excuse me, an evolution as well as an adaptation to the changing environmental context that they are growing within. And these are driven both by genetic changes as well as by nongenetic alterations. In pancreatic cancer, the first genetic event is a mutation that activates KRAS gene. And KRAS mutations causing abnormal growth of the cell, the pancreatic cells that incur that mutation as well as damage to the local pancreatic environment. And there's a co-evolution of the growing pancreatic cells as well as the local environment which leads to a very disorganized tissue structure, unlike a normal pancreas. And this happens, actually, it can be over 20 years. These cancers slowly evolve. An ultimate consequence of this disorganized tissue is that there's a great deal of fibrotic tissue within the tumor and a reduction of blood vessels. Brendan mentioned it a moment ago, angiogenesis. And, in fact, for certain cancer types, there are a lot more blood vessels that are recruited in. But a feature that's characteristic of pancreatic cancers is actually a compressed blood vessel context. The consequences of this, of evolution of a tumor within this very disorganized environment, is ultimately a limited availability of nutrients compared to a lot of normal tissues. And the blood vessels, who are again abundant in the normal tissue and can be very abundant in specific cancer types like kidney cancer, are required for delivering nutrients as well as delivering oxygen. So pancreatic cancers, by virtue of their unique, very dense, and hypovascular microenvironment, have lower nutrient availability, often quite strikingly than normal tissues. A second feature of this environment is that there are replete immune cells and other connective tissue cells that could, in principle, be competing for those scarce nutrients. But they could also be appropriated, and they can collaborate and offset defects in metabolism. So they can share the metabolic burden. And both of those processes are probably ongoing. And I should just say that in the histological image below, the cancer cells, or the tumor cells with mutations, are circled. And you can see that they are embedded in, again, in this very dense noncancer cell matrix that are all participating in the tumor. So ultimately how is this cancer growth achieved despite this limited nutrient availability? We've learned in the last number of years that this balance between growth and nutrient utilization is really orchestrated very much in large part by KRAS mutations themselves. And they're keeping a close concert between growth cues and nutrient acquisition and nutrient utilization. And, again, this is leading to a lot of predictions for how there can be imbalances discovered and exploited. So I said earlier that there aren't any KRAS inhibitory drugs that are currently in the clinic. And on the horizon there isn't immediate clear opportunities for robust KRAS inhibitory drugs. However, we can use genetic tools in the mouse or in human cells. And we can switch off genetically KRAS and demonstrate that, in fact, KRAS is very important in tumor growth. So the images at the bottom show a model for what's observed in experimental systems. Turning off KRAS genetically leads to a very strong regression of tumors as well as a lot of death in the tumor. And we're learning now that a considerable portion of this death is due to a metabolic imbalance, and I'll lead you through that. So, first of all, what is KRAS actively doing? One of the things that it's clearly doing is ensuring that there's robust availability of nutrients and enhanced ability to acquire the available nutrients despite overall limited supply. And these include taking up glucose and glutamine, which are generally abundant in the body and very diverse in being able to be interconverted to generate many of the basic building blocks needed in the cell. There's also specialized scavenging processes that are normally operative in starved cells. A normal starved cell can start recycling some of its cellular components or taking advantage of an improved way to harness nutrients that are available outside the cell. So pancreatic cancers have all of these operating in conjunction. And, finally, they're also very effective in taking up fats. And I'm going to lead through some of these examples of how they are controlled and how they might be exploitable therapeutically. So Marcia introduced imaging for glucose. You can see here in images from a mouse model where on the left, KRAS mutations are on. The tumor is actively growing. And the tumor is actively taking up glucose. That's contributing to the biomass acquisition of the tumor. Very rapidly upon genetic switching off KRAS, the tumors are losing the ability to take up glucose. And this is a very important contributor to their loss of growth capacity. So that's for one nutrient, glucose. Another key nutrient is amino acids. And, again, in this context of limited nutrient availability, pancreatic cancers are specialized at a process called macropinocytosis, which involves capturing extracellular nutrients that could be derived from dying cells or the available serum proteins. And these are ultimately degraded in an organelle, in a compartment of the cell called the lysosome that contains a lot of degraded machinery. And this active process of macropinocytosis is an important source of amino acids, again, one of the key building blocks in pancreatic cancer cells. A related process that dovetails with the lysosome is called autophagy. And this is a process of recycling damaged organelles in the cell. And, again, both of these are operating at high levels in pancreatic cancer cells. And current drug strategies that are being tested in the clinic are inhibiting this cellular recycling program and have shown some promise in pancreatic cancer treatment. Here's an example from experimental models, where the lysosome, so the degradative structure, is very actively degrading material. And so on the left is a pancreatic cancer cell, where there's very little material present in this lysosome because it's actively being degraded. Whereas if we use an experimental approach to inhibit this process, you can see this accumulation of a lot of cellular components. On the right is a graph showing what happens to that cell growth or tumor growth when these degradative process are inhibited, where you can see a very profound inhibition of growth due to inhibition of recycling. So to really fully be able to harness metabolic reprogram, it's important to know both the source of nutrients in a cancer cell but also what are the ultimate fate of these nutrients. What are they being used for? What are those essential functions that are supporting growth? And I've listed some here. Glucose uptake is particularly important in fueling the synthesis of the generation of nucleic acids, and therefore in the production of DNA and RNA. Glutamine is very important in the control of a damaging chemical in the cell called oxidants, so to prevent oxidative stress. And I'll return to that in a moment. I've already alluded to what autophagy does. So by understanding some of these altered utilization of nutrients, we can exploit this. And so Marcia alluded to cancers as having a really revved up metabolism. They're hypermetabolic. And so cancers need to be able to both integrate a growth signal as well as mitigating this kind of cellular stress. And one of these cellular stresses is reactive oxygen species. A lot of you in the room have heard of taking antioxidants as a way to protect our body in general. But it so happens that cancers are actually quite efficient at dealing with the excess oxidative stress that they generate. And they're, in fact, generating their own antioxidants as a protective measure for the tumor themselves. And this slide here sort of brings together how KRAS coordinates both enhanced growth coupled with enhanced protection from damage. So KRAS actively increases glucose uptake and the utilization of glutamine. This on the one hand increases the tumor growth and leads to an oxidative stress. So this very rapid growth can lead to inefficiencies. Just like the car that I showed on the previous slide, where a very, very rapidly driving car can lead to a lot of inefficiencies in the way fuel is burnt and lead to damaging for the car. The same can be operative in a cancer. But KRAS, by acting as this master orchestrator, at the same time increases the generation of antioxidants, both by utilizing nutrient metabolites to generate antioxidants as well as to increase the production of enzymes that are good at, again, enforcing this antioxidant state. Autophagy, or this recycling machinery, also rids the cell of damaged organelles as well as increases metabolic efficiency. So by maintaining this fine balance, KRAS is able to both drive very pronounced growth, while avoiding would be lethal damaging insults. And this gives us a framework to think about where we can intervene to cause imbalances that hopefully will be toxic to the cell. So with the last slide, I'd like to sort of bring things back to how we can take this basic science information and to apply it in the clinic, but also what are the remaining challenges. And, furthermore, what are the opportunities that are emerging from understanding cancer metabolism. One other thing that's very exciting addresses a key challenge really that could be transformative in pancreatic cancer. If early detection were possible, patients who have tumors detected early, often by chance, in the clinic that might be detected for coming in for another indication. They can be cured surgically. And so if we can discover properties of these cancers that are present very early before the tumors metastasize, this might offer opportunities for early detection. And there's been some very exciting work in the pancreatic cancer field showing that a very distinct metabolic production that can be detected in the blood is associated with early pancreatic cancer. And this is being actively explored for whether it's a practical way to increase the potential for early diagnosis. Another aspect is what we call immunometabolism. So cancer treatments, a diversity of cancer treatments, both those that affect cancer cell metabolism but other properties of the cancer cell. It's now emerging that we need to think of how the metabolic properties of the immune cells are being affected, because we want to be able to harness and reactivate immune cells to recognize the tumor. And it's becoming increasingly recognized that we have to consider how our interventions affect immune cell function. A topic that many of us scientists get asked a lot about is how diet affects both the development of cancer and, perhaps particularly savvy people, how it might affect more specifically therapeutic response. And there's been some very exciting developments suggesting that, well, let me turn to the first aspect. So certainly diet can affect pancreatic cancer. We know that obesity is a risk factor. We also are gaining a more precise role of why that's the case. But, secondly, what's emerging more recently, irrespective of obesity, is that certain foods in the diet seem to be able to have a very pronounced effect on therapeutic response, again in model systems. And by dissecting this, we'll be able to both have a more integrated, holistic view of how to harness cancer therapies. Marcia alluded to, and Brendan alluded to, this crosstalk between cancer cells and other types of cells in the tumor. On the one hand, there seems to be some sort of symbiotic relationship between the nutrient supply between the tumor and the noncancer cells that we need to understand. And, finally, we've shown a lot of experimental data that suggests that you can really have strong antitumor effects when you intervene in metabolism. And the public often hears this laboratory data that sounds very promising. And it's not always apparent for why this doesn't immediately translate in the clinic. In metabolism, one extreme challenge is that metabolism can be viewed as robust. And what we mean by that is that there's many ways to generate the same end product. And so there is in very many experimental systems, a kind of whack-a-mole, where inhibiting one process in metabolism can be bypassed by an alternative pathway. And so this is really a plea for more basic science understanding. We have lots of good hypotheses, and we're starting to understand the unique metabolism of different cancer types. But we need to have a better understanding of that circuitry so that we are getting past this whack-a-mole strategy but really being able to durably intervene in metabolism. So with that, I'd like to thank the audience. It's really great to be here and thank you. [APPLAUSE] OK. So thank you all for your attention and for these really terrific questions. So there were a number of questions in different categories. So I'm going to try to read them according to the theme of topic. And then Brendan, Nabeel, and I will do our best to answer. And you can feel free to contact us afterwards, too, with additional questions. Our information is on the website. And you can also look up what our individual labs do and learn more about how to contact us this way. And just to start with, I will not have time to read all of these excellent questions. So I apologize in advance if I don't get to your question. So the first set of questions has to do with on-target versus off-target. How do you ensure that drugs target only the mTOR of cancer cells and do not inhibit normal cell growth? And that goes along with another question directed to Brendan. What are the limitations of targeting metabolic pathways? So I think this is really the most important aspect of any approach to targeting cancer is what the therapeutic window is, because we're specifically targeting proliferating cells and we're targeting the pathways that drive proliferation. So the most common off-target effects, of course, are those that are also affected by traditional chemotherapies. These are proliferating cells, hair follicles, the lining of the guts, and immune cells in particular, which is the most troubling of the on-target, off-target effects. These are cells that, when induced to proliferate, take on a metabolic program that is somewhat similar to the metabolic program I was talking about, that they are driving an anabolic program to promote biomass and expand immune cells, for instance. When they are revving up to attack a foreign entity in our body, they will do a similar metabolism to what the metabolism a cancer cell does. So targeting these metabolic pathways, those are the cells that we worry the most about. But other proliferating cells certainly can be affected. Now we think that there-- history tells us, work from people like Dr. Farber, tells us that there is a therapeutic window to be had for some therapies depending on the cell setting and depending on the underlying metabolic vulnerabilities of that cell setting. So we think that the fact that this metabolic program is occurring in an uncontrolled manner in cancer cells is where that therapeutic window comes from. Our normal cells have tight control over these systems and can shut that system down if things if things go awry. But, again, this continues to be an issue. And I think will continue to be an issue that we are always tackling and coming up with new cancer therapies is what is the therapeutic window. And, Nabeel, would you like to add anything to the topic of on-target versus off-target of cancer metabolism? Well, I think there is a conundrum, because metabolism is operating. We're targeting something that's completely normal or required in all normal cells. And so where does that therapeutic window exist? And so I think this concept of metabolic imbalance is very important, where a normal cell would normally be coupled to nutrient availability. Whereas this constant growth signal in a cancer cell will often drive it to die despite a nutrient lack. So it might be possible to harness this paradoxical situation in the cancer cell, which is insistent on growing despite nutrient limitations. I also want to add that we're not targeting things in the dark. And like Brendan mentioned, cancer metabolism and cancer biology now has to be multidisciplinary, which means that we have a tremendous amount of resources and information. And so one of the most powerful tools that we can go to is to mine genomic data. And so we can look at the gene expression differences between normal cells and tumor cells and really try to avoid targeting pathways that seem to be commonly important in normal cells and tumor cells, and really try to uniquely target pathways that seem to be specifically different in tumor cells or specific stages of cancer. So along those lines I'm going to read another question. And this is addressed to me, but both of you can answer this as well. So are there certain types of cancers that are more likely to use glutamate in metabolism? And on the contrary, which cancers are least likely to use glutamates or glutamines in metabolism as a fuel? And so again, yes, the answer is absolutely. Different types of cancer prefer different types of fuels. So certain types of cancer really like sugars, and those can be imaged by FDG PET imaging. Certain kinds of cancers seem to prefer amino acids and other fuels. And certain types of leukemia, for instance, seem to prefer to burn fatty acids versus sugars. So part of unraveling fuel choice is a major goal of the field. And one way that we can get some clues is to look at one, what are the changes in the oncogenic signaling drivers. And often that's a good first clue, because the signaling pathways often ultimately lead to changes in gene expression. And then you can also make predictions. So, for instance, mixed signaling drives a lot of tumors. And mixed signaling, it's a transcriptional pathway that upregulates the enzymes that are involved in glutamine uptake and amino acid uptake from a cell, as well as a lot of the enzymes I showed that metabolize glutamine and glutamate. And so if you see upregulated glutamine or a mixed signaling signatures, that's a good predictor that that tumor cell type might use amino acids. All right. And here is another question to anybody. So how do you dictate which metabolic pathways to target to turn off? Yeah, so this is a great question. And I think it's one that we don't know completely the answer to. I think as researchers, we've identified lots of metabolic vulnerabilities. The challenge, I think, comes from identifying which patients to treat. This is really something that Nabeel alluded to. But that decision of which patient to treat is really a multifaceted decision. And it comes with many different data points that we must consider, because it's really which types of cancer in which patients will respond best to specific metabolic pathway inhibitors will really be dictated by the genetics of the tumor. So what are the driving mutations that give rise to the tumor? There are anatomical considerations. What is the nutrient niche of the tumor? Say, comparing a pancreatic cancer to a lung cancer, for instance. They're in very different settings, and their metabolic demands will be quite different from one another. And then, finally, there is something that we have a very hard time modeling in the laboratory, which is differences in dietary intake and physiology of the individual patient. And all of these, I think, are going to contribute to the effects of targeting metabolism in individual patients. And so I think what we find in the few drugs that have entered the clinic is that there are responders and nonresponders. And it's very difficult at this stage to predict which ones will respond and which ones won't respond. So the question was about which metabolic pathway to target. And I kind of pivoted it to which patients to target with which metabolic pathway inhibitors. I think that that's the puzzle we're trying to piece together. Just one comment is that the toolbox to be able to ask that question experimentally is expanding very dramatically. So many companies and also in academia, there's been a lot of attempts to make inhibitors for these many, many metabolic enzymes that don't currently have a drug that can inhibit them. So we can use our experimental systems to be able to, perhaps, uncover new what we call vulnerabilities. And so this is an expanding toolkit that will have, that hopefully will give us new hypotheses along those lines. The next question is somebody watching from Facebook from Illinois. So what do we know about metabolic reprogramming of the tumor microenvironment? Nabeel, do you want to take this first? Yeah, sure. That's a great question. So the general view for certain cancer types like pancreatic cancer is that the microenvironment ends up being very low in nutrient availability. But there's also a kind of crosstalk between different cells, so that within pancreatic cancer specifically we know that some of the connective tissue cells' nutrients are actually being effectively used by the tumor cell, so that there's a kind of complicity between these two cell types. That would be one example. Also, there's some experimental data that suggests that the local nutrients that are available in the liver that can be used by cells that metastasized for other organs. And so to give a new fuel source for cancers and perhaps enables the very effective residence of some cancers in the liver. So those are the two examples that I can think of right away. All right. This is a different topic. If you remove the target of one of the metabolic pathways so that there is a metabolic imbalance, do you think that mTOR or another signaling pathway would have some sort of compensation mechanism to bypass it and still function? Sure, I can take that. In the example that I showed in my talk, we tried lots of different-- and this kind of gets to the last question I had as well, which is which pathway to target. What we found is that if we inhibited a specific metabolic pathway, that shut off the TOR pathway. So mTOR-- I didn't get into it today-- is also very sensitive to perturbations in intracellular nutrients. And so manipulating a metabolic pathway can affect the intercellular pool of nutrients. And so what we found was that inhibiting specific metabolic pathways, some metabolic pathways mTOR could sense that that pathway was being inhibited and therefore it shut down. And the vulnerability was lost. So, again, it's the equivalent of us firing the carpenter, but the carpenter sent telling the general contractor, hey, I've been fired. And that then the general contractor says, all right, stop building. We have no carpenter. So the vulnerability is therefore lost because you can't create this imbalance. And so there are settings where this occurs. And I think the TOR signaling turning off in this case is beneficial to the tumor because it will survive. And it won't starve itself to death basically by continuing to drive this anabolic program when it can't build a whole cell. So I think that there are scenarios where the inhibiting a specific metabolic pathway will cause some kind of adaptation that prevents the target from killing the cancer cell. From hitting the target, killing the cancer cell. OK. So the next question hits on a new and really important topic. Do you think targeting cancer cell metabolism will be as effective as immunotherapy? Nabeel. So I think Brendan actually gave an example of the curative form of targeting metabolism, which is nucleotide metabolism, so some of the most classic chemotherapies. So we do have an old type of metabolic targeted therapy that is curing people today. In terms of these new findings where we're targeting various aspects of glutamine metabolism and other things that we're talking about, these are entering the clinic, and they're looking quite interesting. So I think ultimately all of us are feeling that complementary approaches are needed, and it's going to be a case-by-case basis. But certainly there is enough promise here that I think we're all very invested in this area. So for those of you who might not be as familiar with immunotherapy, it's basically a set of new and very exciting therapeutic strategies that activate our body's own immune system to kill the tumor cells. And so in that sense having this immunological memory and seeing the tumor as a foreign agent for some patients gives a really dramatic and long-lasting response that's an anticancer response. And so it's very dramatic because it's such a durable response. And some patients have been followed for years and years, and you don't see recurrence of the tumor in very severe metastatic tumors even. Now the challenge is that immunotherapy doesn't work for everybody. And it actually works for a surprisingly small fraction of the population. So still 10% to 20% of some patients of some tumors are very responsive to immunotherapy. But for some reason we don't understand, many patients do not respond to immunotherapy. And some are some tumor types are just not good candidates for immunotherapy. And so I think another opportunity on the horizon is thinking about how these basic fundamental principles of cancer metabolism could synergize in combination with immunotherapy to kind of widen the spectrum of responsive patients. I think that there's definitely maybe not a new movement but certainly a recognition that there are really no magic bullets. And certainly, hopefully, you don't leave here thinking that specific metabolic pathway inhibitors are magic bullets. We think that they are a previously underappreciated aspect of the arsenal to kill cancer cells. But we think that really combination therapies are going to be key in targeting many different aspects of tumor biology, metabolism being one of these. And so we're trying to find as cell metabolism or cancer metabolism researchers what the most promising therapeutic targets are to add to that arsenal. Certainly we hope that some of these will have single agent therapy activity. But it seems like to get a durable response in cancer therapy, it's more likely we're going to combine these therapies with existing therapies OK. So in the last few minutes, I'm going to read a set of questions that have to do with a topic we have a lot of questions on, and then we can all address that. So from Facebook in California, somebody watching asks are there any diets or foods that are helpful in stopping cancer. Another question was do cancer researchers themselves avoid eating sugar. [LAUGHTER] Another question asked if different fuel types cause different byproducts and turn on/off certain genes within cells, why not focus on what kind of fuels we put into ourselves. So there is a whole theme there. And I think those are very relevant and important questions to address. So I think-- Do you want to answer that? I think there's probably two layers to this. Certainly there are many studies in animal models that suggest that we can manipulate the growth of tumors by changing the diet of the animals, either by restricting their calorie intake, changing specific aspects of their diet, low protein, high protein, a high fat, low fat. And also we can, there are dietary changes that can advance the tumor and make the tumor grow faster. So certainly you can manipulate the growth of a tumor by changing the diet. Now whether this is achievable in us is less understood. Most of the nutrients that are circulating in our blood are homeostatically maintained in a very tightly monitored over a very narrow range. So it's hard to get your body to all of a sudden have no glucose in your blood, because your brain would shut off. So it's a difficult thing to think about in patient populations. I think where the biggest promise comes is whether certain dietary interventions might improve the activity of existing therapies or therapies that are being developed to target metabolism. So dietary interventions in combination with targeted therapeutics that target metabolism or signaling pathways or other aspects of cancer biology, that might be a promising avenue. And I think along those lines, it's equally important to know what kind of dietary interventions are really dangerous in combination with cancer treatment and therapy. And this is something that's highly understudied that deserves a lot more focus. And then going back to the diet and cancer incidence or therapy, we do know that statistically obesity and high fat diets are linked to the increased incidence of 13 different types of cancer. OK. So that relationship is quite clear. And I think what we also know is that if you experimentally test the effects of laboratory models of cancer in diets that are lacking a certain amino acid or a metabolite, you can see that reflected in the metabolite profile of the bloodstream of that animal and in some cases of the tumor. But it's not always clear that matching what you eat will be reflected exactly in the cancer cell. I'll just say that, despite these clear associations, really the massive increase in incidence of cancer associated with, for example, smoking or sunlight in certain individuals, for diet the impact is generally much, much smaller. I think it's the reassuring thing. So I think there's a positive benefit that's clearly in diet. But the epidemiology for many cancer types, this enormous number of studies looking at individual contents of a diet and looking for increased cancer risk, and they're certainly there. But the magnitude, I have to say, is less than for a lot of the very established risk factors. OK. So I want to thank you all for coming, and I hope that you guys have all learned something today. [APPLAUSE] One second, sir. I hope you all have learned something new today about cancer metabolism. And I think you could see from the massive number of questions that we got as well as the hands that were raised that there are many further experiments to do and many questions. And please do reach out to us or Gina beyond this. So thank you again. Thank you Gina in the office and Barbara and Brendan and Nabeel. [APPLAUSE]
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Channel: Harvard Medical School
Views: 54,964
Rating: 4.9198666 out of 5
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Length: 88min 26sec (5306 seconds)
Published: Fri Mar 29 2019
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