Major Trends in Modern Cancer Research 2012: Discussion with Memorial Sloan Kettering’s President

I want to welcome all the hardy souls that have braved yet another event in New York whether to this evening I’m Craig Thompson I’m the president Memorial sloan-kettering and this is our seventh of these lecture series major trends in modern cancer research we started this symposium seven years ago to give the local area high school students and their teachers a flavor what it looks like behind the scenes at a major research institution I think many of you have heard about memorial sloan-kettering um we are a hospital where the where the world’s oldest hospital actually in treating cancer patients we were formed by a group of physicians here in New York who believe that cancer was a separable and identifiable disease in the 1880s and began to want to study that and understand its its underpinnings since that time as our population has gotten healthier for many of the infectious disease that plagued hospitals back then and many of the complications of the disease we’ve seen cancer incidents actually rise sadly part of that has to do with our ability to treat other diseases today for you kids in this room fifty percent of the boys are going to have a risk of getting cancer in your lifetime and a third of the girls are going to get cancer in their lifetime so it is worldwide now the most common cause of death in human beings and so we have a major care in hospital here and where we try and develop new therapies new approaches that both more effectively deal with cancer hoping to help patients be cured or put cannock into a chronic disease day where it can be controlled and at the same time we have over 2,000 people who come to work here to try and understand cancer as a scientific problem and use it to teach us basic lessons about human biology cancer is a unique disorder of organisms of living organisms because it only arises in multicellular organisms it’s a disruption of the normal physiology that allows our cells to work together effectively and so what we’re going to do tonight is actually give you an introduction to three different approaches that we’re taking here to try understand Barry basic issues of cancer how it’s caused how we actually think about it as a disease many people come with the idea that cancer as a single disease here at Memorial we think of cancer is over 200 different diseases so getting the diagnosis what has gone wrong what cell is pole if erating abnormally as you’re going to learn tonight it’s critical for that and you’re going to hear from jason hughes about approaches he’s taken in his research laboratory to that approach we had planned three individual investigators who were going to give you talks today and unfortunately who was going to be our second speaker cat had jagged Tanaka’s has had like many New Yorkers have a family crisis where she cannot be here tonight because of the ongoing events that are going on around the New York area and unfortunately you’re going to get me as a fill-in to give a little bit of an introduction I cat would have given you some wonderful stories about why developmental biology is such a critical thing for us to understand how our cells sort ourselves out into the different organized and organize themselves and so I urge all of the students that they’re interested in some of that aspects to actually go there are part of her work that is on the web and other places that you can look at it and then on the third talk we’re going to actually really look at with Morgan Hughes the real excitement that we have now about understanding how our body itself can participate in helping patients with cancer actually rid themselves of the disease they have and how the immune response actually works in fundamental details to predict us not only from cancer but from very basic infections from viruses and bacteria and so he’ll tell you why an immunologist wants to be here and well how you can ask some very basic questions about how cells know where the problem is and how they go about finding it in our body to eradicate that I wanted to just give a very basic introduction to why societally cancer is a problem one of the things you should come away from this is why we do cancer researcher Memorial sloan-kettering by the end of the day and so what I put up here is actually something I stole from the web so this is what i have shown to many groups including some very senior scientists in other fields as what i think ever is the one experiment that teaches you there’s something wrong with cancer that absolutely everyone in this room has already done and this experiment was

actually done by a college student first-year college student i stole just two of the pictures he took his goal was to actually take a plate in his room and put on his dorm room sill two pieces of bread and take a picture of him every day and see what happened he did it for a month he found out what almost every certainly everyone here that has managed to forget while they were watching TV part of a sandwich and it slipped under the rug or whatever if you ever actually left out food I’m sure your mothers have complained that you’ve done that certainly all the teachers know that they have left something out at some point we know what happens and what grows on that and you can see what happens here is because the problem that is this experiment that this college student has done has already started here this is about the fifth day that he’s filming this so I cut out the first four so we could cut right to the drama and the drama is that one yeast mold cell has landed by air convection in this corner and it suddenly realized that there’s more food than it ever imagined there was in the world provided by somebody who pervy provided this nutritious piece of bread right there and it started to make millions and millions of copies of that initial spore it woke up recognized that there was food and did nothing but try and make as many copies of it could of itself as it could as as it saw the food in its environment you can’t tell but actually to see that little bit of blue color right there there are already millions of cells actually that part of the colony by few days later is actually not the largest part of this problem right now this part which is where the stuff started has actually become limited for growth and there cell C are no longer growing they’re turning back into spores because they’ve run out of food that seven run out of food in this particular case what they’ve run out of his water and they need both the supply of water and a supply of food to be able to duplicate themselves they break that down through all the things you’ve learned in your biology courses the intermediate metabolism that allows having the building blocks to make more daughter cells as they ran out of food yeast are pretty smart they’re filamentous they grow in directions away from their food they become susceptible to air concurrence and in their local environment one broke away from the main herd and found an even better place made even more of itself that problem in cancer we call metastasis a cell that originates in a place acquires a mutation that allows it to think that it’s supposed to divide all the time to help the other cells in our body and once it does that it ultimately acquires the ability to do that anywhere in the body and that’s the most that’s the deadliest thing the thing we can’t help human patients with right now if cancer stayed only in its original site a surgeon could cut it out but because cells begin to learn to live in the local environment and invade elsewhere or metastasize errs the truest metastasize these are all progeny of the same additional spore that started this process has now skipped over to the other piece of bread if you go out and find this on the web you’ll discover by the end of the month this is just two black pieces of toast basically that have been just consumed in making millions of copies of this yeast and so this is the biology of every single organism on earth that lives as a single cell when they see food in their environment they move to capture that in as much as they can and when that food exceeds their needs to just survive they begin to make copies of themselves as many as they can you can actually take that to molecular detail all unicellular bacteria as well as eukaryotic cells like the yeast I just showed you have on their surface receptors where they’re trolling constantly to find food in there environment and those receptors are used to provide what’s called signaling information that allows the cell to recognize that food is in the environment and to alter the transcription of their DNA to produce the genes that are necessary to capture those nutrients inside the cell and real tool the enzymes that allow them to degrade that food into the building blocks not only to provide energy but also by building blocks to maintain themselves that is the biology of all unicellular organisms and so in fact this is the basis of two of the most successful industries you guys as scientists should be starting to think about and that’s the beer in the wine industry if you give yeast baker’s yeast an unlimited amount of food in their extracellular environment Brewers do that by giving them glucose in the world

the yeast will capture all of those nutrients and make a huge pool if eration of themselves and in this form of metabolism where they’re just gobbling everything out of their environment they actually metabolized too much food that they beyond what they could actually put into producing a useful daughter cell and the byproduct of that excess metabolism is ethanol it’s the alcohol content in beer and wine pastor one of the great scientists of the last generations first job was to try and figure out whether or not he could fool the east into not growing but still produce the ethanol is the beer industry would really like to not have to turn off their incubators and get rid of all the accumulated yeast so they could start the process over to make beer he failed because in fact this is a normal process these cells are producing these extra nutrients the ethanol they produce is actually to keep other organisms in the environment from stealing their food supply yeast can live and multiply in eighteen percent ethanol your put pickled at about point one percent and so it keeps a very effective way to maintain a food source that they could ultimately if everything else runs out you by burning to co2 and water to maintain themselves so it’s an adaptive biology and this was known about for a hundred years when people started to turn the problem of why don’t we do that then every single one of you in this room came in not with one cell that could then turn itself into millions of cells you came in with 60 trillion cells that make up you and you’ve got to sort out who gets to divide like this you need somebody to be able to divide because you cut yourself you got to fix that you bleed you got to make new blood cells and so you’re constantly producing new cells in the body but how you control that became the big question basic question for cancer biologists because of a cell decides to go off and do this and make a colony all on its own that’s the start to cancer let’s start to an excess accumulation of a cell a Texas of what you need and it starts to acquire the ability to start looking for other places where it could colonize and take over the organism when you overeat we’ve unfortunately just gotten us through a hundred year experiment the first thing you think when when people overeat when they’re able to not have to hunt for food any longer but actually can go to a refrigerator and get it we have seen for three generations that people got bigger and stronger and faster that our ability to acquire better nutrition allowed our bodies during development to get make more cells make bigger organisms make more effective organism that’s why every Olympic record has been broken over the last three generations every time we have an Olympic unfortunately about 20 years ago we hit that limit there’s a point at which you can’t just buy be given more food in a generation get bigger get stronger get faster ultimately you just get wider and unfortunately that’s the epidemic you guys are growing up in thirty-five percent of Americans today are obese by any standard and so that’s an interesting question why do we to that food sometimes into growth and other times just to turn it into storage and fat and that’s a question a number of investigators work here by all just puzzled about this problem for actually about 25 years when it became understood that in every organ in your body and every tissue type in your body you had adult stem cells cells whose job it was to replace damaged cells of that organ so that you could maintain yourself and live a productive life of 90 or a hundred years and so how do you control when they divide and not divide and the only reasonable explanation both a theoretical and experimental explanation was that every cell in our body had to give up the ability to divide in a cell-autonomous fashion they couldn’t just seafood like all those single-cell you single cells that I just showed you in that experiment they actually have to only divide when they’re instructed to and that led to a wonderful revolution or our understanding of cancer in a basic biology because we came to understand from investigating that idea that that’s true there is no cell in your body that has the cell autonomous ability to become two cells it has to be instructed by other cells based on need and that’s the fundamental barrier to cancer a cell going off and just accumulating in excess for no reason and so what we came to learn from that is that in our bodies and the 60 trillion cells you just brought in there are a variety of signals that have to be integrated for a cell to acquire the information that’s stored in the nucleus and the DNA that

you inherit from mom and dad and execute that to orderly enter and progress through a cycle that allows the cell to produce two daughter cells effectively and in the absence of that signaling the cell can’t do it and it came the appreciation because viruses often steal these signaling pathways to do their bidding that the viruses that caused human cancer stole components of the ways these signals were communicated inside the cell to the nucleus that became the field of signal transduction and how we communicate through growth factors and hormones that are provided outside the cell through receptors to control how we execute the information that’s stored in the DNA through what’s known as transcription and translation and so that launched a very traditional view of the field that cancer was a mutation in one of the genes that contains the components of how you communicate that signaling information from outside the cell where the growth factor tells us so we need two of you through to the nucleus where DNA is transcribed through RNA to make the proteins that allow the cell to progress and then make all the components of the cell and that looked like a really good idea and almost everyone in the basic research unit here started to work on this components and Jose bizogot who just came in our new physician in chief became one of the pioneers and trying to figure out how we capture that information to make new what are called personal or targeted therapies that would turn off the specific mutations that individual pixels cancer had and that’s been a wonderful game changer and a number of drugs have been pioneered here this institution by some of our investigators such as Charles Sawyer’s that specifically turn off signaling pathways that are mutated in cancer that way but our basic vial just went back to think about this again and it was also done by an experiment that all of you have participated in which is that sometime by the time you’ve gotten to high school you’ve ended up in this situation where you’ve had a really bad coal and your lymph nodes have swollen up in your neck and this pace this is a patient that has mononucleosis and your lymph nodes swollen when you recognize that virus of the immune cells that are going to fight you up fight off that virus in fact you’ve all pretty much gone through about a hundred viral infections that you had to stay home from school whether you argued with your mother about whether you should stay home from school and yet you haven’t become one big lymph node all of those cells were instructed to make many many cells that’s why this young man’s neck is swollen up he’s got huge swollen lymph glands from mononucleosis from that virus that you’re fighting on but yet ultimately he’d need a wheelbarrow to carry all those extra cells if he kept them around so somehow the body knows how to get rid of extra cells when they’re not useful anymore and that phenom Alya tis that cells will die off when they’re no longer needed when they’re his neck starts to shrink back to its normal size as you control the virus became a fundamental question and turned in over the last 10 years to be the second answer to why it is that you’re able to control the cell numbers in your body constantly over your life span and that is that you’ve developed a developmental program to get rid of cells that have accumulated in excess the cells that can’t find sufficient signals from their environment just to stay alive actually die off in a process that now is called death by neglect so when there was no immune infection or there’s no infection going on those cells die off by death by neglect and when scientists here started to study that phenomenon what they discovered is not only is it true that signals from the outside tell cells to proliferate cells depend every day every moment of every day in our bodies on extracellular signals just to stay around and stay alive and so the question is how could you make every cell agree to stay alive only if they received extracellular signals what would be the common feature that all cells share and that’s interesting because what common feature of every cell type the cells in your brain the cells in your skin what do they all depend on that you could actually limit and that might make them die off if you didn’t need them anymore it took scientists about five years to understand the problem um the problem can be looked at one way by people studying the genes that were disrupted in signal transduction that initiated cancer from viruses what was discovered is it those jeans when you put them into a cell and this it forces the cell to engage in new gene expression that’s an energy-dependent fashion to put in make new proteins you need energy input you

know so you need ATP that’s produced that allows the elongated protein chain to be assembled and that consumed the cells resources and when people try to do that to mirror human cancer what they discovered is the cell always died and it was studied how it died it died by bioenergetic collapse the cell lack the capacity despite what the textbooks say to be able to take up the sufficient and sufficient amounts of the nutrients that we share in all the tissues of our body to actually maintain energy stores they ran out of fuel exactly what’s crippled New York for the last five days we’ve run out of fuel and even though we’ve got perfectly functional cars and people know how to drive them there’s no place to take them because they don’t have fuel and that’s what’s happening in in these oncogene situations and when we studied normal cells we discovered that in fact every cell depended on extracellular signals for its survival on instruction from the environment to take up sufficient fuel the nutrients that always exist or maintained by our liver and our bloodstream can’t be taken up by a cell except when it receives what are called trophic signal signals that tell it to eat and in the absence of the signals even though we are well fed and we have a refrigerator cells die by starvation in our body and so that said there’s a second barrier that’s this death by starvation and it led to this understanding that if there were mutations in the signaling pathways that told cells to eat there might be a more fundamental understanding to how cancer actually initiates because the genes we learned about from viruses that tell cells to divide almost always end up killing a cell if it’s the first thing that goes wrong in a Cell but mutations in these pathways that tell the cell to gulp more sugar than they need in the form of glucose that’s constantly supplied earn our bread stream actually makes the cell better at executing all of the normal activities because it’s a higher ratio of the fuel supply the ATP to ADP ratio and it since it’s over eating it ends up losing electrons as it tries to produce more ATP in the in the mitochondria or energy factories and those electrons are produced as reactive oxygen species the best characterized of which is hydrogen peroxide water with a couple extra electrons and those extra electrons in the presence of molecular iron can damage DNA in a way that’s mutagenic and so suddenly if there were mutations in this pathway you had a cell that was better able to survive on its own it no longer needed to be told that eat it didn’t couldn’t die by neglect and it knew how to mutagen eyes it the rest of its DNA to see what else it could make what other Habakkuk could do that has led a large group of investigators now here and now internationally to begin to understand that there is a connection between this traditionals field of signal transduction and all the pathways that you’ve started to learn about in high school biology which are summarized here in terms of metabolic pathways when I made this slide in 2007 there was an interesting conundrum for our field of us as we executed cancer therapies these are all the genes you can’t see any of them they’re fifteen hundred genes here of the 18,000 we have that had been implicated in initiating cancer here are all the genes known to control our metabolism this was made by the single person who made all the metabolic charts that you’ve ever seen on a wall in any lab you visited or any high school room where you might have had them one guy did them over the last 50 years he retired in 2007 he made this chart it has four thousand five hundred genes on it and he he said I’ll never need to make another room because we know everything there ever be to know about the science of metabolism now anytime you as science students get told that you know you’ve got something you can investigate there’s not a single gene on this chart that’s on this chart there’s not a single gene on this chart that’s on the other chart yet these are the two most critical things you’re ever going to do as a living organism you’re going to be able to take in fuel and use it to maintain yourself and you’re going to use instruction to produce two daughter cells that allows both the cells and then ultimately the species to perpetuate and so for the last ten years there’s been a very large effort here and elsewhere to link these two pathways to get to a deeper understanding of cancer why did I bother to tell you this and what’s relevant today so take this back we go back to this diagram our mayor here in New York has been trying to tell us that one of the things we do bad to our health is take too many soft drinks that are actually made of pure sugar and has tried to limit that as a public health notice I think everybody

knows his first ten years of his reign he limited your ability to smoke in every public environment that has been the most successful public health campaign in the last 20 years we have have the number of people smoking in New York and that will ultimately lead to dramatic rates decreases in the rate of the number one cause of cancer up until this year which was tobacco but this year the National Cancer Institute announced there’s now a new major cause of preventable cancer this is the incidence of tobacco and this year adult obesity overtook it as a cause of preventable cancer and it will soon be along with cardiovascular complications and leading cause of death in this country if we don’t stave off this illness and the mayor turns out to be right it turns out that sugar is the one that matters overeating glucose fills this paradigm ultimately as you become obese you lose the ability to store the extra sugar you take in your fat cells and in your muscle cells and you distribute to all the other cells of the body at thou these viral lesions that are involved in just the signaling to make two daughter cells are supplied with nutrients because we’re obese and you’re off to the races of initiating the formation of a human cancer and so the final thing that I have to show you is an interesting thing the mayor turns out to be right basic scientists now investigated what food matters we spent 40 years as a community trying to convince ourselves that fats were the cause of all problem every study failed you can’t limit fats and decrease any form of cancer when we went back and said this nutritional thing is telling us something animals have now been prone to cancer subjected to diets rich in all the different types of fats you’ve been told up it has no meaningful effect on the incidence of cancer but you vary the carbohydrates of the diet and the cancer incident goes up with every percentage of carbohydrates that you’ii overeat they are the basic building blocks for everything we do in our body proteins are somewhere in between and so armed with that information we have to change what our nutritional advice is to patients that are going through the cancer paradigm we’re starting to think about how we limit the cancer cells fuel supply and taking some therapeutics and ultimately will hopefully take that into the clinic so that people like dr. basilica can actually see better incomes from the other targeted therapies they do investigating this involves some of the most sophisticated equipment now in the world we use mass spectrometry to analyze now over a thousand of the nutrients that we exist in our blood supply and ask are there certain ones that are implicated in cancer and others that are not and we start to learn some new last year we discovered one new metabolites that no one had ever known about before so despite that fact that that chart said with everything we know there’s one additional one we expect to find others and so again what’s fun about this is you can ask very basic questions from that first experiment i showed you to why it is that that that young man that had mononucleosis cells go away you can take that life experience and do biological experiments to actually teach us something about how we maintain ourselves as organisms and we can do it from the perspective of understanding a disease that ultimately we’d like to help people with because it is I think almost probably every one of you is known someone at this point your life and your family aren’t friends that has had cancer and so you can understand how useful would be to find something about that so that I’m going to stop I’ll take any questions if anybody has any that means somebody’s got to be brave and raise their hand first or we don’t get off first base tonight any questions yeah you mentioned earlier that all cells in the body need signals to survive do they all is there a certain basic signal that every cell needs or do they all have very specific ones yeah it’s a really good question as we started to investigate that as a research community what you are right is that there seems to be a basal signal that almost every cell can derive some value from for survival and that’s a that’s a gene you’ll hear about a little bit it’s being written about in the science sections of the newspapers and you’re probably covered it’s called the insulin-like growth factor-1 and it basically mirrors insulin insulin is the way in which we figure out we’ve eaten a lot of sugar and we store it away in the form of glycogen and liver and in muscle and in the form of fat and fat cells those are the insulin response of tissues and why we need insulin they store for our body all the extra nutrients igf-1 has a few receptors on every cell in our body and it’s actually

fought not yet been fully proven but it looks pretty good that it’s the way in which when you overeat for a long period of time and fill up your stores and your fat cells and in your muscle cells you start to distribute extra nutrients to all the cells in the body because it use exactly the same signaling event to tell the other cells to take up glucose and that’s why we got bigger for three generations as we got better nutrition but igf-1 now actually dr. bazooka just gave it an hour’s lecture to our basic scientists about new ideas they’re going in the clinic for breast cancer and igf-1 blockade was I think your second example isn’t that right so that ideas actually reached maturation blocking that signal looks like it has a benefit for improving on cancer we already treat pretty well the second though is we’ve learned that every tissue in the body has a lineage specific receptor a specific receptor just for that tissue that controls the bulk of the way they do that and it mirrors insulin but it’s the insulin for that tissue and it’s controlled usually by a hormone or growth factor that’s regulated by some other part of the body that says we need more of you and so we’re sorting out all those details but that’s a great question