[SIDE CONVERSATIONS] SPEAKER: Good evening. I would like to welcome all of you to this year's Efraim Racker Lectures in Biology and Medicine. This lecture series began in 1992 with the intention of bringing, both to the scientific community of Cornell but also to the broader public, examples of some of the major developments in biology and medicine by those individuals who have been responsible for some rather remarkable accomplishments.
And in that vein, we've been very fortunate over the years-- right from the very beginning-- to have had some truly outstanding lecturers, including the first lecturer, Jim Watson, and others, including Sydney Brenner, David Baltimore, Harold Varmus, Robert Weinberg, Robert Lefkowitz, and tonight's lecturer, Lewis Cantley. What we've tried to do with this series is to identify individuals whose research interests really epitomize the breadth of Ef's work through his career and his devotion both to basic science and to a molecular understanding of disease.
Ef came to Ithaca in 1966 as the Albert Einstein Professor of Biochemistry after a rather extraordinary career, where he had spent time at NYU and in the Public Health Institute of New York and would continue on an amazing career while he was at Cornell. For those who knew Ef, you know that his research style was one that drew from really an extraordinary creativity and imagination, every bit as much as drawing from technology developments or literature details.
His science is really like his art and his painting, which was, of course, another one of his great loves. And I know he'd be particularly pleased with this year's selection as a lecturer for a number of reasons. One, Ef knew Lew Cantley when he was a graduate student here in chemistry at Cornell with Gordon Hammes, and because Lew's discovery of the PI 3-kinase and really what that has meant to birth factor signaling and cancer and Lew's more recent interest in the roles of metabolism in cancer and disease perfectly parallel Ef's life work in terms of trying to really understand how aberrant metabolism can give rise to disease states, and especially altered glycolysis, the well-known Warburg effect, plays a role in cancer progression.
On top of this. I think Ef would be particularly pleased because Lew has, in effect, really now come to his senses, and after a very distinguished career at Harvard has come back home, so to speak. He's now going to be a director of the Cancer Institute at Weill Cornell. So he has come back to Cornell.
Now, before we-- David Shalloway-- formally introduces Lew, I have one other addition to read. And that is next year, 2013, is going to be the centennial year of Ef's birth. And so to commemorate that, we're all very pleased to announce that in conjunction with Ef's daughter, Dr. Ann Costello, who is here with her husband, John, and her daughter, they're going to be developing a new website that will make past Racker lectures available online and will allow you to view the 78 art albums that were created by Ef from 1936 right up to immediately before his death in 1991.
Also, photographs and stories of life on the Cornell campus during Ef's time in Cornell will also be included. And we're really reaching out to those who might have copies of Racker paintings or stories or remembrances that they might want to share. For those who might and would be willing to contribute, you could contact any of the members of this organizing committee whose emails are on the pamphlets, I think, or on the posters that are outside the lecture hall. So with that, now David Shalloway will formally introduce this year's Racker lecturer.
DAVID SHALLOWAY: Well, up to a few weeks ago, Lew Cantley was the William Bosworth Castle chair in medicine and professor of systems biology at Harvard and the director of the Harvard Associated Beth Israel Deaconess Medical Center as chief of the Division of Signal Transduction, [? no more. ?] As Rick said, we're delighted and honored that two weeks ago, he moved to Cornell and became the director of the Weill Center, Weill Cornell Cancer Center in New York City.
He's one of the world's most preeminent scientists in both basic and clinical research and, as you heard, a Cornell University alumnus. So tonight's Racker lecture is just the beginning of a closer scientific relationship. Dr. Cantley graduated summa cum laude in 1971 with a bachelor of science degree in chemistry from West Virginia Wesleyan College and obtained a PhD in biophysical chemistry from Cornell in 1975.
He conducted post-doctoral research at Harvard from 1975 to '78, when he was appointed assistant professor of biochemistry and molecular biology there. He then went to Tufts in 1985 but returned to Harvard Medical School as a professor of cell biology in 1992. He has made some very important advances in cancer research, stemming from his discovery of the signaling pathway involving [? phosphoinositide ?] 3-kinase, PI 3-kinase, in the mid '80s, which explains a lot about the signal transduction of the growth of the cell that has major implications for cancer.
His pioneering research discovered that human cancers frequently have PI 3-kinase mutations. And for the past three decades, he has worked to identify new treatments for cancer that result from defects in the pathway. This discovery has led to promising avenues for the development of personalized cancer therapies and resulted in novel treatments for cancer, diabetes, and auotimmune diseases. He's quite interested, as you'll hear, in translational research. And his research is funded in part by the charity Stand Up to Cancer and has a strong clinical as well as a basic focus.
Dr. Cantley is a member of the American Academy of Arts and Sciences, the National Academy of Arts and Sciences, and has received many awards that you can read about in your program. What isn't mentioned there is that he was recently featured, along with three others, in a documentary Inspiring West Virginians. It aired on West Virginia Public Radio a couple of weeks ago, a tribute from his home state. We are delighted to have him with us tonight to speak on the future of cancer prevention and treatment, moving from discovery to implementation.
LEWIS CANTLEY: Thank you. Thank you, David. Let me just turn this [INAUDIBLE]. So it's a pleasure to be back here. Actually, I typically make it back to Cornell every two or three years. So it's not like it's been such a long time. But it certainly always brings back memories of the times when I was here.
And I want to start out. My lecture really as three parts to it. First, I want to start with a few little vingettes of my personal interactions with Ef Racker when I was a graduate student here. I was incredibly-- in many ways, he was a mentor to me. I worked for Gordon Hammes in the chemistry department. But my research was really an extension inspired by work that Ef Racker initiated. And I talked to him virtually every week in the time that I was here. And we became very close friends. And even long after I left, we continued to correspond very frequently.
This is a picture of Ef. And my guess is this was about almost the time that I arrived here that this picture was taken, either the late '60s or early '70s. That was probably in his office. Because I remember that I would go over to Wing Hall. My lab was-- Gordon Hammes' lab was in Baker. But I was working on the F1 ATPase, the enzyme that synthesized ATP from mitochondria.
And to purify that enzyme, I had to start out with about at least one beef heart full of-- one cow full of beef heart mitochondria. I had to isolate the protein in order to do the experiments. And Ef was kind enough to allow me to use the mitochondria that they had isolated in his laboratory to start my preparation.
So I would go over to Wing Hall with my ice bucket and spin down the mitochondrion and [? sonicate ?] them and start the first steps of the purification there. And while I was waiting for all that to happen, almost invariably, Ef, who was always in the laboratory, would bump into me. And as a young graduate student, he would pull me into his office and start talking to me about how is ATP really synthesized by this enzyme.
And it was very controversial at that time, 1971, as to how you could actually make ATP in mitochondria. In fact, it was not just controversial. It was really contentious. Because various people had very strong ideas about how it worked. But Ef had a very open mind about this. And he was considering all possible ways by which this could happen.
The chemiosmotic idea was becoming popular but not yet generally accepted and certainly not proven. And so we talked a lot about that. And I was incredibly impressed that as a first year graduate student, he would spend an hour in his laboratory, even though it didn't work for him, discussing these ideas with me while I was waiting for the centrifuge to finish [? pinning down ?] my enzyme preparation.
So those were very impressionable times in those early days. And I should say that about the fourth year of, I guess, well, three and a half years into my degree, Peter Mitchell, who ultimately received the Nobel Prize for discovery in the chemiosmotic idea of how proton gradient could be used to synthesize ATP, came to this at Cornell. He had, at that time, not received a Nobel Prize. And in fact, the definitive experiment to prove his idea had yet to be done.
And he visited. He, Ef Racker, brought him over to visit Gordon Hammes and myself. And I spent about an hour and a half presenting my thesis work to the two of them. So you can imagine. Here's Peter Mitchell. Here's Efraim Racker, Gordon Hammes, and then me presenting the slides of my nucleotide binding to the F1 ATPase.
And every single slide I would show, Peter Mitchell would say, that's consistent with the chemiosmotic hypothesis. And Ef Racker would say, but what about this possibility? And actually, I don't think I got seven words in in the entire hour and a half as the two of them argued over what my data meant. But that was the wealth of excitement there was and the level of contention and the level of importance thought about that work.
So in the end, of course, Ef Racker is the one who actually did the definitive experiment to prove that the chemiosmotic theory was correct. And once that is generally accepted among the community, Peter Mitchell got the Nobel Prize I think today, without any doubt, Ef Racker would have gotten the prize for what he contributed to that work. After all, he purified all the components and proved that that's how it worked. The idea that it was a proton gradient really came from Peter Mitchell.
So that was my exciting years as a graduate student. I'd like to think that I brought something to the theory. But in fact, if you go back and read my PhD work, it was actually pretty boring. In fact, Rick [INAUDIBLE] keeps explaining to me how he went back and looked through my notebooks and decided it was totally worthless and dumped it all in the waste basket. [LAUGHTER] As he followed up on my research.
SPEAKER: [INAUDIBLE] personal story.
LEWIS CANTLEY: I'm not supposed to tell you that. So but the other thing that impressed me about Ef Racker is that he was always-- he was an incredibly creative guy. But he was always coming up with very interesting quotes. And these were meant sometimes to be humorous. But there's always enough truth in them that's they really stuck with you.
And so in 1963, when the controversy about how you ATP in mitochondrion was at its peak, at one of the meetings on this, Ef Racker is famous for having said that, quoting Albert Einstein, that nature may be difficult. But she is never malicious. Ef Racker's response was, well, obviously Einstein never worked on oxidative phosphorylation.
And then follow-up on that is that anybody who is not thoroughly confused by oxidative phosphorylation just does not understand the situation. So that was the level of complexity of this. And I should say that as we try to teach this to biochemistry students, graduate students, undergraduate students, and medical students, as I sometimes do now, I think they still find that it's incredibly complicated and confusing. Now, I'll come back to these kinds of quotes again in a minute.
Another quote that really stuck in my mind-- and this was a quote I think I first heard from him when I came back to give a lecture at Cornell after I had become an assistant professor at Harvard-- and I remember joking with Ef before I gave my talk. I said, well, the last time I talked here, it was you and Peter Mitchell were in the audience and actually didn't get to say a single word during my talk. And Ef was very famous for interrupting the speaker periodically. What did you mean by this? Or what about this?
And so I gave my talk. And he didn't say a single thing through the entire talk. And at the end of the talk, I was offended that he hadn't interrupted me. I felt like maybe I hadn't said anything interesting at all to him. And I said, well, Ef, don't you have a question? And he said, well, you told me not to ask anything.
Of course, at that point, he then started chiming in. But one of the points that he was making-- I can't even remember what my talk was about-- but I must have mentioned something about organelles and how they were specialized for different functions. And he made the point that to solve the complexity of generating life, nature has taken the course recommended by Philip II. Some people claim that it was Julius Caesar who said this, divide and conquer.
And this is really what helps [? a cell ?] accomplishes this complex feat of dividing tasks-- so lipid synthesis, protein synthesis, nucleic acid synthesis-- into different compartments in order to solve the complexity of using sometimes the same components for different purposes. And this turned out to be really important. And to me, it was an insightful thought. I always wondered, well, what the hell are all those organelles there, anyway?
I should say, I've never had a biology course. I was trained entirely as a chemist. And so to me, to look at a cell with all this stuff in it was totally confusing. [? And what it was was ?] just a bag of enzymes. And so Ef Racker's comment about this got me thinking about, oh, OK, that makes sense.
So I then like to paraphrase some of Racker's quotes with regard to cancer. And Ef Racker was very interested in cancer and was very much persuaded by Otto Warburg, whom I will bring up in more detail in a moment, in his thoughts about cancer. But to paraphrase Ef Racker in the context of cancer, again, if you consider Albert Einstein's comments about nature being difficult but not malicious, my response to that would be, obviously Einstein did not work on cancer. Cancer is a malicious disease, without any doubt.
And I should also say that, again to paraphrase another one of Racker's comments, that anyone who thinks we will cure all cancers-- in other words, anyone who thinks that cancer is not complicated and that we'll cure it all in the next 10 years as we continue. So I think every 10 years, somebody states, we're going to cure cancer in the next 10 years. Anyone who thinks that doesn't really understand the disease. It's an incredibly complicated disease.
And then finally, I would say that to have an impact on cancer, we must take a lesson from nature and divide and conquer. So this idea of dividing and conquer really is a theme of what I'll be talking about tonight with regard to cancer. We have to divide and conquer cancer to conquer cancer.
So I'm going to give a very brief history, a modern history of cancer. I'm not going to go into the detailed history of how cancer was initially found in the ancient times. But if you are interested in a very detailed and very old, going all the way back to ancient times, about how cancer has been observed and treated over the years and the modern breakthroughs in it, there's a really very nice book by Sid Mukherjee, who actually worked with one of my trainees when he was a fellow in the Harvard system. And it's called The Emperor of All Maladies and won the Pulitzer Prize-- extremely well-written and a very accurate history of cancer for those of you who want, who after hearing me talk [INAUDIBLE] things tonight, want to read in more detail.
But I want to start just 90 years ago, really, or a hundred years ago, to one of the first breakthroughs with our understanding cancer at a molecular level. And that came from work of a fellow named Peyton Rous. And what's interesting about Peyton Rous to me, one of the things that's interesting, is that the temporary office I currently have at [INAUDIBLE] Cornell looks straight onto the building where he worked and made the discovery that I'm about to tell you about.
So he was at the Rockefeller. And he made the observation that chickens come down with cancers. And that there was something infectious about the cancer that they got, in that you could extract particles from that cancer and give them to another chicken. And that chicken would come down with cancer, too.
And he ultimately purified that component that was transmitting the cancer from chicken to the next and concluded that it was a virus. And so this had a major impact in the early part of the 20th century in our thoughts about cancer. So as Peyton Rous was saying, cancer is a transmissible disease. I should say ultimately, Peyton Rous got the Nobel Prize for this discovery, but not until 1966. And as I tell a little bit more history, you'll see why it took so much later before he was acknowledged for having an impact in the field.
And in fact, the reason that his discovery did not have a bigger impact or that the impact was rather felt to be short-lived, is that as people looked at human cancers and looked for transmissible agents, they found that it was extremely rare that you could find-- it wasn't possible. We know there are viruses like papilloma virus. Even HIV can predispose you to cancer. So there are cancers that clearly are affected by viruses, leukemia. But they're extremely rare.
So the general concept that all cancers are caused by viruses was clearly not true. And since cancer was really thought it was a single disease, if you found a single exception to its cause, you would conclude that, therefore, that is an epiphenomenon is not related to cancer. It's not a [INAUDIBLE] [? agent. ?]
So his ideas didn't really have much traction in the middle part of the 20th century. Instead, another scientist [? who ?] really rose to prominence in the cancer field. And this is a fellow named Otto Warburg. And Warburg was a classic German biochemist and in the day when the German biochemists really ruled the world.
In 1924, he was looking into the biochemistry metabolism in cancers. And he took out a tumor, tumors from various animals, and compared the metabolism in the tumor to the metabolism of the normal tissue from which the tumor rose. And he was particularly interested in glucose metabolism. So what happens to sugar when it goes into the tumor versus it goes into the normal tissue?
And he found that most of the sugar that went into the normal tissue was metabolized in an oxidative way. In other words, oxygen was being consumed. He took the glucose away. Oxygen consumption went down. You added glucose, oxygen consumption went up. And the glucose got converted to carbon dioxide. That's the way most normal tissues did.
But when he did this with a tumor, he found that most of the glucose-- first of all, the tumor was eating glucose about 20 to 50-fold faster than the normal tissue. And secondly, it wasn't burning it. It wasn't converting it to carbon dioxide the way that normal tissue. It was what he called fermenting it, much like what yeasts do to convert sugar into alcohol.
The tumor was converting the sugar into lactate. And that wasn't consuming any oxygen. And this was a process which ultimately became called glycolysis that did not involve burning, but rather converting the chemical energy of glucose into the chemical energy of ATP.
And so what we later learned about this process is that it's incredibly inefficient way to make ATP. And it became a rather mystery of why the cancer should have such a very inefficient way to make ATP. But this observation held up very strongly throughout the 20th century. Almost every cancer that one looked at had this phenotype, this so-called became known as the Warburg effect of eating glucose at a very high rate but not burning it but rather converting it to ATP and spitting out lactate.
Now ultimately, Warburg got the Nobel prizes as well. In fact, he got it before Peyton Rous did-- not for this discovery but for other work that he did in metabolism. But he was convinced throughout his career that the secret to understanding cancer was to understand this shift from oxidative phosphorylation to glycolysis.
Now, the reason I tell you this story in some detail is because Ef Racker was really the person who figured out oxidative phosphorylation, purified the whole components. And he, throughout his career as he was trying to understand how ATP was made by this process, was continually intrigued by why cancers don't do this efficient mechanism for ATP production, but rather do glycolysis. And so many of my discussions with Ef Racker as a graduate student really centered around this question, why is this happening? And as many of you know, he thought about this throughout his career.
So then let's speed forward to more modern times. And I called them modern times. 1971 is really modern times, because that's when I started as a graduate student. And so some of you may think this is actually ancient history, 1971. But to me, it sounds like yesterday.
So in 1971, Richard Nixon declared war on cancer. And I think at some point in that announcement, he expected, stated that we would cure cancer in 10 years. Almost everyone who has ever had a prominent position in cancer at the NCI has at some point said we would cure cancer in 10 years. Obviously, it didn't happen. And I'm not going to say it tonight, either.
But the war on cancer was declared. And at the time the war on cancer was declared, Peyton Rous had come back into favor again. He'd just gotten a Nobel Prize because in the '50s and later in the '60s, more and more viruses were being found in mice and chickens that cause cancer, like the Rous sarcoma virus. And so at the time that Nixon declared war on cancer, there was a much greater enthusiasm for embracing these viruses.
DNA had been discovered. RNA had been discovered. And the viruses clearly were primarily DNA and RNA. So we felt, well, we can figure out with DNA and RNA does. So let's focus on how DNA and RNA imported into cells cause cancer.
And so that's-- a lot of the early funding at NCI really went into this area. And it was a useful time to do it. And it made a major breakthrough. And then in 1976, Mike Bishop and Harold Varmus at the UCSF at that time discovered working with [? Aton ?] [? Rous ?] sarcoma virus circovirus that the mechanism by which that virus was causing tumors in chickens was that it had picked up endogenous chicken gene.
The virus infected the chicken, reverse transcribed a messenger RNA from one of the genes that the chicken normally makes, which ultimately was called the sarc gene. But in the process of reverse transcribing it, it mutated it. And that mutation made it much more active than the wild type gene. And that activity ultimately explained why the virus caused the cancer. David Shalloway has spent much of his career trying to understand how the normal sarc gene really does cause cancer and how it's regulated.
So that discovery was enormous. Because it told us that you could mutate the normal human gene, or at least a normal chicken gene-- we assume something similar could happen in humans-- and turn it into what they then called an oncogene, a cancer gene. Now, yet there was still some reluctance to believe that this was generally going to be relative to cancer. Because again, most cases were not caused by viruses.
But in 1982, Bob Weinberg, who was a former Racker lecturer here-- and so those of you who've been attending these every year have already heard this story-- made the discovery that you can get the same kind of oncogenic mutations by sporadic mutational events that can caused by mutagens, reactive oxygen species, radiation. UV light can mutate genes. And you can end up with exactly the same mutation sporadically that the virus induces when it infects.
And that was first observed in regard to a gene called [? ras ?] that caused tumors in mice. And so at that time, by the mid-1980s with Weinberg's discovery and Bishop and Varmus, it was generally accepted that cancer really was a mutagenic disease. And the question then was, well,what do these oncogenes do? And so by this time, I was actually even an associate professor by that time and was very excited by moving my lab into trying to understand what these oncogenes.
Now, I'll rush to the future and tell you that now that we can sequence genes at a very high rate-- it costs about $10,000 now to sequence an entire genome of a tumor, and there are thousands of tumors now being sequenced. And within a year, it will only cost about $1,000 to do it. And so 10 years from now, everyone will wonder, well, why didn't you sequence? You went to the doctor? Yes. Why didn't you sequence your genome? It only costs $50. So this is going to be a very routine process.
But what we've already from sequencing a few thousand tumors is that there are only about-- the good news is that there are only about 100 or so, maybe 150 at most, genes whose mutations are driving cancers. That's good. That's good news. Because we have more that 20,000, 22,000 genes in our body, but we only have to worry about 150 to 200. And in fact, most of the cancers that we look at are really confined to mutations in only about a few dozen genes. But let's say roughly 100 genes we have to worry about on the average as being responsible for the majority of cancers that we run into.
So that's the good news. Now, the other good news is that mutating a single gene is, at least in humans, is almost certainly not enough to cause a cancer. You have to have several mutational events, or we now know, sometimes epigenetic events, before the cancer can emerge.
And so that's good news as well. Because that says that these are relatively infrequent events. And to have three of them happen in the same cell is going to be rare. And that's why we can live to be 60, 70 years old before we're likely to get cancers. So that's the good news.
The bad news is the same math kind of works against us. Because if you really do have to have at least three genes, three to five genes, and any of these roughly 100 genes can mutate to form cancer, can occur almost in any random order and still result in a cancer. And as we're sequencing more and more, we see that things tend to be fairly random in the set of genes that get mutated.
Then if you do the math on this, then the number of different types of cancers likely to exist are roughly 100 times 99 times 99 instead of one, two, three in any order. And that comes out to a million. So you know, a rough estimate it that there are a million different cancers.
Now, most clinicians say there are about 20 different cancers. They're calling cancers based on the tissue from which they emerged. Actually, if you look at the more rare ones, there may be as many as 50, but not a million.
And so this is actually rather scary. It says that no two people who have breast cancer probably have exactly the same disease. And so if we really start going to the molecular level to define our cancers, we're going to find that they're really breaking down into many, many, many subsets. So that could be a problem.
So the next issue that came up-- and this was, of course, very central back in the '70s and '80s as these oncogenes are being discovered, is what do these cancer genes do? A lot of them turned out to be kinases. Some of them turned out to be transcription factors. They were in signaling networks-- so-called signaling networks. Nobody knows what that means. That means that they're talking to each other in some complex wiring diagram.
But the real question is what do they do to cause the cancer? And as only in the last 10 years or so have we really begun to figure out what the downstream events are that are critical that these oncogenes control that convert a normal cell into a cancer cell. And for the most part, most of these events turn out to be changing the metabolism in the cell.
So what we've discovered is after 90 years of research, is we've come full circle. And we've finally come back to Otto Warburg again, that what all these oncogenes do is shift the metabolism to a different state. And so it seems a little frustrating that we made it back to 1924 after all this work. But I think we have learned a lot along the pathway.
Because we now understand a lot about the wiring mechanism by which these oncogenic mutations switch metabolism so that cells that are normally designed to be static and only grow if there's an injury will now grow continuously as though they had an injury continuously. So these oncogenic mutations tend to shift the metabolism into doing growth patterns, using glucose amino acids to make DNA, RNA, proteins, and liquids in order for a cell to grow and divide, rather than just making ATP in order to keep the cell alive. So that's the major thing these oncogenes are doing.
So the question then is if there's a million different ways, mutations that could potentially do this, how do we figure out how to conduct therapies? How can we reduce this to a simple enough problem that we can attack it? So for those of you who are not scientists in the audience, this slide is totally meaningless. It looks like a wiring diagram, something you would see in the manual to your refrigerator that explains how the fan and the compressor all work and where the resistors and capacitors are.
And in some ways, this wiring diagram kind of works like the wiring diagram for your refrigerator. But in the end, at the very bottom, you'll see protein synthesis, glycolysis, and in fact, metabolism in general being regulated by this network. This is a network that my lab has worked on one for more than 20 years, PI 3-kinase which David Shalloway introduced in my introduction, the enzyme that we discovered back in-- it's called PI 3-K here-- that we identified back in the late 1980s, is central in this pathway.
And it's regulated by a host of different receptors, molecules on the surface of the cell that respond to growth factors, things even like insulin or insulin-like growth factor, factors that come in to tell a cell to repair itself if there's an injury in the tissue. And so it is one of the components of the signaling network. We discovered it because it was associated with a number of viral oncogenes. In fact, it itself turns out to be a virally-encoded oncogene.
Ras, the gene that Bob Weinberg discovered, is mutated in human cancers but is also picked up by viruses, it also in this component. In fact, ras and PI 3-K directly touch each other and are involved in regulation in that way. You notice that ras is much smaller than PI 3-K in this pathway, just to tell you the relative importance of those two genes.
So you may recognize some other genes, raf. And some of you may have heard of BRAF, the gene that is most frequently mutated in melanoma. There's a lot of excitement about drugs that target this. So what we and others have worked on in many years is trying to figure out how all of these various oncogenes, including the-- everything in red here, I should say, is an oxygene that many of which were picked up initially in viruses that are sporadically mutated or amplified in human disease and how they all interact with each other, to communicate signals that ultimate regulate metabolism, including this increasing glycolysis that Otto Warburg described in 1924.
So we're finally getting to understand why this is happening in a disease. I should say, everything in blue is a tumor suppressor gene. And that means that if you lose these genes, you get cancer. If you gain function in these genes, you get cancer. So it's a very complex array. But we're beginning to make sense of how it all fits together.
Now that tells us, once we understand the wiring diagram, we don't necessarily have to have a different drug for every single mutation, because we can focus on key nodes that all come together. Maybe we only need a few dozen therapies. We don't need a million therapies if we can understand the wiring diagram. So that's the hope. And that's how we hope-- that's how we think that we'll ultimately make progress in cancer, is by understanding the wiring diagram and attacking it logically.
The one thing I should caution about these wiring diagrams is that you notice a lot of redundancies. This pathway circles back to here. This pathway circles back to here. And so you can imagine that you shut off this branch, you may not block the cancer, because the other branch can accomplish the same things. So these redundancies make single agent drugs not necessarily effective. And so we have to understand the wiring diagram to figure out how to use drug combinations to treat cancers.
An illustration of the Warburg effect is actually shown here in a mouse, in which we introduced the PI 3-K gene. We introduced actually a mutant form of the PI 3-K gene, using a mutation that is very frequently found in human breast cancer and to some extent also in lung cancer. And so putting the human mutated gene into the mouse lung alveolar tissue and turning it on in a drug-dependent manner, we found that after about three months of this gene being on, the mouse developed the cancer.
Now, this cancer-- this gene alone is not enough to cause the cancer. But During That three month period of time, additional events happened. Other mutations that we don't yet understand occurred that allowed the cancer to occur in a single cell. Even though every single cell in the lung had this gene in it, only one of them ultimately became a cancer. Because it acquired the additional mutations necessary to transform.
But what we learned was that this cancer was still addicted to that particular oncogene, because we could turn the gene back off and the cancer would go away. Or we could add a drug that inhibited the activity of PI 3-K and the cancer would go away. But the first thing we noticed was that the cancer, first of all, takes up the glucose at an incredibly high rate. This is what Warburg observed in his rats back 80 years ago, 85 years ago.
And we see the same thing when we put PI 3-K into the tumor. It drives glucose uptake. And we can see it as using a radioactive form of glucose, a fluorodeoxyglucose. Some of you may know relatives or friends who have actually had this radioactive molecule injected into their bloodstream in order to visualize their cancer. Our doctors still today use the Warburg as way to figure out where your cancer is in your body. Because it's taking up glucose so much more than surrounding normal tissue.
You turn off this enzyme. And within 48 hours, the glucose uptake goes away. So this cancer is eating glucose at a very high rate because it has it has a mutated PI 3-K. You turn PI 3-K off, the glucose uptake goes away, by three days the tumor-- four days, the tumor is massively reduced. By three weeks, the tumor has gone away. So in this simple model, we can actually cure this mouse by reversing the functions of the PI 3-K.
Can we accomplish this in humans? The first evidence that we can do really came from a drug called Herceptin, which some of you may have heard of, very frequently used in breast cancer. It's used for a very specific subset of breast cancer called the HER2-positive breast cancers.
And it went into clinical trials from Genentech in the 1990s because of the observation that HER2, which is a tyrosine kinase in one of these receptor types at the top. It's right here. So it's an activator of PI 3-kinase. And you can-- since it's on the cell surface, an antibody will attack it. And so Gentech developed an antibody that attacked this tyrosine kinase.
They put it into clinical trials. And it got approved. Relatively minor effect, like three-months life extension in end-stage disease. But that got it approved.
Once it went into adjuvant therapy and following it up in the next 10 years, we've noticed about a 70% to 80% reduction in recurrence of this disease if you take this monoclonal antibody after surgery. And so this is not that effective in curing the disease once it's in the metastatic stage. But preventing the metastasis from occurring by treatment after surgery has been remarkable with this drug-- saved many, many lives.
We can say these have been cures. They been cures by preventing relapse, not at the end-stage disease level. But that's exciting.
A second very strong excitement that came slightly after that was a drug called Gleevec, which is another tyrosine kinase inhibitor. And this attacked a drug, a target called [? ABL-- ?] actually [? BCR-ABL-- ?] that was molecularly defined as a translocation back in the 1960s, the so-called Philadelphia chromosome translocation-- it was observed in a microscope-- that ultimately later was found to be an activation of an oncogene called ABL.
This drug attacks the ABL enzyme. And it went into phase one clinical trials back in the late 1990s. And what was found in the phase one trial is that every single patient who took the drug, their disease disappeared-- virtually every one. So typically, to get a drug approved, even in the case of Herceptin, you're talking about a 5,000, 10,000 patient, five, six, seven year trial to try to see a three-month life extension.
This drug, by the time 50 people had taken it, everybody responded. It was unethical not to give everybody the drug. So it was approved in a remarkably short period of time. And I know people who've been on this drug for 10-- more than 10 years that still have not had a recurrence.
It's not yet a cure, though. You take the drug away and the disease comes back. And some people have become resistant to it.
But these two examples inspired pharmaceutical companies to go down this route of scientifically approaching cancers based on what's going on in the mutations because of these two early successes. And we now have a number of targeted therapies, including a therapy that attacks the EGF receptor, another one of these tyrosine kinases on the surface of the cell, very much like HER2.
And this is really good lesson for us to learn with regard to clinical trials. So this drug, much like Herceptin attacking HER2, this drug was attacking-- [INAUDIBLE] molecule was attacking the EGF receptor. It went into-- the first drug was a drug called Gefitnib-- went into a large phase three clinical trial. And this is roughly what the trial looked like. I made up this data, I should say. But it's roughly what the trial looked like.
And the red line is the drug-- the patients who were treated with the drug. And the blue line is a placebo. Now, the FDA decides whether to approve the drug as to what the difference is for the 50% survival rate is how many years that is or how many months that is. So in the case of Herceptin, that was about three months. And that was enough to get it approved. This was about two months, not enough to get it approved.
But what the doctors recognized was that there were these subgroup of patients, about 5% to 7% of patients in the trial, who had miraculous responses. They at end-stage disease. They were on oxygen. They couldn't even walk. They took the drug. And a week later, they're waking around without oxygen. And three months later, they're out jogging. That had never been seen in lung cancer before.
But they couldn't understand, why is it only 5%? And why is, on average, not much going on at all? It turned out that these 5% or so all turned out to have mutations in the gene. They were giving the drug to everyone, whether or not they had a mutation. Because they didn't even know mutations existed in this gene.
And clearly, the majority of people did not respond at all. But a subset did. So that still didn't get the drug approved. They had to go back and do a second trial. And the second trial looked more like this.
They now selected patients that had the mutation. And now you see a year or two differential between the placebo and the drug treatment. Now-- and of course, ultimately, this drug was approved.
So this tells you the difference between doing blind therapies the way we've been doing them for the last 30 years, which is large placebo control in unselected patients, 10,000, five or six years. And then you unblind it at the end. And you discover maybe a three-month life extension, maybe nothing, and actually selecting patients that you know are going to respond. And everybody responds. And after 50 patients, you have the drug approved.
Obviously, we want to do the latter, not the former. But surprisingly, still a majority of clinical trials are done today like this, not like that. That's what we have to change. And that's what I'm excited about. And that's the reason I took the job at Weill Cornell, because I think we can put into place the infrastructure there to ensure that all the trials that we do, at least at Weill Cornell, fall into this latter category.
How much time do I have left? 10 minutes-- OK, so I'm going to very briefly then tell you about-- David mentioned in my introduction that I received this $15 million grant from Stand Up to Cancer. This is a group of Hollywood producers and ad agency executives who wanted to implement an organization analogous sort of to the [? age ?] activists, where they would accelerate drug combinations and treatments for cancer to get things into the clinic much faster and get them approved much faster.
And so I put together a team. And we applied for this money and got $15 million. Now, the team that we put together-- $15 million sounds like a lot of money. But actually, we have 65 people on our team in seven institutions. And by the time you divide that up, it's not a lot of money. But per person, it's clearly not a lot of money.
But because it held us together as a team-- and this team includes surgeons, oncologists, molecular pathologists who know how to look for these mutations. Obviously, we need the surgeons and the oncologists to enroll the patients. And to help to design the trial, we have clinical trial experts. We have people who are experts in the pathway that I told you about and people who are experts in-- excuse me-- and people who are experts in mouse models for these cancers.
And so we all got together and worked as a team to figure out which drugs are most likely to work and particularly how to find the drug combinations we combine with PI 3-kinase inhibitors that could be useful in treating cancers. And the reason we focused on PI 3-kinase is not just because of that's the discovery of my laboratory, but rather, because we were discovering that in women's cancers by far, PI 3-kinase mutated much more frequently than any other gene-- far more frequently than HER2, for example.
And so how might we figure out how to develop drugs that we had [INAUDIBLE]? We also have patient advocates. In fact, some of our patient advocates are also experts in clinical trial design and nurses who've worked in cancer clinical trials.
So was the pathway we really wanted to target. We wanted to figure out how to target multiple nodes in the pathway to have a better effect than a single agent drug would likely have. Because these single agent drugs, even the EGF receptor inhibitor and the ABL inhibitor and the BRAF, inhibitors which were recently approved. These don't cure people. They extend life. They definitely extend quality of life. But ultimately, the tumor comes back.
So how do you figure out how to prevent the tumors from coming back? One of the things we did up front was just assess, what is the frequency of mutations in those nodes in that network that I showed you in women's cancer. So we looked at all the tumors that we could get sequence from, from all the seven institutions, and added up all of our numbers and asked, what's the frequency of PI 3-K mutations?
You can see it in bold there-- you may not be able to see back there-- but everything in bold, it means at least 20% of the cancers have that particular gene mutated. PI 3-kinase is clearly the champion here. A third of ER-positive breast cancers have this. 25% of HER2-positive breast cancers have [? PIC3C ?] mutations. And other, you can see very frequently, other events in this network.
Now, pharmaceutical companies have already begun to develop inhibitors of every node in this pathway. Every that they can figure a way to drug, they were putting drugs in the clinical. There are 23 PI 3-kinase inhibitors currently in clinical trials.
They're also [? ATT ?] inhibitors. So you look at almost every node in this pathway-- and I left off all the drugs that hit this pathway, the BRAF inhibitors and MEK inhibitors, et cetera. And of course, there are all the tyrosine kinase inhibitors, many of which have already been approved. So we have really a plethora of drugs to choose from. But if we randomly chosen every possible combination, we wouldn't have enough patients on Earth to do all the trials you would need to do to get these drugs approved.
So there has to be a scientific logic to decide which is the better combination to use. How do we arrive at the logic? That was the task that I assigned our team to figure out. What are the best drug combinations to use based on the mutational events that are going on in particular patient?
Now, we had some early data on single-agent trials with PI 3-K inhibitors. This is a drug that has a lot of promise. It's in still early-- it's about to go into phase two trials, a drug from Novartis. And this is what's called a waterfall plot. Each one of these bars represents a patient that-- some of these are breast, some are colorectal, head and neck, or other cancers.
And everything below the line here means that the tumor is shrinking while on the drug. And everything above the line means the tumor is growing on the patients on the drug. And you can see that about half the patients who went on this drug had some responses. And half continued to progress. And there was some who [? had what's ?] called progression-free disease.
Clinically, to call it a true response, it has to be below the dotted line here, more than a 30% reduction in tumor size. There were a few of those occurring. The question was, what's different about this group of patients from this group? Why did they respond? And why did they not?
We had to figure that out so that we can select for a trial, only put patients like this on it and it would be approved very rapidly. But if we ended up diluting with patients like this, first of all, we would do the patients no good. You don't want a patient on a trial if you know they're not going to respond. So we have to get these patients on this trial on to some trial that's going to work for them.
So that was our task. And I won't go into great detail about how we approached this. But basically, it required a lot of work to figure out what you can actually do in a clinical setting, getting so-called CLIA-approved biomarker analyses. We're on a short half time. You know, they gave us only three years to cure cancer. I told you we needed 10.
They gave us three, actually, they just gave us a fourth year. We're just going into our fourth year. We haven't yet cured cancer. But we definitely think we've made progress in figuring out what trials to do and what combinations to use.
And so one of the techniques that's really been extremely powerful in this is to engineer mouse models that have exactly the same mutations we see in our human patients. So we have mice that have PIK3CA mutations in the breast that also have HER2 mutations in the breast or HER2 amplifications in the breast and the various other events that you saw on that graph.
We just recreated mice that have those same events. And then we asked, how did those various mice respond to single-agent drugs or combinations of drugs that nodes in that pathway. And once we found combinations that worked in that in vivo setting, we would then set up a trial. And then we continue with the mouse work in parallel with the human disease so that our mice are really slightly ahead in our human clinical trials in telling us what we expect to see next in our patients and how we can anticipate and prevent a resistance from occurring.
And that's-- I just want to end with one very last comment. Because I had in my title, how might we also prevent cancer [INAUDIBLE]. Everything I've talked about today is when once have a cancer, how do you treat it? And how do you prevent it from coming back as a metastasis after surgery?
But in fact, our greatest chance of curing cancer or preventing is to prevent it. If you can prevent the cancer from ever appearing, obviously, you can save a huge amount of money, a huge amount of agony, and obviously prevent deaths. The danger is that right now-- I should say that we've had progress in reducing cancer rates in some areas, because of mainly just by reducing smoking.
You know, 30 years ago, if we were sitting in this room, half the people would be smoking during my lecture. And there's be a huge cloud here. And you would only barely be able to see the slides. I don't see anybody smoking here this morning. It's amazing. The smokers are all outside, I hope.
So that's kind had a big impact on lung cancer and other cancers as well. But the scary thing is that as we're reducing smoking, we're also increasing rates of obesity. There are dramatic increases in rates of obesity, particularly in the red states. Don't why they're red states. But that seems to be a perfect correlation with obesity.
And that's leading to diabetes, and surprisingly, because no one was really anticipating this, a dramatic increase in cancer. There's a strong correlation. So why is that true? And it turns out, we think-- this, again, is a hypothesis. And I'll just end with this idea-- that the reason comes back to PI 3-kinase again.
So we discovered PI 3-kinase because of its implication in cancer. But as we began to study it, we realized that PI 3-kinase is actually what mediates everything insulin does. And as a consequence, even if you have too much PI 3-kinase activity, you can get-- in epithelial cells-- you can get cancers. That's what I was just telling you about.
However, if you have too low a PI 3-kinase activity, particularly in liver, muscle, and fat tissue, you get diabetes. You first get insulin resistance. And ultimately, you get diabetes. So it's a failure of insulin to be able to activate PI 3-kinase that causes diabetes. And this is caused by lack of exercise, by overeating. And there's also a genetic predisposition to it.
So the two of the two major diseases we worry about right now both PI 3-kinase-- in one case, too, much of it, in the other case, too little of it. And the surprising thing is the two are linked. And we think the link is that as you go from obesity to insulin resistance-- and I don't have time to get in detail as to why overeating can cause insulin resistance, but we know that it does-- at that stage, insulin levels become very high in your serum.
And insulin is the best possible way to activate PI 3-kinase. And what we're discovering is that a lot of the cancers, particularly these cancers in breast, endometrial-- a lot of the cancer that we're studying in our dream team-- have insulin receptors on the surface of the cancer. So that period of time of insulin resistance, where your body is making 100 times more insulin than it should be making, is driving the growth of those cancers. That's the best way to make them grow.
Now, by the time you get type II diabetes, the ability to make insulin begins to drop. Because the islet cells begin to poop out and can't quite keep up with the demand. But the dangerous time is this period of insulin resistance. So we think that to get to the model, that this insulin resistance, raising serum insulin levels, is driving these micro tumors into growing at a very high rate. And this is what;s predisposing obesity to cancer.
And the question is, how can we prevent this from happening? Obviously, the best way is to get people to eat less and do exercise so that their insulin levels will come down. Tell them, don't eat rapid-release carbohydrates. The best way to raise your insulin level is to drink Coca-Cola that has sugar in it. Your insulin is going to up a hundred fold in the next hour.
If you have a cancer there that has insulin receptors on it, I would be pretty worried about that. So lowering the intake of rapid-release carbohydrate, keeping insulin levels from fluctuating so high, that we think is going to be really important in preventing these types of cancers.
Now, I'll just finish by saying that once you have insulin resistance-- actually, insulin resistance typically is a silent disease. It's often not treated at all. You don't even know you have it. It's not until you get type II diabetes that the doctor tends do something about it.
And the doctor has several choices. In some cases, it can inject you with insulin. You know, if you can't make enough insulin to keep your glucose level down, then you're going to have to be injected with it. But you're going to be injected with very high levels of insulin if you're insulin resistant in order to bring the tumor back-- I mean, to bring the glucose levels back down. So as a consequence, insulin injection obviously raises insulin as it controls glucose.
The endocrinologist isn't worried about that. I am worried about it. And I think a lot of oncologists are beginning to worry about it. But the endocrinologists typically don't think about this. Their job is to get the glucose down.
Now, there are other ways to control this. There are agents that stimulate insulin released from the islet cell. They also raise insulin levels. They break glucose down. So to the endocrinologist, they've accomplished their feat.
There are other approaches, like metformin, where you can bring insulin down by suppressing gluconeogenesis. In that case, you're bringing both insulin and glucose down. Sounds like a better way to do it.
And there are also PPAR gamma effectors that can perhaps accomplish this same event. So although the endocrinologist might consider all of these equally valuable therapies, in fact, we would argue that this is the preferable approach to take over this one if you have the option and can make it happen. Obviously, the best approach is to do exercise and reduce carbohydrate intake. But if you have to be medicated, let's think about what you take.
Now, that raises a question is whether metformin, the drug that suppresses insulin levels and glucose, might be one of our best therapies. And it turns out that a number of retrospective studies done in independent countries, independent investigators, have all arrived at the conclusion that the subset of type II diabetics who take metformin have a 25% to 30% reduction in cancer deaths compared to those who take other therapies.
And so this actually raises a questions whether metformin is actually the best cancer drug currently on the market. It has probably saved more lives than any other cancer drug. Now the question is, is this really working by the mechanism that we're proposing. Or are there other alternative explanations for this?
I don't have time to get into it. But I think it's-- as a consequence of these observations, there are more than 100 prospective trials now going on in which metformin is being given to patients who are not diabetic in order to see whether it reduces their cancer rates. So with that, I'll finish and glad to take questions if we have the time left. Thank you very much.
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Leading cancer researcher Dr. Lewis Cantley, director of the newly established Cancer Center at Weill Cornell Medical College and NewYork-Presbyterian Hospital, delivers the annual Racker Lecture, November 15, 2012.
Cantley is credited with the discovery and study of the enzyme PI-3-kinase, now known to be fundamental to understanding cancer.