Hello. Good evening. I'm Gina Vild. I'm the chief communicationsofficer for Harvard Medical School, and I am thrilledto welcome you here tonight. This is the 19th year that we'vebeen offering Harvard Medical School's Mini-Med Schoolto those in Boston, and more recently, tothose throughout the world. So to all of you herein the auditorium and to those of you who arewatching us on the live stream, thank you for joining us. Over the past twodecades, this program has allowed many thousands tolearn about science and health issues from Harvard'sexpert faculty. Think of this as yourclassroom, and we will think of you as students. So you'll have an opportunityto both learn and ask questions from our expert facultyabout the latest research and medical breakthroughs. The people you willbe learning from are on the front linesof science and medicine. I'm happy to reportthat last year, we had more than120,000 students. Viewers from 84countries participate in our Longwood seminars. 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So whether you're hereor watching from afar, please join ourTwitter conversation. You may know if you'veattended in the past that we offer certificatesto those who've completed threeor more seminars, and we also offer teachersprofessional development points. For more information onhow to receive these, please check our website ortalk to a member of our staff. On the website, you'll also findthe seminars from past years. Our speakers will be takingquestions-- your questions-- at the end of the program. So if you are herein our audience, you were given an index card. A member of our staff will bewalking through the aisles. Please hand them--pass your question in. If you are watchingfrom around the world, please post your question inthe comment box on Twitter, on Facebook, and on YouTube. And please also indicate whereyou are from, because we'd love to share that. So now for thisevening's seminar-- Cancer Metabolism, fromMolecules to Medicine. Did you know that there were17 million new cases of cancer worldwide in 2018? Worldwide, there will be27.5 million new cases of cancer each year by 2040. That's astounding. And so this evening,you're going to learn from some of theleading scientists at Harvard Medical School whoare working to tackle this devastating disease. By illuminatingmolecular pathways, researchers have discoveredthat cancer metabolism actually changes the activities of cellswhen compared to normal cells. Research is nowunderway to figure out how metabolism becomesreprogrammed in cancer cells, and then to find new andeffective treatments to stop the disease from spreading. I'm delighted to introduceyou to our panel of experts who will share theirinsights with you. Brendan Manning is Professor ofGenetics and Complex Diseases and Director of the PhDprogram in Biological Sciences and Public Health at theHarvard T.H. Chan School of Public Health. Nabeel Bardeesy is HarvardMedical School Associate Professor of Medicine,Assistant Geneticist in the Center forCancer Research, and the Gallagher Endowed Chairof Gastrointestinal Cancer Research at MassachusettsGeneral Hospital. But first we'll hearfrom Marcia Haigis. Dr. Haigis is Professorof Cell Biology at the Blavantnik Instituteat Harvard Medical School. She is a member of thePaul F. Glenn Center for the Biology of Agingand the Ludwig Center at Harvard Medical School. Her lab continues towork on understanding the role mitochondria plays inhuman aging and age associated diseases. So thank you forbeing here with us. We're just thrilled tosee so many in attendance. And please welcomeour first speaker. Thank you. [APPLAUSE] Thank you very muchfor coming here today. Thank you for thatwonderful introduction. And I am so thrilled tobe here and share with you all tonight's program, CancerMetabolism from Molecules to Medicine. And so 2018, the WorldHealth Organization reported that cancer remainsa leading cause of death globally. And, in fact, in 2018one in six individuals had cancer as thecause of death. So these remarkablestatistics really highlight the urgent need tofurther study cancer biology with a hope to identifyimproved therapies to improve patient care. So today I'm goingto talk about fuel. And these are some ofthe 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 fuelsto generate their energy so that they can do the workthat needs to be done also has the side productof generating byproducts. And, in fact, it's becomea major and very important dialogue today to consideralternative fuel sources that result in a cleaner,more efficient fuel utilization, maximizing waysto process fuels efficiently, and also generateless byproducts. And think about how do wedeal with these byproducts. But you might be askingyourself, what does this have to do with cancer. So I'm going to talk about adifferent kind of fuel today. And this is a picture of a saladthat I had last week in Italy. This is the kind of fuelthat our bodies use. And so when we consumefoods, these foods are broken downinto metabolites. And here's a metabolite cartoonof 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 ofthis cellular metabolism, metabolic byproductsare also generated. And understanding how fuelmetabolism is processed in cells and how thataffects cell biology has really blossomed into thisnew field of cancer metabolism. And it makes us wonder,is cancer metabolism an Achilles heel that will leadto a new class of therapies. And I think to fullyunderstand this point, we need to discussa few questions. And so in the field we haveseveral driving questions, and I'm going to talkabout mainly the first one. And you'll hear about thesecond and third points today from Brendan and Nabeel. But we're interestedgenerally in understanding how do tumor cellsdiffer from normal cells in their metabolismof cellular fuels. How do tumor cellsintegrate growth signals and nutrient metabolism inorder to proliferate and survive different environmentsand promote tumorigenesis? And this coordination,you'll hear, is really criticalto tumor cell growth. And what is themetabolic communication between tumor cells and theirsurrounding environments? And understanding how all ofthese influences interact. And the bottom line iswe want to understand, can we actually exploit theunique metabolic properties and vulnerabilitiesof cancers in order to improve patientcare and therapy. And so what are fuelsand why do we care? Why do we care aboutfuels in cancer biology? So if there are lotsof different fuels that our cells can use,and a few are shown here, sugars, fatty acids, aminoacids broken down from proteins. And they're taken up by cellsand converted and processed in order to make moleculesimportant for providing the cell withenergy such as ATP, and also forgenerating molecules that contribute tothe essential building blocks of macromoleculesimportant for cell life. And these macro moleculesinclude DNA, RNA, proteins-- I can't really reachway up there but-- membranes to form lipid bilayersto form membranes around cells. And so you might think how dothey actually help contribute to building a cell. So these macromoleculesare actually the building blocks thatform the physical components of a cell. And so you might imagine thata cell that proliferates a lot needs a lot of thesemacromolecules. And so it's apparent, so youneed genomic information, you need RNA in a cell. Cells are full of proteins. And cell boundaries andorganelle boundaries are framed by membrane layers. So all of these components areabsolutely critical for cell growth and cell proliferation. Now normal cells needthese components, too, and they use fuels togenerate energy and maintain homeostasis. That's important to theirspecialized function. So if you consider thespecialized or normal cells in our bodies, our brain cells,our heart, our muscle cells. They need to metabolize fuels. But a lot of the fuelsare used to make energy so you can domuscle contraction, or also to providehomeostasis and maintain repair and the health andviability of that cell. But by contrast cancercells are kind of punctuated by their uniqueability to proliferate. And they have uncheckedproliferation, in part because of mutations. There are many causes of cancerand mutations and unchecked growth signaling pathwaysand coordinated upregulation of fuel uptake and metabolism. And the fuels are used in cancercells not only to make energy, but tumor cellsupregulate the fuel usage in order to make more ofthe macromolecules needed for the building blocks to makethe mass and the physical form of the cancer cell. And we see evidence ofthis in patient care today. So you can put a probe, alabel, onto a sugar molecule and administer that to patients,an image where the tumors are through PET imaging. And that basically measureswhere is the glucose taken up. And so you can see glucose takenup in highly metabolic tissues like the brain and the heart. But you also see it here inthis patient with a lung tumor because it's highly metabolic. And so we know that thesetumors don't metabolize fuels in isolation. But instead there is thisreally dynamic competition of fuels for the tumor cellsand the normal healthy cells surrounding it andin other tissues. And so what we want to do isknow can we actually identify the precise molecular pathwaythat tumors use in order to exploit metabolic fuelpreference to target the tumor cells, and maybe minimize theside effects in healthy cells and also improve patienttherapy and care. And so the rationaleis really simple. And we know that signalingand cell-cell interactions and immune cellsaffect tumorigenesis. And we know that this synergizeswith altered metabolism, because tumor cells have totake up more fuels in order to make the buildingblocks for their mass. So standard of care historicallyhas targeted this one arm of signaling andcell interactions to try to block tumor growth. And, of course, there hasbeen therapeutic success. But ultimately in many casesthere is emerging resistance. And not every patientresponds similarly. So we want to know bytargeting the fuel, by targeting the energy pathwayand the building blocks, can you synergize with standardof care available in order to actually improveoutcome and maybe help to overcome resistance. And so in order toanswer those questions, we need to dig deeper. And so far I've told yousome of the big picture concepts of fuel usage andhow the fuels are taken up and metabolized by tumor cells. But in order todesign precise drugs, we actually need to identify themetabolic pathways themselves that are altered betweennormal cells and tumor cells. And this is showingan overview schematic. And it is simplifiedof the difference in how a normalcell handles sugar compared to how a proliferatingcancer cell might handle sugar. And so in a normal cell, youcan see the glucose is taken up and it's converted tothese intermediates through a processcalled glycolysis. And then it'smetabolized further in this round organellecalled the mitochondria. And in the mitochondria,the glucose metabolites, namely pyruvatemetabolites, are further metabolized to generate ATP. Now in a tumor cell, theyhave more glucose uptake. And in addition to moreuptake, the process of the handling ofthe sugar differs. So you don't justhave simple metabolism of glucose throughglycolysis to make energy. But instead many of thecarbons from the glucose are diverted intopathways that you can see form thesecritical building blocks importantfor macromolecules that contribute to the mass andphysical properties of a cell. And so in understandingsome of those properties, we can also see thatburning fuels in cells contributes to metabolicbyproduct production. And so here is an example ofhow healthy cells versus tumor cells metabolize an aminoacid called glutamine. And high levels ofglutamine breakdown generates this smallmetabolite called ammonia. And what happens is thatammonia really builds up in the tumor environment, calledthe tumor microenvironment. And so we wanted toknow in our lab, what is the role of this metabolicbyproduct in cancer. And so there are two hypotheses. One hypothesis isthat it's simply secreted from the tumor cells,detoxified through the urea cycle, and thrown awayas cellular waste. But another hypothesis isthat a rapidly dividing cell would need those nitrogensto form building blocks and support cellproliferation and growth. So we actuallymeasure the effects of this metabolic byproductin tumor cell proliferation. And so first of all,ammonia accumulates in a tumor microenvironment. If you use a mousemodel of tumorigenesis, you can actually measurethe level of ammonia in the bloodstream or in thefluid surrounding the tumor and find that it does accumulateto a high level in the tumor cells, in the fluidaround the tumors. Moreover, if you addammonia to estrogen receptor positive breast cancercells, it actually stimulates their proliferation. And so this shows that thecancer cells actually use their waste, or metabolicbyproduct, to fuel growth. Moreover, if westop this process by inhibiting or reducing thelevel of the enzyme that's important for this metabolicwaste recycling, called glutamate dehydrogenase,you can slow down cancer growth in vivo, inan animal model of cancer. And so you can seethat here, if you look at ER positivetumors that have normal levels of metabolicbyproduct recycling, shown in this blueline, compared to the levels of tumor growthin tumors lacking the ability to recycle nitrogen. And so in this simple study,we found a new pathway where ammonia in normal cellsis known, as the dogma states, to be produced by cellsand secreted by cells. But, paradoxically,tumor cells are able to kind of reharnessthis additional ability to use this metabolic byproductwhich accumulates in that tumor cell environment. And then they kindof start to eat it, and they can use that to makeglutamate amino acids that are important forprotein production. And so through thispathway, they're able to recycle theirnitrogen waste products. So going back to my startingquestion, is cancer metabolism a new Achilles heel. Well, to reallyanswer this question, we still have morequestions that we have to work on solvingand starting to address. So what are themetabolic signatures of specific tumor types? We know that differenttumors arising from differentcells of origin have unique metabolic properties. And so we need to learnmore about those in order to better targetcancer metabolism. We need to understand with arational, logical way, what are the best combinationsof metabolic inhibitors with approved drugs. We have to understand howdoes tumor metabolism differ with tumor genotypeand signaling, and you'll hear more aboutthis from Brendan Manning. It's really critical tounderstand which genotypes and which patientpopulations might be more sensitive toparticular metabolic inhibitors and combinations. And so when I thinkabout cancer metabolism, I really think aboutthis as a field that's at the tip of an iceberg. So this field reallystarted decades ago with the studies of OttoWarburg looking at how glucose was handled by cancer cells. But now in the last10 years or so, it's really had this dramaticand exciting Renaissance that has deepened ourunderstanding of how tumor cells use fuels. But I think also exciting to meis that beyond cancer biology, these lessons we learnedfrom cancer metabolism have taught us simpleproperties that are critical fortumor cell biology, like understanding mechanismsthat let tumor cells survive, proliferate, and progress. Our understanding ofcancer cell metabolism has also created an open newfield of metabolic research in other biological systems,and these range from immunology to stem cell biology. So these sameprinciples of how fuel use in macromoleculebuilding hold true when you think about immunecell activation in response to an antigen, which triggersmassive cell proliferation, as well as in theprinciple of stem cell biology, proliferation,and differentiation. And so this is just really,really basic science that's kind of been uncoveredfrom these mechanistic studies in cancer biology. And, in addition, studiesof cancer metabolism are continuallypushing the envelope of technology development,and I find that also extremely exciting. When we're trying to mapthese precise mechanisms and pathways, it alwayspushes for further technology development. And that also just supportsa lot of other studies. And so I want tothank my lab for doing the work, all the wonderfulcollaborators that we have at Harvard and beyond. And some of the collaboratorsinvolved in the breast cancer study are shown here. These are my lab members wholove to draw mitochondria, as you can see. And I thank you allfor your attention [APPLAUSE] So I'm pleased to introduceour next speaker Dr. Brendan Manning. [APPLAUSE] Thank you. I'm very honored to participate. I'm very honored toparticipate in this symposium to bring what we do every dayas scientists to the public as well as to those onlinelistening around the world, including my boys,Garrett and Cameron. Hopefully, they don'task any hard questions during the questionand answer period. So I'm going to drill down onan aspect of cellular metabolism that Marcia touchedon in her talk, and that's the conceptof cell growth. This is something that mylab is very interested in. We have a laboratory across theway at the Harvard T.H. Chan School of Public Health, just inthe back corner of the Harvard Medical School quad. And we're very interested inthe concept of cellular growth, and in particular the metabolismthat underlies cell growth and how that metabolism iscontrolled in cancer cells. So just as a take home-- let me back up here. So cell growth isreally a concept that underlies cell proliferation. A cell must increase its size. It must double its cell sizebefore it divides in order to form two cellsof the same size. So this is a simpleconcept, but it may not be one that'sobvious to everyone. If a cell divideswithout growing, the cells will get smallerwith each subsequent division. And this is why cells mustincrease 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 thatMarcia touched on is that cells utilizenutrients and energy. And they consumenutrients and energy in a process ofanabolic metabolism in order to drive thebuilding of a new cell. Through the consumptionof nutrients and energy, you can producethe macromolecules that underlie cellgrowth, that underlie that the productsthat are used to make, to double a cell's mass. So we refer to thisas cell biomass. About 2/3 of our cells are madeof water, not surprisingly. But when I say cell drymass or cell biomass, I'm really talking aboutthe dry weight of a cell. So cells are reallycomprised primarily of these four components here. 55% protein, 25% nucleic acids,15% lipid, and about 5% complex carbohydrates, give or takeon each of these numbers. And so in order to do thisseemingly simple process, a cell must takenutrients and energy and build these macromolecules. And it does that by drivinganabolic metabolism, by driving metabolic processes. So I think a good analogy ofhow this functions is really in the concept ofbuilding a house. So in building ahouse, in this case-- excuse me, keep-- the materialsto build the house, rather than nutrients, arebuilding materials, everything from shinglesand lumber and wires. These materials are utilizedby specialized contractors that build differentaspects of the house. And you can view the contractorsas metabolic pathways. So each of these contractorsis using these building blocks to build differentaspects of this new house. Just like that newhouse, metabolites are utilized by metabolicpathways rather than contractors. And these metabolites are util--and some of these metabolites include glucose andamino acids, the things that Marcia talked about, thefuels that Marcia talked about. These are utilizedthrough metabolic pathways and turned into thosemacromolecules that underlie cell growth. So these nutrients are turnedinto the protein, lipid, nucleic acids, andcarbohydrates that I talked about on thatfirst slide through these metabolic pathways. So, however, this process is-- it doesn't occur on its own. Cells in our body growonly when they're told. They're very disciplined,and they really only grow when they're told to do so. So they reallyonly grow when they receive a signal from othercells that it's time to grow. And this is really in the formof growth factors, hormones, and cytokines, which are inour blood and circulating and are messagesfrom other cells to a cell that tell itto either grow or not. Sometimes the signaltells it to die. But a growth signal will startthis process of cell growth by stimulating theprocesses, the metabolic processes that I wasjust referring to. So what distinguishesa normal cell and its controlledgrowth that's induced by growth factorsand a cancer cell is that a cancer cell growsin an uncontrolled manner. It receives this growth signalwithout the growth signal even being there. So the cancer cell,through a variety of different cancer causingmutations, and Dr. Bardeesy will talk about akey mutation that's very common in humancancers in his talk. These cancer causingmutations drive cell growth by manipulating the cellgrowth signaling pathways to promote cell growth inan uncontrolled manner. So this cycle doesn'toccur just once. It can it occurs continuouslyin an uncontrolled manner, therefore giving you a tumor. Looking more closelyat this, the way that cell signalsare propagated, and growth signals arepropagated within cells, most of the time initiatesat the cell surface by receptors that receivethese growth factors signals. Those receptorsare then activated to propagate a signalinto the cell that tell the cell to grow. And I'm going to tell youabout one key growth signaling pathway today. Cancer cells are receivingthat growth signal, and generally the mutationsthat effect cancer cell and cause it togrow uncontrollably affected these samesignaling pathways, these lines of communicationwithin the cell, and signal to thecell to grow even in the absence of anexogenous growth signal, so that you haveuncontrolled cell growth. So in thinking about whatthis signal hits in the cell to tell it to grow,it's really useful to think aboutthis growth signal as being a generalcontractor, if we go back to our house analogy. So these individual pathwaysor specialists-- the roofer, the carpenter, the electrician--that helped to build the house are coordinated,often coordinated, if you're going tobuild a house de novo by a general contractor. Hopefully somebody whois more competent than this general contractor here. If you are a generalcontractor, I apologize. This is not how I view you. So the general contractor reallycoordinates the specialized workers that build the house. And this is reallywhat that growth signal hits in ourselves. It hits the generalcontractor of the cell. And that is a protein calledmTOR that my lab and many labs are very interested in. This is a protein called themechanistic target of rapamycin The title, the name of theprotein, is not so important. But it is a keydownstream target of growth signaling pathways,and it drives cell growth. And the way that itdrives cell growth is by programming the cell toconvert nutrients and energy through metabolicpathways into biomass, into the macromoleculesto build cells. So it is a coordinator of thisvariety of metabolic pathways to drive cellular growth. And what happens in cancer cellsis that mTOR gets flipped on, and it stays on. So it is receivingthat growth signal through cancer causingmutations such as the one that Dr. Bardeesywill talk about. And it, therefore,is being turned on in an aberrant manner. It's receiving a growthsignal that's not really there and, therefore,driving cell growth in an uncontrolled manner. It's not surprising,given that mTOR is activated in themajority of human cancers, that there's intense interestin targeting the pathways that lead to mTOR activationas well as mTOR itself in human cancers. And this has shown some promise. It's certainly nota magic bullet, and I'll talk alittle bit about why that might be in a few slides. But of course, there'sintense interest in targeting thegeneral contractor to stop this entire program. So let's go back to thatgeneral contractor analogy. This is the analogy of firingthe general contractor. If you fire this contractor,basically work on the house generally stops orat least slows down. So construction is halted. So this is somethingthat would be good if you're trying to stop thebuilding of a cancer cell and stop thebuilding of a tumor. You want to at least slowthe growth of the tumor, if not completely stopthe growth of the tumor. Another strategy, whichmay not be as obvious, is instead of firingthe general contractor, to fire a singleperson within this, that is underneath the generalcontractor that's driving the building of the house. So in this hypothetical,if you fired the carpenter, for instance, without tellingthe rest of the specialists or the general contractorthat the carpenter had stopped working on the house, you couldcreate, in theory, a setting where you have astructural imbalance and the house collapses. And this is really whatwe want to do to a tumor. We want the tumor to collapse. We want to create animbalanced setting that causes the tumor to collapse. And this is really a conceptthat my lab is interested in, and many labs that arestudying cancer metabolism are interested in, whether wecan create metabolic imbalance in a tumor. And I just want totell you a little bit about that concept here. So, again, if wego back to our mTOR signaling drivingcancer metabolism slide, and we think about theusefulness of targeting mTOR, again, the general contractorin this case of the cancer cell. What will happen, and we dosee this in many settings, is that these metabolic pathwayswill slow their function in the growth of the cell,and the growth of the tumor will slow down. OK? Often, this isfrequently accompanied by another pathway beingactivated, which turns mTOR back on, or other pathways beingactivated that can then turn on these metabolic pathways. This is frequentlywhat happens, and you get the developmentof resistance to those targeted therapeutics. Again, going back toour analogy of targeting the individualcontractors instead. If we can take out asingle metabolic pathway that mTOR controlswithout telling mTOR, and mTOR stays onand is still driving the activation of theseother metabolic pathways, we might be able to createmetabolic imbalance such that we ultimately cankill the tumor cell. And this is somethingthat we have examples of in the literature. I'm going to show you just onepiece of data from my own lab that demonstrates this concept. This is actually twoseparate experiments, one done in cellculture, 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 cellsthat are basically identical to one another. The only differencebetween these two cells-- this is a normal cell,which has growth factor control of the mTOR pathway. So you need growthfactors in order activate mTOR inthis particular cell. This cell has a mutation thatleads to uncontrolled mTOR activation, like one of thesecancer causing mutations. mTOR is just on, and it'sfully on all the time. And what we've done,you can see there's a little bit of a differencebetween these two cell types. First of all, they're all purplebecause we stain them purple. There's not somethingspecial about the cells. One thing you might noticeis that these cells have a different shapeand they're bigger, and that really is controlledby this uncontrolled mTOR signaling. But what we've donehere is treat either with a control compound or ametabolic pathway inhibitor that inhibits specifically justone of those metabolic pathways I showed on the previousslide that mTOR usually drives to promote cell growth. Just one of those pathways. mTOR is still on, andall the other pathways that mTOR is activatingare still on. So one pathway hasbeen eliminated, and we see collapseof those cells. They die. We see the samething in a tumor. This is a mousetumor that's caused by uncontrolled mTOR signaling. You can see that the tumoris here in this tissue stain. If we stain mTORsignaling, you could see that the mTOR signalingis very active really exclusively in the tumor. The rest of the normalkidney is pictured out here. And what happens when youtreat with the same inhibitor that we did on this slide isthat the cells within the tumor all die. Importantly, the remainingcells still have activated mTOR. So mTOR is really still on. And this turns out tobe an essential element of this treatment. If you turn mTORsignaling off, they lose sensitivity to this drug. So you need to be drivingthis program in order to have this antitumor response. So with that, I want totake a step back and just talk a little bitabout targeting cancer metabolism in generaland the cancer metabolism field. So targeting the keymetabolic processes that underlie cancer cellgrowth is not a new concept. Really the first antimetabolitetherapy ever discovered was discovered across thestreet by this gentleman here, Dr. Sidney Farber. He discovered, working withchildren that have leukemia, he discovered anantimetabolite that would kill leukemia cells thatotherwise were untreatable, thereby sending theseleukemias into remission. And what he did wastarget a pathway necessary fornucleotide synthesis. So nucleotides areone of the pathways that I showed onthe previous slide that mTOR drives, drivesnucleotide synthesis. Nucleotides are usedto make nucleic acids. That's the DNA andthe RNA in the cell. This comprises about 25% ofour biomass, give or take. Nucleotides are really madefrom exogenous nutrients. They're made from glucose,amino acids, and vitamin B9, or folate or folic acid. And what Dr. Farber found wasthat treating these patients with antifolates thatblocked the use of folic acid to produce nucleotidescould selectively kill the leukemia cellsand, therefore, send them into remission. And this is still a therapy,this antimetabolite therapy, is still somethingthat's in use today. So targeting cancer metabolismis not a new concept. But it's been re-energized inthe last 15 to 20 years really by modern technology,our improved ability to measure metabolism,metabolites, metabolic flux, as well as improvedunderstanding and a deeper understanding of cancerbiology in general. We've really started tounravel many aspects of cancer metabolism that are targetable. And this is reallywhat we're looking for is targetablemetabolic vulnerabilities. And the field of cancermetabolism in general is inherently multidisciplinary. It draws on lots of differentaspects of biomedical research and also contributes a lotback to various aspects of biomedical research. And so just inclosing, I want to say that I've really talked aboutone small piece of cancer biology today. I've talked aboutreally the early stages of tumor development,how a single cell that acquires a genetic mutationcan give rise to a tumor. But we know that cancer reallyis a complex disease that-- sorry, keep mixingup the pointer. And so that as thetumor grows, we see that various aspectsof metabolism kick in. And the tumorundergoes a variety of different metabolicadaptations as it progresses. At some point duringits development, the tumor will reach a pointwhere parts of the tumor may be starving for nutrients. And at this stage, thetumor will send out signals that tell the body togrow more blood cells, more blood, more blood vesselsgoing into the tumor, in order to resupplythe tumor with food, because the blood is reallythe source of nutrients for the tumor. So this is a process calledangiogenesis, which I'm not going to talk about today. But basically what angiogenesisdoes is refuel the tumor and provide nutrientsback to the tumor. And then finally one of theworst aspects of tumor biology, one of one of the most dauntingparts of tumor biology, is the fact that tumorcells will ultimately leave the primary tumorand metastasize and move to another site in ourbody and set up camp there, and therefore metastasizeand form a metastasizing tumor. And in that setting, thereare other metabolic challenges that that tumor cell facesas it's entering a new tissue niche and experiencing adifferent nutrient environment. And so I bring this up becauseI'm not rooting for the tumor cells except tosay that these are all challenges that the tumorcell faces that are targetable and that we can take advantageof as cancer researchers and clinicians totarget cancer metabolism and therefore eradicatecancer by targeting these differentmetabolic pathways. So with that, Iwant to hand it over to Nabeel Bardeesy, who isgoing to pick it up from there. [APPLAUSE] So I'd also like to thankeverybody for attending here in person and live streaming. It's a real pleasurefor us to be able to give a public lecture. We're so used tospeaking to each other, and it's a bit ofa challenge for us to try to conveythings in a more broadly interesting manner,but it's also a lot of fun. Brendan and Marcia,my colleagues, nicely laid outgeneral principles in metabolicreprogramming in cancer. As Marcia noted,individual cancer types use different strategiesto rewire metabolism that are often in keeping withtheir specific environment of that tissue. As an example of this,I'm going to talk about metabolic reprogrammingin pancreatic cancer, which is an area that my lab workson in Mass General Hospital. The pancreas is an organinvolved in digestion, so producing enzymes todigest food in the intestine, as well as theproduction of insulin to control blood glucose levels. Unlike many othercancer types, progress has been actually quitelimited in the therapies for pancreatic cancer patients. In the graph on the right,pancreatic cancer survival rates over five years, five-yearsurvival rates, and how they've changed over the last40 years are on the bottom. Whereas much morepromising advances have happened inother cancer types, the cancers tendto be detected late and respond very poorly toconventional chemotherapies and radiotherapies. And so we really needto understand much more about the biology if we'regoing to make clinical headway. The central, or one ofthe central, bad actors in pancreatic cancer is thegene KRAS, whose normal function is to be coupled veryclosely to growth signals and to act as aconductor to orchestrate a whole set of eventshappening at once, regulating cell metabolism,migration, modulate modulating the immunesystem, but in a very controlled manner. And this is important inthe normal development of the organism, ordifferent tissues, as well as in repairin adult tissues. In virtually allpancreatic cancers, and 20% of all cancersthroughout the body, KRAS is mutated. And so there's no needfor any upstream signal. The protein isalways on and always acting in an uncontrolled wayto drive all of these processes. Unfortunately, in oneof the great, let's say, unmet needs in oncology is aspecific and effective KRAS inhibitor. In the absence ofsuch an inhibitor, and yet despite decades ofattempts to develop one, many scientistsaround the world are trying to investigatewhat KRAS is specifically doing within thecancer cell in order to curtail what we call thedownstream effects of KRAS. And one particularlypromising area is in understandingand exploiting KRAS mediated alterationsin cell metabolism. All cancers undergoa gradual evolution, which is driven both by-- excuse me, anevolution as well as an adaptation to the changingenvironmental context that they are growing within. And these are drivenboth by genetic changes as well as bynongenetic alterations. In pancreatic cancer,the first genetic event is a mutation thatactivates KRAS gene. And KRAS mutationscausing abnormal growth of the cell, thepancreatic cells that incur that mutationas well as damage to the localpancreatic environment. And there's a co-evolution ofthe growing pancreatic cells as well as the localenvironment which leads to a very disorganizedtissue structure, unlike a normal pancreas. And this happens, actually,it can be over 20 years. These cancers slowly evolve. An ultimate consequence ofthis disorganized tissue is that there's a greatdeal of fibrotic tissue within the tumor and areduction of blood vessels. Brendan mentioned it amoment ago, angiogenesis. And, in fact, forcertain cancer types, there are a lot more bloodvessels that are recruited in. But a feature that'scharacteristic of pancreatic cancers isactually a compressed blood vessel context. The consequences ofthis, of evolution of a tumor within this verydisorganized environment, is ultimately alimited availability of nutrients compared toa lot of normal tissues. And the bloodvessels, who are again abundant in thenormal tissue and can be very abundant inspecific cancer types like kidney cancer, are requiredfor delivering nutrients as well as delivering oxygen. Sopancreatic cancers, by virtue of their unique, very dense, andhypovascular microenvironment, have lower nutrientavailability, often quite strikingly than normal tissues. A second featureof this environment is that there arereplete immune cells and other connectivetissue cells that could, in principle,be competing for those scarce nutrients. But they could alsobe appropriated, and they can collaborate andoffset defects in metabolism. So they can sharethe metabolic burden. And both of those processesare probably ongoing. And I should just say that inthe histological image below, the cancer cells, or thetumor cells with mutations, are circled. And you can see that theyare embedded in, again, in this very dense noncancercell matrix that are all participating in the tumor. So ultimately how isthis cancer growth achieved despite this limitednutrient availability? We've learned in thelast number of years that this balance betweengrowth and nutrient utilization is really orchestratedvery much in large part by KRAS mutations themselves. And they're keepinga close concert between growth cues and nutrientacquisition and nutrient utilization. And, again, thisis leading to a lot of predictions for how therecan be imbalances discovered and exploited. So I said earlierthat there aren't any KRAS inhibitory drugs thatare currently in the clinic. And on the horizon there isn'timmediate clear opportunities for robust KRASinhibitory drugs. However, we can usegenetic tools in the mouse or in human cells. And we can switchoff genetically KRAS and demonstrate that,in fact, KRAS is very important in tumor growth. So the images at thebottom show a model for what's observed inexperimental systems. Turning off KRASgenetically leads to a very strongregression of tumors as well as a lot ofdeath in the tumor. And we're learning nowthat a considerable portion of this death is due toa metabolic imbalance, and I'll lead you through that. So, first of all, whatis KRAS actively doing? One of the things thatit's clearly doing is ensuring that there's robustavailability of nutrients and enhanced ability toacquire the available nutrients despite overall limited supply. And these include taking upglucose and glutamine, which are generallyabundant in the body and very diverse in beingable to be interconverted to generate many of thebasic building blocks needed in the cell. There's also specializedscavenging processes that are normallyoperative in starved cells. A normal starved cellcan start recycling some of its cellularcomponents or taking advantage of an improved way toharness nutrients that are available outside the cell. So pancreatic cancers haveall of these operating in conjunction. And, finally, they're also veryeffective in taking up fats. And I'm going tolead through some of these examples ofhow they are controlled and how they might beexploitable therapeutically. So Marcia introducedimaging for glucose. You can see here inimages from a mouse model where on the left,KRAS mutations are on. The tumor is actively growing. And the tumor is activelytaking up glucose. That's contributing tothe biomass acquisition of the tumor. Very rapidly upon geneticswitching off KRAS, the tumors are losing theability to take up glucose. And this is a veryimportant contributor to their loss ofgrowth capacity. So that's for onenutrient, glucose. Another key nutrientis amino acids. And, again, in this context oflimited nutrient availability, pancreatic cancers arespecialized at a process called macropinocytosis, whichinvolves capturing extracellular nutrients that couldbe derived from dying cells or the availableserum proteins. And these are ultimatelydegraded in an organelle, in a compartmentof the cell called the lysosome that containsa lot of degraded machinery. And this active processof macropinocytosis is an important sourceof amino acids, again, one of the key building blocksin pancreatic cancer cells. A related process thatdovetails with the lysosome is called autophagy. And this is a process ofrecycling damaged organelles in the cell. And, again, both of theseare operating at high levels in pancreatic cancer cells. And current drug strategies thatare being tested in the clinic are inhibiting thiscellular recycling program and have shown some promise inpancreatic cancer treatment. Here's an example fromexperimental models, where the lysosome, so thedegradative structure, is very activelydegrading material. And so on the left is apancreatic cancer cell, where there's verylittle material present in this lysosome becauseit's actively being degraded. Whereas if we use anexperimental approach to inhibit thisprocess, you can see this accumulation of a lotof cellular components. On the right is agraph showing what happens to that cellgrowth or tumor growth when these degradativeprocess are inhibited, where you can see a veryprofound inhibition of growth due to inhibition of recycling. So to really fully be able toharness metabolic reprogram, it's important to know both thesource of nutrients in a cancer cell but also whatare the ultimate fate of these nutrients. What are they being used for? What are thoseessential functions that are supporting growth? And I've listed some here. Glucose uptake is particularlyimportant in fueling the synthesis of thegeneration of nucleic acids, and therefore in theproduction of DNA and RNA. Glutamine is veryimportant in the control of a damaging chemical inthe cell called oxidants, so to prevent oxidative stress. And I'll return tothat in a moment. I've already alludedto what autophagy does. So by understanding some ofthese altered utilization of nutrients, wecan exploit this. And so Marcia alluded to cancersas having a really revved up metabolism. They're hypermetabolic. And so cancers need to be ableto both integrate a growth signal as well as mitigatingthis kind of cellular stress. And one of thesecellular stresses is reactive oxygen species. A lot of you inthe room have heard of taking antioxidants as a wayto protect our body in general. But it so happens thatcancers are actually quite efficient at dealing withthe excess oxidative stress that they generate. And they're, in fact, generatingtheir own antioxidants as a protective measurefor the tumor themselves. And this slide heresort of brings together how KRAS coordinatesboth enhanced growth coupled with enhancedprotection from damage. So KRAS activelyincreases glucose uptake and the utilizationof glutamine. This on the one handincreases the tumor growth and leads to anoxidative stress. So this very rapid growthcan lead to inefficiencies. Just like the car that I showedon the previous slide, where a very, very rapidlydriving car can lead to a lot ofinefficiencies in the way fuel is burnt and lead todamaging for the car. The same can beoperative in a cancer. But KRAS, by acting asthis master orchestrator, at the same timeincreases the generation of antioxidants, both byutilizing nutrient metabolites to generate antioxidantsas well as to increase the production of enzymes thatare good at, again, enforcing this antioxidant state. Autophagy, or thisrecycling machinery, also rids the cellof damaged organelles as well as increasesmetabolic efficiency. So by maintainingthis fine balance, KRAS is able to both drivevery pronounced growth, while avoiding would belethal damaging insults. And this gives us aframework to think about where we can intervene tocause imbalances that hopefully will be toxic to the cell. So with the last slide, I'dlike to sort of bring things back to how we can take thisbasic science information and to apply it inthe clinic, but also what are theremaining challenges. And, furthermore, whatare the opportunities that are emergingfrom understanding cancer metabolism. One other thingthat's very exciting addresses a keychallenge really that could be transformativein pancreatic cancer. If early detectionwere possible, patients who havetumors detected early, often by chance,in the clinic that might be detected for comingin for another indication. They can be cured surgically. And so if we candiscover properties of these cancersthat are present very early before thetumors metastasize, this might offer opportunitiesfor early detection. And there's been somevery exciting work in the pancreaticcancer field showing that a very distinctmetabolic production that can be detected in theblood is associated with early pancreatic cancer. And this is beingactively explored for whether it's a practicalway to increase the potential for early diagnosis. Another aspect is whatwe call immunometabolism. So cancer treatments, adiversity of cancer treatments, both those thataffect cancer cell metabolism but otherproperties of the cancer cell. It's now emergingthat we need to think of how the metabolicproperties of the immune cells are being affected,because we want to be able to harnessand reactivate immune cells torecognize the tumor. And it's becomingincreasingly recognized that we have to considerhow our interventions affect immune cell function. A topic that manyof us scientists get asked a lot aboutis how diet affects both the development of cancerand, perhaps particularly savvy people, how it mightaffect more specifically therapeutic response. And there's been somevery exciting developments suggesting that, well, letme turn to the first aspect. So certainly diet canaffect pancreatic cancer. We know that obesityis a risk factor. We also are gaininga more precise role of why that's the case. But, secondly, what's emergingmore recently, irrespective of obesity, is thatcertain foods in the diet seem to be able to havea 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, andBrendan alluded to, this crosstalkbetween cancer cells and other types ofcells in the tumor. On the one hand,there seems to be some sort ofsymbiotic relationship between the nutrientsupply between the tumor and the noncancer cellsthat we need to understand. And, finally, we've showna lot of experimental data that suggests thatyou can really have strong antitumoreffects when you intervene in metabolism. And the public oftenhears this laboratory data that sounds very promising. And it's not always apparentfor why this doesn't immediately translate in the clinic. In metabolism, oneextreme challenge is that metabolism canbe viewed as robust. And what we mean bythat is that there's many ways to generatethe same end product. And so there is in verymany experimental systems, a kind of whack-a-mole,where inhibiting one process in metabolismcan be bypassed by an alternative pathway. And so this is really aplea for more basic science understanding. We have lots of goodhypotheses, and we're starting to understandthe unique metabolism of different cancer types. But we need to have a betterunderstanding of that circuitry so that we are getting pastthis whack-a-mole strategy but really being able todurably intervene in metabolism. So with that, I'd liketo thank the audience. It's really great tobe here and thank you. [APPLAUSE] OK. So thank you allfor your attention and for these reallyterrific questions. So there were anumber of questions in different categories. So I'm going to tryto read them according to the theme of topic. And then Brendan, Nabeel, andI will do our best to answer. And you can feel free tocontact us afterwards, too, with additional questions. Our informationis on the website. And you can also look upwhat our individual labs do and learn more abouthow to contact us this way. And just to startwith, I will not have time to read all ofthese excellent questions. So I apologize in advance ifI don't get to your question. So the first setof questions has to do with on-targetversus off-target. How do you ensurethat drugs target only the mTOR ofcancer cells and do not inhibit normal cell growth? And that goes along with anotherquestion directed to Brendan. What are the limitations oftargeting metabolic pathways? So I think this is reallythe most important aspect of any approach totargeting cancer is what the therapeutic windowis, because we're specifically targeting proliferatingcells and we're targeting the pathwaysthat drive proliferation. So the most common off-targeteffects, of course, are those that are also affectedby traditional chemotherapies. These are proliferatingcells, hair follicles, the lining of the guts, andimmune cells in particular, which is the mosttroubling of the on-target, off-target effects. These are cells that, wheninduced to proliferate, take on a metabolicprogram that is somewhat similar to the metabolicprogram I was talking about, that they are driving ananabolic program to promote biomass and expand immunecells, for instance. When they are revving upto attack a foreign entity in our body, they willdo a similar metabolism to what the metabolisma cancer cell does. So targeting thesemetabolic pathways, those are the cells thatwe worry the most about. But other proliferating cellscertainly can be affected. Now we think thatthere-- history tells us, work frompeople like Dr. Farber, tells us that there isa therapeutic window to be had for some therapiesdepending on the cell setting and depending on the underlyingmetabolic vulnerabilities of that cell setting. So we think that the factthat this metabolic program is occurring in an uncontrolledmanner in cancer cells is where that therapeuticwindow comes from. Our normal cells have tightcontrol over these systems and can shut that system downif things if things go awry. But, again, thiscontinues to be an issue. And I think will continue tobe an issue that we are always tackling and coming up withnew cancer therapies is what is the therapeutic window. And, Nabeel, would youlike to add anything to the topic of on-targetversus off-target of cancer metabolism? Well, I think there is aconundrum, because metabolism is operating. We're targeting something that'scompletely normal or required in all normal cells. And so where does thattherapeutic window exist? And so I think this conceptof metabolic imbalance is very important, where anormal cell would normally be coupled tonutrient availability. Whereas this constant growthsignal in a cancer cell will often drive it to diedespite a nutrient lack. So it might bepossible to harness this paradoxical situationin the cancer cell, which is insistent on growingdespite nutrient limitations. I also want toadd that we're not targeting things in the dark. And like Brendan mentioned,cancer metabolism and cancer biology now has tobe multidisciplinary, which means that we have atremendous amount of resources and information. And so one of the most powerfultools that we can go to is to mine genomic data. And so we can look at thegene expression differences between normal cellsand tumor cells and really try to avoidtargeting pathways that seem to be commonlyimportant in normal cells and tumor cells, and reallytry to uniquely target pathways that seem to bespecifically different in tumor cells or specificstages of cancer. So along those lines I'm goingto read another question. And this is addressedto me, but both of you can answer this as well. So are there certaintypes of cancers that are more likely to useglutamate in metabolism? And on the contrary,which cancers are least likely to useglutamates or glutamines in metabolism as a fuel? And so again, yes, theanswer is absolutely. Different types of cancerprefer different types of fuels. So certain types ofcancer really like sugars, and those can be imagedby FDG PET imaging. Certain kinds ofcancers seem to prefer amino acids and other fuels. And certain types ofleukemia, for instance, seem to prefer to burnfatty acids versus sugars. So part of unravelingfuel choice is a major goal of the field. And one way that wecan get some clues is to look at one,what are the changes in the oncogenicsignaling drivers. And often that'sa good first clue, because the signalingpathways often ultimately lead to changes in gene expression. And then you can alsomake predictions. So, for instance,mixed signaling drives a lot of tumors. And mixed signaling, it'sa transcriptional pathway that upregulatesthe enzymes that are involved in glutamineuptake and amino acid uptake from a cell,as well as a lot of the enzymes Ishowed that metabolize glutamine and glutamate. And so if you see upregulatedglutamine or a mixed signaling signatures,that's a good predictor that that tumor cell typemight use amino acids. All right. And here is anotherquestion to anybody. So how do you dictatewhich metabolic pathways to target to turn off? Yeah, so this isa great question. And I think it'sone 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 somethingthat Nabeel alluded to. But that decision ofwhich patient to treat is really amultifaceted decision. And it comes with manydifferent data points that we must consider,because it's really which types of cancer in whichpatients will respond best to specific metabolicpathway inhibitors will really be dictated bythe genetics of the tumor. So what are thedriving mutations that give rise to the tumor? There are anatomicalconsiderations. What is the nutrientniche of the tumor? Say, comparing a pancreaticcancer to a lung cancer, for instance. They're in verydifferent settings, and their metabolicdemands will be quite different from one another. And then, finally,there is something that we have a very hard timemodeling in the laboratory, which is differences indietary intake and physiology of the individual patient. And all of these,I think, are going to contribute to the effectsof targeting metabolism in individual patients. And so I think what wefind in the few drugs that have entered the clinic isthat there are responders and nonresponders. And it's verydifficult at this stage to predict whichones will respond and which ones won't respond. So the question was about whichmetabolic pathway to target. And I kind ofpivoted it to which patients to target with whichmetabolic pathway inhibitors. I think that that's the puzzlewe're trying to piece together. Just one commentis that the toolbox to be able to ask thatquestion experimentally is expanding very dramatically. So many companiesand also in academia, there's been a lot ofattempts to make inhibitors for these many, many metabolicenzymes that don't currently have a drug thatcan inhibit them. So we can use ourexperimental systems to be able to,perhaps, uncover new what we call vulnerabilities. And so this is an expandingtoolkit that will have, that hopefully will give us newhypotheses along those lines. The next question is somebodywatching from Facebook from Illinois. So what do we know aboutmetabolic reprogramming of the tumor microenvironment? Nabeel, do you wantto take this first? Yeah, sure. That's a great question. So the general view forcertain cancer types like pancreatic cancer is thatthe microenvironment ends up being very low innutrient availability. But there's also akind of crosstalk between different cells, sothat within pancreatic cancer specifically we know that someof the connective tissue cells' nutrients are actually beingeffectively used by the tumor cell, so that there's a kindof complicity between these two cell types. That would be one example. Also, there's someexperimental data that suggests thatthe local nutrients that are available in the liverthat can be used by cells that metastasized for other organs. And so to give a new fuelsource for cancers and perhaps enables the veryeffective residence of some cancers in the liver. So those are the two examplesthat I can think of right away. All right. This is a different topic. If you remove the target ofone of the metabolic pathways so that there is ametabolic imbalance, do you think that mTOR oranother signaling pathway would have some sort ofcompensation mechanism to bypass it and still function? Sure, I can take that. In the example thatI showed in my talk, we tried lots of different--and this kind of gets to the last questionI had as well, which is whichpathway to target. What we found isthat if we inhibited a specific metabolic pathway,that shut off the TOR pathway. So mTOR-- I didn'tget into it today-- is also very sensitiveto perturbations in intracellular nutrients. And so manipulatinga metabolic pathway can affect the intercellularpool of nutrients. And so what we foundwas that inhibiting specific metabolic pathways,some metabolic pathways mTOR could sense that thatpathway was being inhibited and therefore it shut down. And the vulnerability was lost. So, again, it's the equivalentof us firing the carpenter, but the carpenter sent tellingthe general contractor, hey, I've been fired. And that then thegeneral contractor says, all right, stop building. We have no carpenter. So the vulnerabilityis therefore lost because you can'tcreate this imbalance. And so there are settingswhere this occurs. And I think the TOR signalingturning off in this case is beneficial to the tumorbecause it will survive. And it won't starveitself to death basically by continuing todrive this anabolic program when it can't build a whole cell. So I think thatthere are scenarios where the inhibiting aspecific metabolic pathway will cause some kindof adaptation that prevents the target fromkilling the cancer cell. From hitting the target,killing the cancer cell. OK. So the next question hits on anew and really important topic. Do you think targeting cancercell metabolism will be as effective as immunotherapy? Nabeel. So I think Brendan actually gavean example of the curative form of targeting metabolism, whichis nucleotide metabolism, so some of the mostclassic chemotherapies. So we do have an old type ofmetabolic targeted therapy that is curing people today. In terms of thesenew findings where we're targeting variousaspects of glutamine metabolism and other things thatwe're talking about, these are entering theclinic, and they're looking quite interesting. So I think ultimatelyall of us are feeling that complementaryapproaches are needed, and it's going to bea case-by-case basis. But certainly thereis enough promise here that I think we're allvery invested in this area. So for those ofyou who might not be as familiarwith immunotherapy, it's basically a set ofnew and very exciting therapeutic strategiesthat activate our body's own immune systemto kill the tumor cells. And so in that sense havingthis immunological memory and seeing the tumor as aforeign agent for some patients gives a really dramaticand long-lasting response that's an anticancer response. And so it's verydramatic because it's such a durable response. And some patients have beenfollowed for years and years, and you don't see recurrenceof the tumor in very severe metastatic tumors even. Now the challenge isthat immunotherapy doesn't work for everybody. And it actually works for asurprisingly small fraction of the population. So still 10% to 20% of somepatients of some tumors are very responsiveto immunotherapy. But for some reasonwe don't understand, many patients do notrespond to immunotherapy. And some are some tumortypes are just not good candidatesfor immunotherapy. And so I think anotheropportunity on the horizon is thinking about how thesebasic fundamental principles of cancer metabolism couldsynergize in combination with immunotherapyto kind of widen the spectrum ofresponsive patients. I think that there's definitelymaybe not a new movement but certainly a recognitionthat there are really no magic bullets. And certainly, hopefully,you don't leave here thinking that specificmetabolic pathway inhibitors are magic bullets. We think that they are apreviously underappreciated aspect of the arsenalto kill cancer cells. But we think that reallycombination therapies are going to be key in targetingmany different aspects of tumor biology, metabolismbeing one of these. And so we're trying to findas cell metabolism or cancer metabolism researcherswhat the most promising therapeutic targetsare to add to that arsenal. Certainly we hopethat some of these will have single agenttherapy activity. But it seems like to get adurable response in cancer therapy, it's morelikely we're going to combine these therapieswith existing therapies OK. So in the last fewminutes, I'm going to read a set of questionsthat have to do with a topic we have a lot ofquestions on, and then we can all address that. So from Facebook in California,somebody watching asks are there anydiets or foods that are helpful in stopping cancer. Another question was docancer researchers themselves avoid eating sugar. [LAUGHTER] Another question askedif different fuel types cause different byproductsand turn on/off certain genes within cells, why notfocus on what kind of fuels we put into ourselves. So there is a whole theme there. And I think thoseare very relevant and importantquestions to address. So I think-- Do you want to answer that? I think there's probablytwo layers to this. Certainly there are manystudies in animal models that suggest that we canmanipulate the growth of tumors by changing thediet of the animals, either by restrictingtheir calorie intake, changing specific aspectsof their diet, low protein, high protein, ahigh fat, low fat. And also we can, thereare dietary changes that can advance the tumor andmake the tumor grow faster. So certainly you can manipulatethe growth of a tumor by changing the diet. Now whether this is achievablein us is less understood. Most of the nutrients thatare circulating in our blood are homeostatically maintainedin a very tightly monitored over a very narrow range. So it's hard to getyour body to all of a sudden have noglucose in your blood, because your brainwould shut off. So it's a difficultthing to think about in patient populations. I think where thebiggest promise comes is whether certain dietaryinterventions might improve the activity of existingtherapies or therapies that are being developedto target metabolism. So dietary interventionsin combination with targeted therapeutics thattarget metabolism or signaling pathways or other aspectsof cancer biology, that might be a promising avenue. And I think alongthose lines, it's equally important to know whatkind of dietary interventions are really dangerousin combination with cancer treatmentand therapy. And this is somethingthat's highly understudied that deserves a lot more focus. And then going backto the diet and cancer incidence or therapy, wedo know that statistically obesity and highfat diets are linked to the increased incidence of13 different types of cancer. OK. So that relationshipis quite clear. And I think what we also knowis that if you experimentally test the effects oflaboratory models of cancer in diets that are lackinga certain amino acid or a metabolite, youcan see that reflected in the metabolite profile ofthe bloodstream of that animal and in some cases of the tumor. But it's not always clearthat matching what you eat will be reflected exactlyin the cancer cell. I'll just say that, despitethese clear associations, really the massive increase inincidence 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 thereassuring thing. So I think there's a positivebenefit that's clearly in diet. But the epidemiologyfor many cancer types, this enormous number of studieslooking at individual contents of a diet and looking forincreased cancer risk, and they're certainly there. But the magnitude,I have to say, is less than for a lot of thevery established risk factors. OK. So I want to thankyou all for coming, and I hope that you guys haveall learned something today. [APPLAUSE] One second, sir. I hope you all havelearned something new today about cancer metabolism. And I think you could see fromthe massive number of questions that we got as wellas the hands that were raised that there aremany further experiments to do and many questions. And please do reach outto us or Gina beyond this. So thank you again. Thank you Gina in the office andBarbara and Brendan and Nabeel. [APPLAUSE]
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