Lewis Cantley - Obesity, Diabetes and Cancer: The Insulin Connection

Galla wanna start by giving all of my conflicts I have actually a lot of different companies that I work for have started own stock in listed here Petra adios epi pharmaceuticals cell signaling technologies I've not been on any speakers bureau so I don't talk for companies I have grant support from Petra one of the companies I started but mostly from the NCI gray foundation breast cancer research foundation stand up to cancer and I'll talk some about to stand up to cancer work that we're doing in a ACR and I'm stockholder and companies that I founded I have done an honor area for Sanofi and novo nordisk in the past year but those are the only two companies and I won't talking about any of the drug is made by any of the companies on this slide so I only consulted on things that I don't know anything about so so I have to say that the last course I had in biology was in 1964 so I'm entirely a chemist my undergraduate degree was in chemistry my PhD in physical chemistry and biophysical chemistry and I avoided taking in any biology courses in college or in graduate school so as a consequence I had no prejudice about how biology works I just assumed that it didn't disobey any law of chemistry or physics and that actually has served me pretty well but I did get interested when I I said I I should say I worked as a PhD student I worked on how you convert a chemical gradient an electrochemical gradient into a high-energy molecule notice how do you make ATP from a proton gradient in the mitochondria and chloroplasts so that actually is one of my first movement into something somewhat biologically relevant but as I started my laboratory at Harvard as an assistant professor in 1978 I became interested in how you get molecules in and out of just some very simple questions how do you get glucose in a cell how do you take up sodium or push out sodium move in potassium and in the course of trying to understand that I got even more interested in how hormones and growth factors hormones like insulin alter the ability to take glucose up and amino acids up into cells and at that time insulin signaling was a total black box we knew what insulin did it would drive growth of cells it would drive glucose uptake etc but we had no idea how that worked so I began to focus on that question how does how does insulin stimulate glucose uptake and since it's an event that happened at the plasma membrane I thought well maybe some lipid is involved and I got for reasons I don't have time to get into I got interested in the lipid phosphatidyl inositol so phosphatidyl inositol gets phosphorylated to four position and the five position of the Nauset all ring those are those two circles in black with the pee those are phosphates and that was discovered actually the year I was born 1949 that when P 32 was added to tissue whew 32 inorganic phosphate was added at tissues some of the rate of activity ended up in the lipid they looked to see what it was and it was this lipid this doubly phosphorylated lipid and so these deaths in fact was thought the only two forms of phosphorylated phosphatidyl inositol known to exist in 1988 before we discovered this enzyme were pi/4 p and p i4 v p to know it's phosphorylation at those two sites there are black Peas what we discovered was that there was an enzyme that Co purified with the insulin receptor but it also coped arrived with a variety of other growth factor receptors and importantly it co purified with virtually every unko protein that we purified so all the viral induced akka genesis viruses that caused cancer that Rous sarcoma virus polyomavirus that caused cancers and chickens and mice when we isolated the angka proteins the enzymes or proteins that were made by those viruses to transform the cell and looked at them we found this activity was Co pure fighting with all those proteins but was all could also Co pure fighting with the insulin receptor so the bottom line is the insulin receptor makes a lipid this triply phosphorylated lipid shown at the bottom which I call a aqua but if you will a cancer-causing lipid as its normal mechanism of action we now know that everything that insulin does in every tissue in your body all probably everything we've yet to find an exception goes through making this lipid but every all these oncogenes that transform cells also manage to turn up the level of this lipid so even by the late 1980s and early 90s I was pretty convinced there was some dramatic connection between insulin and cancer so what might it be so the bottom line is and I won't go into all the details of the signaling pathways we've worked on for the last 30 years to explain this but the bottom line is what we now know is that this lipid is if this look this lipid has to be made in order for a cell to grow and if you if everything is working normally then when a child eats or a young fly eats or a young worm eats or fish anything this is conserved in all multicellular animals then that stimulates the release of insulin insulin goes to various tissues activates pi3k this enzyme produces this lipid and this lipid then signals that a number of events that tell the cell to take up glucose and to drive anabolic processes and that's how animals live if you knock this enzyme out and flies or worms or in the case of animals we've knocked it out in the heart of mice and other tissues muscle skeletal muscle fat etc live the consequence is insulin doesn't work in that tissue anymore the cells in that tissue are smaller and you essentially they become acutely insulin resistant now as long as everything is working normally this look that is only made when insulin is high and it tells the tissues what to do whether it's to grow in a growing organism or in a mature organism insulin still works but in this case not to tell the cell to grow but rather to tell which cells should take up the glucose and to tell a muscle and fat to take up the glucose and to tell liver to quit making glucose and store it as glycogen so there's somewhat different effect of insulin during development and develop in insulin in adults now there has to be a way to get rid of this lipid and we didn't know until ten years after we discovered pi3 kinase how the cell gets rid of it and it was discovered in nineteen in about seven years after we discovered pi3 kinase a gene was identified called p10 for phosphatase on human chromosome ten that we now know is second only to p53 the notorious tumor suppressor gene as the most frequent event that happens in all of human cancer so this gene was positionally cloned as a tumor suppressor gene well when it was when the events who nobody knew what it did it looked like a phosphatase but it wasn't cure what clear what it's substrate was and jak Dixon's laboratory jak being a beautiful wonderful biochemist sought a substrate and tried pip3 and it turned out to be dramatically the best substrate for this enzyme so p10 the most frequently after p53 second most frequently mutated tumor suppressor gene works by getting rid of this lipid so as long as p10 is functional and pi3 kinase has only turned on when insulin is high then this three is only generated briefly in various tissues and then goes away becomes p10 gets rid of it but if you lose ability to turn it over with p10 or there's there are activating mutations in pi3 kinase or the gene for Piazza kinase is amplified so there are many many copies of it then this level of this lipid goes up and that drives cancer so that's what cancer is a majority of cancers work by this mechanism so the genes so there turns out they're actually four different pi3 kinase genes that encode enzymes that make this lipid so the B cells and T cells do it differently from the liver and muscle they use a different gene called pick 3 CD and that gene also drives not only the growth of normal B cells and T cells but it also group drives the growth of lymphomas the result from B cells and T cells so drugs targeting that enzyme have already been approved they work quite effectively in blocking the growth of those tumors but they're different in that those enzymes are not regulated by insulin so the only genes where you actually see mutations in pi3 counties the only gene is then the one that responds to insulin pik3ca is the name of the gene so the other three still drive growth but they don't respond to insulin and they're virtually never mutated so that's telling us it's really insulin and what those mutations do is increase the ability of that enzyme to respond to insulin so those genes those mutations are not really by themselves activating the enzyme activity is not much different and the mutated enzyme versus the wild-type except now it requires less insulin to activate the mutated genes so we can then ask now you know the TCGA thanks of TCGA more than 20,000 genes sorry 20,000 human tumors have been sequenced every gene in 20,000 patients with tumors have been sequenced so we have a vast amount of data now that we can go in and interrogate so if we go in and ask well how often do you see that activating mutations in pik3ca which are indicated in green on these bars or loss of function mutations or deletions of p10 which is the light blue and dark blue or amplification of pi3 kinase which is the red and then the sum of all of those events is shown at the top of the bar and what you'll notice right off is GBM that's glioblastoma more than 90% of glioblastomas have either a loss of function of p10 shown in blue or an activating mutation in pik3ca the insulin responsive pi3 kinase uterine cancers more than 80% have and most of those are activating mutations in pik3ca lung squamous renal bladder breast all the way down the line so all the cancers the majority of calls the majorities of deaths the United States are driven primarily by mutations in these two genes just two genes everybody's heard probably if k Rass an oncogene it's still you know it's what dominates in lung cancer and pancreatic cancer it's not as frequent as big three CIN mutations if you count all types of cancers together and I should say by the way the mutations in K wrasse allow it to activate pi3 kinase better so that's also driving through pi3 kinase now it turns out that the same mutations that we see in cancer they didn't enhance the sensitivity to response to insulin can occur as a mosaicism during development so it during embryonic development if the single cell in the embryo picks up that same mutation we see in cancer then all the progeny of that cell all the cells downstream have the ability to respond to insulin better than other cells in the embryo and as a consequence all the cells that drive that lineage grow outgrow the other cells in the body so if this happens very late just in the tip of the toe then you just get a large tip of the toe if it happens earlier you might see an entire leg or half of the body with this massive growth too handsome if it happens in a neuronal cell then you get that's in the brain then you get a cluster of enlarged neuronal cells that respond to insulin far better so anybody have a guess as to what disease that might cause epileptic seizure so you now have insulin being able to drive the response of those neuronal cells far better than any other tissue and that for you know for many years we had no idea what caused these epileptic seizures but often they were surgically removed so you can go in with a needle and remove that part of the brain and the seizures would go away but about seven years ago people started sequencing the genes in that region and found that they were different from the rest of the genes in the body and they turned out to have the very same mutations that you see in this lake and these various diseases and we're all called different diseases because they occurred in different tissues they were given different names they're now all called one disease called pik3ca related overgrowth syndrome or pros and pi3 kinase inhibitors are now going into clinical trials to treat these diseases because otherwise surgical intervention is the only way to do it so how do we try to block epileptic seizures we already heard about this right ketogenic diet why does it work but worse insulin right and since these mutations enhance response to insulin it makes perfect sense why that works but we figured out empirically without knowing why it works I think now we know why it works okay so you know 100 years ago or 90 years ago 95 years of it I guess it now was a German scientist named otto warburg made the observation that if you chemically induced mutagenic li induced to cancer in a rat and then looked at glucose uptake into that tumor and glucose metabolism in that tumor compared to the tissue from which the tumor emerged that the tumor was taking up glucose at a much higher rate and it was driving anabolic metabolism at a higher rate and this was called the Warburg effect that time at that time Warburg got the Nobel Prize for figuring out how mitochondrial metabolism works not for this observation but he's most remembered for the so-called Warburg effect that cancers were different in how they metabolize glucose and in fact back about thirty years ago with the insight that this was pretty common most cancers had this Warburg effect floridi oxy glucose a radioactive form of glucose was developed as a way to try to determine where the cancer is in the body so FDG pets I think probably everybody in the room has heard or knew have a relative or someone who's had an fdg-pet that's why it works because you've activated pi3 kinase pathway and that stimulates glucose uptake into the tumor so this is an example of a woman who went on the stand up to cancer trough I should say that stand up to cancer AEC are provided me and my team a 16 million dollar grant to try to work with industry to figure out how better to develop pi3 kinase inhibitors as they were going into phase 1 phase 2 clinical trials about ten years ago and so I was really again not being a medical doctor not knowing anything about biology obviously I had to have a really good team first thing I learned in science is you must make sure that everybody you hire is smarter than you are it makes your job easier you don't have to tell them what to do so that's what I concentrate when I got some of the best clinical trials in the country working on our team and we worked particularly with Novartis to try to figure out how to since they had some of the first drugs going into clinical trials how to best make their drugs work either by changing how they're delivered or doing drug combinations so this is one of the earliest patients to go on a trial and a combination we wanted to do was an aromatase inhibitor plus a pi3-kinase inhibitor because what we'd noticed was even then long before the 20,000 tumors were sequenced was it breast cancer it's very frequently had pik3ca mutations in the subset that had them were the ER positive breast cancer patients so we had drugs the roam taste inhibitors for treating er positive they were pretty effective but a lot of patients failed to respond or ultimately became resistant to that therapy alone so we reasoned that this might be a good trial to do and in fact as I say the pik3ca mutations were mainly in the r+ subgroup in fact 40% of women who are er positive have pik3ca mutations and that's the most frequent subtype of breast cancer so this was one such patient to go on to our early trial and we combined an aromatase inhibitor letrozole with the pi3-kinase inhibitor Alf ELISA and I'll tell you a little bit more about this drug in a moment so this is a drug that's highly specific for just the pik3ca type of pi3 County so the one that insulin stimulates so you can see by fdg-pet this woman was had metastasis to the liver of multiple lobes in the liver had tumors growing in them she had failed aromatase inhibitor alone as a single agent she also was her2 positive she went on Herceptin Feld that did a combination of those two still failed and she was progressing and run out of choices at this point when she came into our trial so we tried where he gave her the pi3 kinase inhibitor in combination with lectures all and two weeks later by fdg-pet there was no glucose up going into that those nodes and deliver anymore now it turns out if we image the tumor in other ways MRI CT scans then that's still tumor there it had not shrunk it just couldn't take up glucose anymore because we turned off pi3 kinase the mediator of glucose uptake into the tumor so that all made sense that's exactly what we hope to see this woman ultimately after three months the tumor shrunk and she was pretty much disease-free for about a year and a half but ultimately progressed so this wasn't a cure but it was definitely a long-term response so we were excited about that and went on to a number of patients now unfortunately she was in the minority so everything most of the patients that we put on this trial had pik3ca mutations and they were er positive and yet some of them responded dramatically like her led to majority didn't and so we did ftg pets at two week intervals before and after drug on about twenty of these patients and we found that that most of them had either very little change at all in the fdg-pet and some actually the FT pet was bigger more glucose going on after giving the drug than before which was kind of shocking now till you explained to you in a moment why that was so but that was kind of shocking to the oncologist not quite as shocking to me because I'll see um I am reasoning in a moment so it turned out that the patients whose ftg pets were like this one of going away immediately they all had clinical responses their tumors shrunk but those who had very little change or the glucose actually went up went off the trial very quickly they progressed so this was actually early indicator and we actually proposed a Novartis that every patient that went on their trials and in fact their label would be that unless you saw a change in fdg-pet in two weeks you don't continue on the drug they didn't like that idea first of all costs $8,000 per pet and I had to pay for all these pets myself because the company wouldn't do it but we learned a lot from that meantime we were making mouse models here was an ER positive breast cancer mouse model with a pik3ca driven tumor and again you can see they're very pet positive when you turn on the mutant gene indicating it's really this mutated form of the gene that allows it to respond to insulin and turn up glucose uptake into the tumor so as bright colors air a glucose going into the tumor here's another this actually is a this is a bracha driven tumor again the pi3 kinase inhibitor you can show you on the left is before giving the inhibitor on the right is after we don't completely turn off glucose uptake into this tumor but we definitely slow it down and we can see clinical see responses in this disease setting as well this tumor doesn't actually have a picture you see a mutation but it still is dependent on pi3 kinase to take the glucose up I should add that in our phase one B trials of combining letrozole was pi3k we did admit about 22 patients who did not have pik3ca mutations and about five of those responded had clinical responses in fact very long clinical responses even though they didn't have a mutation so this wasn't like you know EGF receptor mutations in lung cancer where everybody who has a mutation responds EGF receptor inhibitor people who don't have mutation had no response same thing with b raf mutant melanoma only the patients who have the mutations respond this is not what we saw in this disease there was a skewing towards patients with pik3ca mutations responding but there were patients without mutations who responded and there were many patients back to majority with mutations that didn't respond so what's going on why isn't simple like EGF receptor or b-raf so again getting back to the mutations you can see that if we look at just pik3ca so in this graph I've left out the p10 mutations you see it's women's cancers that dominate the pik3ca mutant subgroup uterine cervical breast ovarian all have high rates of either mutations or amplifications of pi3 kinase so when we put our standard for cancer team together we decided to focus entirely on women's cancers because that would really capture majority of patients with mutations in the gene so there were complications in how we would do this as I indicated earlier pi3 kinase inhibitors the target picked 3 C Delta the one that's in B cells that drives b-cell lymphomas were very effective and got approved quite quickly 3 different such drugs have already been approved but they don't have the problem of being insulin driven so they're driven by b-cell receptor and so we don't have to worry about insulin elevations affecting the response to the drug but the drugs at Target pik3ca the insulin responsive pi3 kinase had been very difficult to get approved as I said that trial that I showed you that was started almost ten years ago so what's the problem well the problem is that if you give a pi3 kinase inhibitor what do you think is going to happen to blood glucose if you inhibit pik3ca did they pee up the insulin driven pi3k what's going to happen to blood glucose if you inhibit that enzyme it's going to go up right you're going to get acute insulin resistance and we'll go into that in a little more detail now if the insulin levels go up you can now act if it gets up high enough you can override the effect of the drug because you never can get a concentration the drug and gives a hundred percent inhibition of the target there's always an efficacy toxicity problem with doing that so if you can get insulin high enough you can reactivate the remaining amount of enzyme and bring everything back to homeostasis again keep in mind the pik3ca mutations we see in cancer allow the tumor to respond better to insulin than your liver or muscle if you happen to be somewhat insulin resistant then the tumor has tremendous advantage of any other tissue in your body if responding to insulin that's why when you do an fdg-pet the glucose is going into the tumor much better than it's going into any other tissue in the body except the brain I should say but even with the brain which there was a trend most amount of glucose going into the brain with a pet signal if you have a glioblastoma and pik3ca mutations that's still even brighter than the normal brain so anytime you turn on by mutation this insulin responsive pi3 kinase that tissue has an advantage over the rest every other tissue in the body so this is now shown as a cartoon for those who don't like words so we've seen versions of this over and over again this is the muscle in this case very simplified you eat your pasta for those of you who still eat pasta I'm sure nobody here ever puts sugar in their coffee so we don't worry about that I replaced the sugar in the coffee with the pasta you would never drink apple juice I assume nobody it does that anymore any event the glucose gets into the bloodstream either slowly or rapidly if it gets in rapidly it's a bigger problem the pancreas starts releasing insulin it activates pi3 kinase in muscle that drives that excess glucose into the muscle it gets stored as glycogen and everything's flying if you happen to be walking around it'll actually burn that glucose to make ATP same thing it can go into the brain the brain probably at rest just using up about 1/3 of your glucose is getting burned in the brain so those of you who are actually thinking right now and maybe moving around a little bit you know you're in good shape so it is everything is working fine that's why it works and the glucose level comes back to me 6 very quickly we saw lots of that if however your insulin resistant or you take a pi3 kinase inhibitor then very quickly the the blood glucose goes up insulin goes up to try to bring that glucose back to homeostasis and as a consequence you try to you know that elevated insulin is attempting to bring everything back to homeostasis if you have a pi3-kinase inhibitor it's going to take a lot more insulin to come back to homeostasis than if you didn't or if your insulin resistant it's going to take a lot more insulin so the insulin levels are going to be higher in people at insulin resistance and then you give up I three kinase inhibitor on top of the insulin levels are going to be sky-high higher than ever seen in a human being before and that's exactly what we see in humans who take this drug and in mice that we give the drug to so well if however the tumor has a mutation in pi3 kinase then it will respond to very little low levels of insulin and even in the presence of the drug will still respond pretty well that's why we're having trouble getting the drugs approved that enhanced response to insulin means that the ambient insulin your blood stream can override the drug effect in the tumor and that has been the problem so I'll tell you about to approval trials that just got announced over the last six months the first one was from Genentech Roche drug called GDC oo3 to which in our hands and our preclinical models and even in our phase one models with that drug it was actually looked like the most promising drug for inhibiting pi3-kinase in the clinical setting so it went into phase 3 clinical proven trial along with a drug fluvus trot that targets the estrogen receptor for er-positive breast cancer patients and they selected pik3ca mutant breast cancer patients so this trial seemed very well designed over 570 patients went on the trial and the result was announced in June 2000 2018 now I should say and I'll show in the next slide a little more to tell about the competing trial was from Novartis virtually identical trial same number of patients same disease setting er positive pik3ca mutant breast cancer a same secondary cava Stratton combination and both trials so basically the same trial and and Novartis started their trial about a year and a half to two years earlier than Genentech but Genentech finished their trial faster so a little surprising Nate were able to leap ahead the problem was the trial filed the trial failed so this was revealed at ASCO in June and one day after the trial was presented Roche abandoned the drug so this is now a dead drug lots and lots of money spent on this over about eight years and it was abandoned taste illicit even though it looks so promising and preclinical and early stage trials if you looked at the data there were some regions in the world this is a worldwide trial there were some reasons the world where there was zero benefit so the overall benefit was like two and a half months that's not enough to get a breast cancer drug approved and in many areas and of the of the world there was zero benefit not a single month progression-free survival so the second drug that went in trove was the one that I showed you in that patient the woman whose PET scan went away byl seven one time now called Alba Lissa again same drug same combination again about five hundred and fifty patients or so and the endpoint was eleven month extension instead of two and a half so what was the difference and I would argue this hasn't been proven yet but when we worked with Novartis on the phase 1b trial with this drug I insisted that any patient that had to be managed on insulin had to be excluded from the trial so imagine you get so first of all anyone who had type 2 diabetes was immediately excluded but a lot of people were insulin resistant and didn't know it as we've heard over and over again you know half the people in America are insulin resistant so if they didn't know they were in some resistant they could they could enroll in the trial endocrine consultant called in on every patient for the first dose followed them and we watched you know monitoring both the glucose and the insulin level and if the glucose went up more than three-fold and I should say everybody went on metformin right off to anticipate that it was going to be insulin resistance and if the glucose level did not go up more than two to two and a half folds and the patients could stay on the trial if they went up higher than that in the trial that we did enough with Novartis and they couldn't be managed with metformin they had to go off the trial so we as a consequence something like a third the patients we tried to enroll had to be taken off the trial and that's why it took so much longer to get that trial enrolled in the phase three because they maintained that requirement if you had required insulin to keep the glucose managed you had to go off the trial Genentech had no such requirement it was entirely up to the endocrine allá gist how to keep the glucose in control they wanted a fast enrollment they wanted lots of patients and so guess what Bob will bet that majority of their patients were managed with insulin so you already have very high insulin and now you add more insulin and the chances that you that will override the inhibitor is remarkably likely so this is again what's happening you you have this case I'm showing the liver instead of the muscle but similar story you eat sugar pancreas makes insulin insulin stimulates glucose up blocks gluconeogenesis in the liver stimulates up taking gluten and muscle and fat but if the tumor has insulin receptor in most tumors do then it will also stimulate glucose uptake into the tumor if you happen to be in some resistance in your ants ambient insulin is high all the time your insulin resistant in the liver and muscle but you're not insulin resistant in the tumor the tumor has a mutation to make it hyper insulin sensitive and so it gets all the glucose that should have gone into your muscle or fat hence the fdg-pet signal easily seen it in the tumor on a high glycemic diet you can imagine just gets worse and worse if you're on a high glycemic diet so how do we manage this so a pasta thin is that if we could keep the insulin level low the drugs should work better because it won't override and reactivate pi3 kinase and the tumor so this is this data is from a mouse but it's actually identical to what we saw in the human draws so as I said all the human trials we everybody went on metformin before taking the first dose to try to anticipate the glucose overshoot so the blue is just normal child no metformin the green is with metformin the red is a ketogenic diet but we only started the ketogenic diet the day before so the we did no glycogen depletion no long-term ketogenic diet we just made sure that the time that they were given the drug they had no rapidly released carbohydrate no carbohydrate in food very little less than 10% the purple is the sodium-glucose cotransport or inhibitor which as many of you probably know better than I in human trials or human studies can be much more effective than metformin in keeping glucose low this drug keep in mind block Sri absorbance of glucose in the kidney and so the glucose ends up in the urine major side effect being yeast infections but in fact it's pretty good at keeping glucose under control the part the right part is the insulin levels at the end of this treatment after two hours and you can see that ketogenic diet on the right is by far the champion in this case this was a ketogenic diet for a week run in before we measured the insulin level acutely after giving the mice the pi3-kinase inhibitor so metformin is really not very effective that's what we were using in the clinic and all the patients was not very effective in keeping glucose down or insulin down sodium glucose transporter inhibitor was better ketogenic diet is the best so the question is is that going to be helpful is it really true that if we can keep the insulin level we can have a better effect on the drugs and the answer is absolutely so this is a breast cancer pik3ca mutant breast cancer patient like that Mouse I showed you earlier with the fdg-pet signal and you can see that a pi3 kinase inhibitor even though it slows down that tumor some doesn't cure that tumor ultimately the tumor keeps going and that's what we typically see in human patients as well but if we put that Mouse for a week on a ketogenic diet and then begin and continue on the diet throughout the therapy then that tumors just go away so we've now done this in eight different types of tumors including AML where we were surprised that we were looking for a tumor that would not respond this way even a single tumor had been a nice control we've yet to find one that doesn't show this kind of response whether or not they have a pie 3-kinase mutation this one does but all of them we do did not even pancreatic tumors that never have picked receive mutations just completely go away if you combine a pi3 kinase inhibitor with the ketogenic diet the ketogenic diet by itself in some cases has some slowing down the tumor other cases has no effect on the tumor so I wouldn't say that a ketogenic diet is ever going to be an effective therapy for a tumor maybe glioblastoma but it's not going to cure it but you put together a pi3 kinase inhibitor with the ketogenic diet and invariably and every model we've looked at we see these kinds of dramatic effects here's an example of the tumor this was actually an endometrial tumor a human endometrial tumors organoids so it grew it organoid out of the patients in a material tumor from surgical material implanted it in a immune compromised Mouse and then we wealth multiple mice and we tried treating either with no drug at all that's the vehicle vehicle at the top and the brown stain insuk indicates Auto phosphorylation in the insulin receptor this is an antibody recognized specifically sites phosphorylate on the insulin receptor and you can see some brown in there it's not a whole lot of brown but it this is without the inhibitor if you look directly below that that's what it looks like after you give the inhibitor you can see the activation of the insulin receptor in the tumor is dramatic when you give a pi3 kinase inhibitor unless in the right bottom panel you give a unless you give a ketogenic diet and then the same drug at the same dose and then all that brown stain goes away so it's clearly clear that you can prevent insulin from activating the tumor by giving a ketogenic diet because it just lowers insulin so here's another tumor this is a triple negative breast cancer tumor that has from patient I should say transplanted into the breast of a immune compromised Mouse it has to pick three CA mutation and we look to see what happens and a whole different a whole lot of different combinations and nothing works until we combine in Braun a ketogenic diet in the pi3 kinase inhibitor and this tumor completely disappears however in blue the blue triangles are what you if you use that same combination but at the same time every time you inject the pi3-kinase inhibitor you also inject insulin at the amount that we typically would see in the bloodstream of the mouse had it not been on the ketogenic diet so we're not causing ketones here or making them go away we're just replacing the insulin that goes away when you go on a ketogenic diet and now the tumor does not respond at all so it's not the ketones that are killing the tumor it's the absence of insulin that's allowing pi3 kinase to kill the tumor so I think this pretty much nails it I should say that it took us a year and a half to get this published in nature because the reviewers just were completely shocked by all the results although in retrospect it's completely obvious that this is the way it should be once you think about what pi3 kinase is designed to do and what these mutations do so I'll stop there I just have some references which you can look at it your leisure if you pull down the slides that there's now a host of papers that have argued it's insulin resistance more than obesity that's driving cancer and that's you can see that if you have insulin resistance ambient high levels of insulin in a cell in your body picks up one of these pik3ca mutations it's now going to get all of the glucose in your body and it's going to grow so I'm quite confident that that's why we see the correlation between insulin resistance obesity itself does not correlate a nice paper by us by Strickler there on the middle one in this slide showing that if you look at breast cancer women who are overweight or obese but carry the fat peripherally and not in the liver are not do not have a higher rate of breast cancer and women who are thin but insulin resistance have the same risk as women who are obese and insulin resistant so it's really insulin resistance I think is our problem so summary I think I've already said all this it's I think it's pretty obvious I just want to get to the acknowledgment so the paper that shows all this data if you want to go into is just recently published in nature in the summer this was a lot of this work was based on a clinical trial that we did with my stand up to cancer team that's listed there is a second reference and I just wanted the third reference I put in for those of you who wonder how insulin stimulates glucose uptake into various tissues other than just muscle and fat where you have glute it shows that protein called TX nib which degrades the glucose transporter is killed it's destroyed is degraded when you activate pi3 kinase pathway a KT and that probably explains the fdg-pet signal so that's why that paper I think is really important and I'll stop there Robert go ahead more questions than a symposium I was wonderful a truly tour de force and you know in in retrospect yeah why didn't we think of that three questions but I think they're all ultimately the same question get rid of the pasta put back the apple juice yeah okay yeah apple juice is worse than pasta yes way worse and the question is why so we talked just briefly yesterday about the fact that there are a whole bunch of sugar depending cancers and they all seem to be endodermal and large and in fact female cancers breast cancer endometrial cancer ovarian cancer etc liver cancer pancreatic cancer all from endodermal origin they're not going through pi3k the fructose is not going through pi3 kinase because that's a glucose transport or not a fructose transporter my question is do you know if these tumors also have the glute 5 transporter number one which I do not know the answer to number two many tumors of endodermal origin have an enzyme called Transkei delays which can convert fructose to glucose so that they could potentially power the cell irrespective of insulin and is that one of the ways this works and have you measured or studied transit rescue delays in these and the third one was this thing you just threw out at the end as you know this little you know throw away this TX snip because as you know Richard Lee at Harvard has shown that TX snip is the thing that transports fructose across the intestinal epithelial cell and it's self induced in other words the more fructose the more TX snip the more TX nib the more transport and if you're blocking TX snip could you be blocking sugar dependent cancer and is that a potential target how many questions is that yeah we may we may have to answer some of these over a drink but I'll say for very long drink yeah and sort group 5 is we have a paper that's close to being accepted of science it shows that in in colorectal tumors you definitely maintain glute 5 so they can take a fructose from the gut and that's actually helping them drive and it probably explains why the forty ounce coke is driving your colorectal cancer gross and probably explaining why we're getting colorectal cancers in the 30s even the 20s occasionally now which was unheard of the cost of the higher sugary drinks the second question it's a good five we don't see it we've looked at a lot of other tumors because like you we thought maybe fructose is really driving a lot of tumors but it's not in part we know because very little fructose is in the circulating blood it all gets off tough whatever makes it in the blood pretty much gets soft up in the liver well that's that's only true if you're drinking in 8 ounce coke if you're drinking a 20 ounce coke you weighed pass hepatic hepatic extraction and in fact there's a fructose transporter on beta cells which increase insulin secretion so you can overwhelm yeah I'm sure you're right about that yeah so still when we've looked at a lot of tumors we're not seeing group 5 that often TF snip by the way I think will also affect route 5 to every glucose transporter we look at it it regulates so I think it also gets turned off by a and P kinase so that you can bring in glucose when you're energy deployment stressed okay so I don't know what at a question I forgot to answer well so there was the glue v there's the Transkei delays question yeah transmittal ace we haven't really looked into that that much in these colorectal tumors that are using fructose to drive their growth it's really it's working by sopping up all the ATP in phosphorylating in the one position so they have key to exit kinase yeah phosphorylate the one position but they don't have an outer lace that will hydrolyze so it doesn't go into anabolic glucose as we heard in the previous talk so you can't make fats out of that fructose it just stays there is for kids one phosphate but it's also enough ATP to allow the ATP shut off of glycolysis to be eliminated now the glucose it's coming in with it so a perfect storm is glucose plus fructose well now the glucose is doing all the growth but the fructose is acting catalytically just speed it up but why couldn't the fructose be used as carbon fragments for growth we thought it could be but we did carbon tracing and all the fat is being made from the glucose even because we labeled in both ways it's not this is just colorectal I'm not you know I'm not saying others couldn't do it differently but the colon that's the way it works I said thank you Lots being written about fasting plus chemo for cancer or fast mimicking diet plus chemo you you're talking about a ketogenic diet I wonder if you have any ideas on contrasting the two dietary therapies yeah so very nice talk given by Joshua Vinny wits Josh was also the one who had the paper on exceeding the capacity of the epithelial tissue gut epithelium that we were discussing earlier in the previous talk but Josh had a nice presentation at a meeting in Brooklyn last week a CR meeting two weeks ago that tried this exact same thing that we did except in pancreatic cancer he was using conventional chemotherapy not a pi3 kinase inhibitor but he got exactly the same result so keeping insulin down in the pancreas and of course that those of you who are in the chronologist know this better than I the the ambient insulin level in the pancreas is always 10 or 15 maybe even 20 fold higher than in peripheral blood because that's where it's made and then downstream of that is the liver which also has higher insulin than the rest of the body so the even though you never see victory see mutations in the pancreas it they're still very dependent on pi3 kinase in that ambient high insulin is keeping the pancreas going even with the k-ras mutation you still need pi3 kinase so i answered two questions Roberts second question and yours I think and let that make sense so I think that a lot of Kimo theory there are papers scattered through the literature on either starvation diets or low carbohydrate diets effects on conventional chemotherapy in mouse models but I've not seen a clinical trial published to prove that what you see in the mouse really is going to work in humans but I may have missed it but I thought my bet is a will and the problem is I talked to the oncologists no matter where I am working on my team and I say well what are the patients doing during chemotherapy they're sitting there in the IV well they're taking in sure because we want no one want him to lose weight think about it it's very sugary drink while you're taking your chemotherapy I mean it's just crazy so who's next so my impression is this is mostly a discussion on treatment of cancers and patients have already acquired mutations and p10 or pi3 kinase do you have a sense of what's driving mutations in those pathways to begin with him so do you think insulin resistance is contributing to that and that people might prevent themselves remember developing cancer by being on a ketogenic diet or yeah well you know obviously for a mutation to occur you need some kind of a mutagen probably most of the mutations that we're seeing in these tissues are due to reactive oxygen species hyper metabolism of glucose hyper metabolism mitochondrial electron transport thief you know problems are probably what's generating the mutagen we're trying to figure that out by because you can get signatures and if you do a full genome sequencing you can get a signature of what the mutations are that correlate with either Ross or other antigens you can get to nicotine effect ross effect etc DNA mismatch repair defects they all show up them a signature that tells you what's actually probably driving that tumor but I don't think that keeping I mean keeping insulin down probably will help keep the Ross at a lower level so you'll get less mutations in look in general but you know a lot of mutations are just luck every time a cell divides there's a chance of mistake and so even if we looked a perfect life eventually some mutations would build up I'm just saying that if you have high insulin once you get one of those mutations that cells going to grow better than any other cell in the body so you've got little micro tumors they're getting driven by that high insulin okay thank you some notables in the low carb community have been developing a hypothesis of cancer as primarily a mitochondrial disease and they refer to one famous study in JCI in which many years ago in which mitochondria or nuclei were cytoplasm where nuclei were transplanted back and forth cancer non cancer and the cancer phenotype was reproduced based on mitochondrial transfer of from a tumor but not from the DNA so one model relating to the last question could be that there's reactive oxygen species that creates genomic instability is that consistent with what you know and why would that instability if that you know if the problems were originating in the mitochondria why would they so consistently be hitting these two genes rather than you know like all the other genes I mean reactive oxygen species shouldn't be selective and we should be able to distinguish this hypothesis from you know the classic DNA mutation yeah so first of all you know Warburg when he saw this glucose uptake he said they must be mitochondrial defective because they have plenty of oxygen why aren't they using it the way the normal tissue is so that that idea dominated cancer in if you know 30s 40s 50s 60s even though I was a graduate student mutated oncogenes didn't exist when I was a graduate student that you know Harold Varmus and bishops sark mutation thing didn't appear until 1976 77 so it was you know that's everybody thought it was like what you said it's just mitochondrial defects it's a metabolic disease we we now know that there are and kidney subsets of kidney cancers really are due to a mutation in mitochondrial metabolism IDH - mutations accompany actually my my lab when combination with agios is the ones who figured how those work they idh1 idh - mutations and so that you know it does happen but every cancer has a different way of evolving it's just that when the pik3ca mutation occurs it allows that cell to respond to insulin better and many other mutations don't most of there's still a katie mutations will also allow respond insulin and p10 law will allow abundant respondents and so it's frequent but it's not invariable many other pests it could be taken of exogenous ketones could you imagine a chemotherapy in which you develop an antibody to insulin and basically shut down insulin you know in that way and then just support the patient with with ketones it's an interesting idea i you know i think that i love the idea that ketones can replace the majority or at least half the glucose requirement in in the body and and i particularly like this because i always like to think about everything in terms of evolution and if literally we're not metabolically we're not a whole lot different today than we were fifty eighty thousand years ago a few differences we pick up we can maintain the ability to metabolize lactose you know with age that's the biggest mutation we see but most other things we haven't changed a whole lot in metabolism we were hunters and gatherers mainly hunters probably and what we gathered even before we had fire we didn't cook anything so if you think about all the things we learned today that we're healthy there were things that were eaten by cavemen you know eighty thousand years ago uncooked vegetables roots the only time we got fruit was like one month out of the year if you lived in a temperate climate climate so any human beings that lived in a temperate climate had to figure out how to survive for long periods of time without any food so in some ways we took the same evolutionary path as the bear so bears go to an extreme they not only slow down their metabolism they actually go to sleep but before they go to sleep what do they do they wander through the woods and eat every piece of fruit they can find somebody once told me to eat something like the average bear eat some 30,000 blueberries in Maine before it hibernates they will they will climb trees and eat honey out of the in spite of being stung all of it if I still still eat that honey and you'll do it in the fall right at the end of this season and they put on a hundred pounds or more in a month and then they get become severely insulin resistant slowed down their metabolism fall asleep and there's enough fat stored to make it till the next season where there's still roots now available they can dig up and have something to eat again we're kind of like that that's why we become insulin resistant and that's why we love sugar we love sugar because eighty thousand years ago any human being that didn't go through the same cycles of bear and put on twenty or thirty pounds at the end of the growing season by eating every fruit in sight and becoming insulin resistant and slowing down their metabolism was going to die of starvation before the next root was available when the ground thawed out three months later or four months later so that's why we love sugar it's you know people died of starvation they didn't die of obesity it's just that we now have all that sugar available all year round so I know there wasn't any question about that I just wanted to say it [Music] [Applause]

Channel: JumpstartMD

Views: 25,327

Rating: 4.8759122 out of 5

Keywords: jumpstartmd, weight of the nation, wotn

Id: S395qX6G6HM

Length: 58min 23sec (3503 seconds)

Published: Wed Jan 30 2019

Reddit Comments

[u/wtgreen]

Great presentation, even if much of it was too technical for me to fully absorb. That said the presentation clearly shows how common it is for cancers to be highly dependent on glucose and have mutations that increase their glucose uptake, and how treatment combined with a keto diet was dramatically effective, significantly moreso than treatment or diet alone.

[u/1345834]

https://www.nature.com/articles/s41586-018-0343-4