 So, to round out our series of didactic lectures, we've asked Dr. Eric Yonash to bring his crystal ball and to tell us what the future holds for the treatment of patients with kidney cancer. Thank you very much and thanks for coming today. What I want to do is I want to talk a little bit from a little bit of a standpoint of what do we know but also trying to put myself in the shoes of a patient who's getting on to perhaps one of the websites to look at the clinical trials that are there and sort of think about this in terms of what are the doctors thinking and how are they actually coming up with these treatments. I'm going to use kidney cancer, RCC and renal cell carcinoma interchangeably in this talk with regards to and it's all going to be talking about kidney renal cell carcinoma. I'm going to specify some of the subsets of renal cell carcinoma with regards to whether it's clear cell or non-clear cell as I move forward. So late last night I got on to clinicaltrials.gov and I'm not sure how many of you actually have gotten on to this website and I typed in renal cell carcinoma and I found 1,394 studies which is pretty daunting even for somebody who does this for a living and then I used some of the filters and I got down to 332 quote unquote interventional studies which would be studies that would probably be something that the doctors are doing something about and the question I asked myself is in terms of what we and my peers around the country and around the world are doing what are the new approaches that we can see are being currently tested and based on my knowledge what are the promising new avenues in the treatment of kidney cancer. So I did this analysis and I looked at all the drugs that are being tested and here's the laundry list of agents and again I looked at this and I have to admit I have to look up a couple of these and now organized it into various different categories of things that are being tested in 2015 for RCC and these include angiogenesis inhibitors or blood vessel starving therapies very similar to the ones that have been approved that Dr. Tenir eloquently described. There are tumor cells signaling modulators things that are kind of getting inside the tumor cell itself to change the way it behaves. There are what I would call Trojan horse therapies taking advantage of receptors or proteins that are uniquely found on the surface of kidney cancer cells that allow us to deliver some sort of lethal payload. There are the old fashioned DNA damaging agents that's old fashioned chemotherapy stuff fair number of immunotherapies and then something called epigenetic modulator which we're not really going to be able to get into today. So quite a few different things. What are these drugs all trying to do predominantly point number one is what we've been most successful at is blocking angiogenesis point number two the new up and coming and exciting things that Dr. Gao nicely outlined are these immune system modulators number three are ways to actually say this is how a cancer cell is different from other cells can we actually target it that way number four is breaking DNA and again this is a really old fashioned thing but probably in three or four years from now and we talk again number four is probably going to get kind of exciting again and then number five is targeting unique aspects of the cancer metabolism because they don't use fuels the same way that that normal cells do in some cases and that's another thing we can do. So what I'm going to do now is I'm going to sort of take us on a tour of why does renal cell carcinoma happen what are these sort of initiating events what are the things that make them evolve into the things that they are and what are a couple of the things that are being done now to try to treat it. So coming up with a cure for kidney cancer requires peeling back of the onion there's many many layers and the more all of us who do this for a living are doing this the more we sort of think hey we know something and then you realize that there's another layer of complexity and that layer of complexity is really important because the the law of cause and effect when you do one thing and you think it's going to do another if there's a whole bunch of other things are going to happen afterwards that you're not aware of you might end up actually being further back than you thought. So we need to identify the driver genes and this is this idea that we've that Dr. Taneer talked about saying if we can do a biopsy we can look at the genetic mutations and that will then be able to maybe give us some sort of way of targeting drugs against those mutations. The problem is we have to understand how do those mutations affect the proteins that they generate and we need functional understanding. The next thing we need to do is we need to understand how do those proteins that are mutated and not working properly interact with other ones because in isolation we might again be doing one thing that's going to do the opposite. And then we have to be able to test this in what we call model systems. Obviously the ultimate test of any treatment is to do this in patients and that's what we do when we're pretty confident but ideally we'd have something where it could take a step back and we would either have an animal system or something that could allow us to basically do a test drive of these things before we try them in patients that would be ideal. And in 2015 those model systems really are not that well developed. So what are we made of? How do we actually come about? Chromosomes. So here's 23 chromosomes or 46 in total because they're paired and actually one little neat thing is how are they numbered? How do chromosomes get numbered? Because number one was the biggest one and 22 was the smallest so that's why you know 1 through 22 so you actually don't need to be an expert on chromosome biology to know which chromosome number you are if you're looking at the others. So kind of interesting in it. We've got the XY chromosomes here at the end. So in the chromosomes we have a variety of different genes. So you'll have one allele, one of the genes and one chromosome and the same and we have pairs of these genes. And these genes then express these proteins and the reason we have two copies is so that in case one gets broken the other one will kind of work. Well sometimes you'll get a mutation and you'll have one of these proteins or genes that gets messed up and that's obviously bad. Then you might have the second one that's broken and that's going to be really bad and you're going to have loss of that particular protein in the cell or function of that cell and depending on how critical it is that could have some major consequences. In clear cell, renal cell carcinoma the consequences of loss of the VHL gene are pretty significant. This seems to be the truncle, the sort of the original problem that gives rise to clear cell kidney cancer. And this is a depiction, the red is the depiction of the VHL protein and it associates with other proteins to create a complex and it does something which is it blocks HIF, hypoxia-disable factor. And HIF is a factor that then goes and tells the cell to produce blood vessels. Clear cell renal cell carcinoma as I mentioned has mutations in VHL. So what does VHL do exactly? So here we have a cell that has low oxygen level. What's going to happen then is you're going to have VHL is basically going to stand back and HIF is going to be able to combine and it's going to be able to tell the nucleus to then transcribe blood vessel forming genes like VEGF. And that's why renal cell carcinoma, if you look at it under the microscope, it's got tons of blood vessels. That's one of the synaquanons of clear cell renal cell carcinoma. So then if you have normal oxygen levels and the cell says, you know, I'm perfectly happy, thank you very much, VHL is then going to grab onto HIF and it's going to degrade it somewhat more quickly. It's going to make it go away and that way you don't get those abnormal blood vessel formations. But if you have a mutation in VHL what ends up happening is you don't have the control over HIF and you get all of these blood vessels that are forming inappropriately. And that seems to correct and that in itself might not actually cause other mutations and things like that but it creates what I would call a nice nest for all sorts of nasty experiments to occur in those cells, those damaged cells, which then result in the other mutations from occurring. So there's other things that are required to make a kidney cancer, a renal cell carcinoma, a renal cell carcinoma. You've got to have the VHL mutation but you need to have other DNA alterations. So it's VHL plus that then makes the tumor. And then further alterations that then actually make the cancer progress and become really, really dangerous. And so the question then really is VHL plus what else is necessary to make this kidney cancer begin? And we actually in 2015 are only starting to understand what the other things are. And they're things like set D2, PBRM1, and BAP1. So there are other mutated genes that have to work together. You can start seeing how this is getting a little bit complicated. The next point is that then the chromosomes, you know I showed you those nice pictures of 46 chromosomes and that's the way it should be. But in tumors what happens is you start losing and gaining entire chromosomes. And so what we have here is we have clear cell kidney cancer and we've got red meaning you're missing something and green meaning you've got too much of something. And then we've got 1, 2, 3, 4, 5 all the way up to 23 or 22 actually here. And you can see that this up here is clear cell kidney cancer. You can see that chromosome 3 for the large part is missing. We can see chromosome 14 in more aggressive tumors is missing and we have gains of chromosome 7. So there's a chromosome 5 and 7. So there's things here that start changing as well and you lose entire amounts of numbers of genes here. This is now below here is papillary kidney cancer where you see it's a different pattern. Here we see chromosome 7. There's a lot extra chromosome 7 and it turns out I'll talk about in a little bit. Met is a very important protein that if you have too much of it it again creates that environment that the tumors can start forming in. So as I mentioned before there are a couple of genes that are frequently lost in addition to VHL. VHL is lost and then that arm that 3, that short arm of chromosome 3 is lost and these genes in addition then you lose an additional copy of PBRM172 and BAP1. And for ways that we don't quite understand yet that's how kidney cancer start developing. The last little piece of biology here and the quiz is only going to be about 20 questions afterwards so you don't have to pay too much attention. So is that when you then look at a particular tumor and you ask the question of well what are the mutations in this corner of the tumor versus the mutations in that corner of the tumor. It turns out that it's actually somewhat different and what's happening is that you've got this little engine of badness if you will and the mutations that are occurring in a somewhat random fashion and there's competition within these subcells for the ones that are going to have the greatest fitness and the ones that ultimately are going to be the worst for you, the patient. And so our understanding of what these processes are that actually sort of get the ball rolling down the hill for cancer formation are critical for us to be able to ask the right questions, do the right tests, come up with the curative therapies. So this is the sort of stuff my patients are asking Dr. Yonish what do you do when you're not seeing patients. So it's trying to figure out how to put ourselves out of business and thinking about this underlying biology so that we can actually come up with better therapies. So here's now let's say pretend there's a tumor. We've got not just the cancer cells, we've got the cancer cells here at the bottom. We've got blood vessel cells that supply blood to the cancer and we have these glue cells that I would call them which are a combination of things that kind of literally glue things together plus the cells that Dr. Gower's talking about the immune cells. And when we're treating a cancer, we're treating an entire organ, okay. It's an organ that's made up of blood vessels of immune cells that are in there, some which are good for us, the patients, some are bad and the tumor cells. And again when we come up with treatment strategies, we have to think about it on that macroscopic scale. So onto some of the treatments that are coming down the pipeline. We know that anti-vegeta therapy or blood vessel starving therapy like Suthent and Votrient are fantastic drugs. They really have made a difference. They're not enough. We know that there's about 20 or so percent of people who when they start receiving these drugs they don't benefit at all. We know that most people who are on these drugs although we have some wonderful outliers in our clinics, most people eventually these drugs will kind of run out of gas for reasons that we don't fully understand yet. So what are the things can we do to come up with other treatments? So I'm going to talk a little bit about some ideas like for example fixing broken VHL. Number two, are there other proteins that are upregulated in cancers that we should also be targeting in addition to VHL and VEGF? A bit about the metabolism story that I talked about and the last one is the Duke polio virus because I've gotten a lot of questions from patients about should we be getting the virus. So let's talk about each of these. First of all let's talk about fixing broken VHL. So as I mentioned before obviously VHL mutation is one of the key things that happens in clear cell kidney cancer. So wouldn't it be great if we could do like gene therapy? We could just put the VHL gene back in that cell and maybe the cell would stop behaving, misbehaving. So there's a couple of ways that we can kind of indirectly get at that. The first is I mentioned that one of the key things that VHL does is it regulates HIF. So you lose VHL, HIF goes up. So why don't we try blocking HIF directly? And the second thing is why don't we go all the way back and is there maybe a subset of VHL mutations we can directly fix? So blocking HIF has actually been really, really hard. So coming up with a drug that actually will stop some protein from being expressed in a cell, sometimes it's easy, sometimes it's hard. HIF is a transcription factor and that class of drugs is actually remarkably difficult to target. But fortunately recently very smart chemists have come up with a drug that seems to be doing that to some degree. And there's actually in that laundry list that I showed at the beginning there's this one study testing a novel HIF2 alpha inhibitor. We don't know anything about how good it is yet, but it is actually trying to get closer and closer to the source, if you will. It's like one step removed from VHL. So this is an example where you have lots of VHL. You have VHL which is blocking HIF, which causes too much VEGF. So here we're directly trying to block HIF. One of the problems with that is that although, again, this is another layer of the onion, we said that HIF is a really important target for VHL. VHL actually does a bunch of other things. So when you lose VHL and you remediate the HIF side of things, you're still left with several other points that might be a problem. So actually getting VHL completely normalized would be even better. So what's interesting is if you look at various VHL mutations, so how many of you know what a western blot is? Well, here's a western blot. So basically what this is, is we're taking proteins from different cells and we're allowing us to quantitate them by looking at them side by side in this blot thing. And the bigger the band, the more protein there is. And so these numbers here on the top are different mutant VHLs that we've introduced into cell lines. And you can see that there's big differences in this, right? Here's a normal one. You can see there's a fair amount of it. And you can see quite a number of these other VHL mutants are much, much lower expressed. But what's interesting is if you actually look at their function, they're still able to do, for example, getting rid of HIF. So you can see here, this one here, there's no HIF. So it's doing its job. Well, this guy here who's got low levels isn't doing that good a job of doing it. This one here is still able. So maybe if we could raise the level of some of these proteins, we might actually get them to work better. And there are some drugs that can block the degradation of proteins, Bortezimib is a proteasome inhibitor, which is an example of this. And we can see here that if we give Bortezimib, we can raise VHL levels, and we can lower HIF levels. So it's an interesting idea. Maybe works. We tested this in 12 patients so far. We're limited by the kinds of drugs we use. And so we used a drug called Carfizimib, which actually had a fair number of side effects. But we're right now testing whether or not any of those individuals we treated, whether or not their VHL mutation was rescuable or not. And we have a number of grants that have been submitted and they're underway trying to find better ways to do this. So it's just an example of kind of thinking outside of the box, how can we actually change the way we treat patients? So something that's perhaps a little closer to us and might actually get closer to real time is targeting Met and Axel. So as I mentioned, Met is up-regulated in papillary kidney cancer, and I'll show you that in a second. And it also seems to be up-regulated in clear cell kidney cancer. And there's another closely related protein called Axel. So let me tell you a little bit about those. So back to the chromosomal copy number. Chromosome 7 is where Met lives. And if you look at papillary kidney cancer, you can see here that there's lots of extra chromosome 7, which means there's lots of extra Met. And that makes the tumor cells happy and us not so happy. If you also look at clear cell kidney cancer, you see there's also extra chromosome 7, meaning there's extra Met. If you then look at whether the over higher levels of Met are associated with worse outcome in patients with kidney cancer, the answer is yes. So we looked at this in tissues from our clinical trials. And we saw that if you had a high Met level, your overall survival was lower. And also your response to the time that you were responding to blood vessel starving or anti-angiogenic therapy was less. So high Met is not good, even in clear cell kidney cancer. And then what we did is we asked the question in a model system where we grew tumors in the flanks of mice, we treated with Sutent, and then we said, all right, when the tumor starts developing resistant to Sutent, and we add Cabosantinib, which is a drug that actually blocks Met and Axel, can we actually make the tumor shrink again? And the answer is yes. Good news is that there are drugs that are in clinical trials that are testing this now. There's one called Forretinib, which was tested in papillary kidney cancer, which I mentioned is a disease that seems to have lots of Met. And it looks like there was some really interesting early results. And there's the Meteor study, which has been completed, which in patients with clear cell kidney cancer who had progressed on anti-antigenic therapy got either this drug, this Cabosantinib or Cometric, or they got Affinitor, Everlimus, and they were looking at whether or not one side did better than the other. Well, we don't know the results yet, but there was a press release on Thursday that Cabosantinib has just received what's called Breakthrough Status from the FDA for Development and Kidney Cancer, and this gives them certain privilege. It's kind of like getting premium status on United Airlines in terms of getting your thing processed. It doesn't mean that it's gonna get approved, but it means that there's some evidence that this could be a good thing. And we're probably gonna find out at ASCO this year. There's several other Met agents. That's not the only one that are being tested now in kidney cancer, and it'll be interesting to see what happens. So Axel is another protein that's upper alien kidney cancer, and Dr. Amato Giaccia, a collaborator of ours who's currently at Stanford University, asks the question of if you have high levels of Axel, how do patients do? And you can see here what these are, these survival curves. Here's the percentage of people and the y-axis of surviving, and then the y-axis, the x-axis is time over months, and if the line goes down faster, that's bad. So you can here see the people who have high Axel levels. They are dying considerably faster than people who had low Axel levels. So this is obviously a bad thing. He then looked at this in terms of whether or not blocking Axel decreased growth of cells either in tissue culture or in animal tumors, and the answer is yes, it did. And he then, because he has ideas in a company, developed a product which is now about to enter into clinical trials, which is going to test whether or not Axel inhibition is useful in individuals with metastatic kidney cancer. Targeting cancer metabolism. So as I mentioned before, tumors use sugars and various other things differently from normal cells, and this could be a vulnerability. So I won't torture you with what's called the Krebs cycle or the TCA cycle, but just suffice to say that normally, in a normal happy cell, what we do is we take a sugar up here, we put it through this little grinder, if you will, which produces a whole bunch of energy, ATPs for us that makes our cells survive, all right? Tumor cells actually don't do this. They do some things through much more inefficient pathways, the kind of like SUVs of the cell world in that way, but they then kind of use part of this pathway to use some amino acids to do other things that they need. And so this difference, what matters is that, A, there's a difference and B, that there's a vulnerability. And so if you come in on this pathway and you block this reverse metabolism that tumor cells use, this can kill cancer cells, okay? And this is something that's been demonstrated often, Iliopolis at Harvard has done a lot of this work. He's demonstrated that this might actually be an Achilles' heel for cancer. And there's a drug that is now being tested here at MD Anderson and other places. In terms of the kidney cancer cohort, I think it's actually closed now, but it's being looked at as a way potentially specifically targeting cancer cells with metabolic inhibitors. So now last, I think, but not least the Duke polio virus study. So this was on 60 minutes and it was very exciting, I think, but what is this? It is a knowledge that the polio virus receptor, because the way a virus gets into a cell is it has to actually have a receptor on the surface of the cell. The receptor for the polio virus seems to be expressed at much higher levels in cancer cells in a number of different cancer cells compared to normal cells. What this researcher did, and this is actually something that they've been working on now for 20 plus years, was they modified the polio virus to kind of neuter it somewhat so it didn't actually cause polio, but it still killed the individual cells that it got into to then say, hey, if we use this, maybe we can use this sort of as a Trojan horse that it'll get into these particular cancer cells but not into normal cells. And it'll kill those cells. Now the problem is that the way this is being done now at this Duke study is it's being done in brain cancer patients, where they only, they don't have metastatic disease, but what they have is they have a cancer that's in one spot and in a very bad spot, and they directly infuse these viruses into the tumor. This particular receptor is expressed at low-ish levels in other organs of the body, including the normal kidney. So if you were to give this by vein, for example, you probably have a fair bit of toxicity in other organs, which would not be a good thing. So at this point in time, it's very interesting, it's very novel, it's very out of the box. It's certainly not ready for prime time for kidney cancer. So in conclusion, there's no question we've dramatically improved treatment for kidney cancer. We have antigenic therapies, which I think have prolonged the lives of a number of individuals. We have immune therapies that are dramatically better than the old immunotherapies, but I think all of these are going to have limitations and plateaus, so we have these newer other things that are gonna be targeting metanaxel. There are novel ways of perhaps doing antigenic therapy even better, and there are ways of taking advantage of the new features of tumor metabolism that might give us the next set of therapies that we're gonna be talking about in clinical trials in five to 10 years from now. But I'd like to thank everyone for being here, and again, I wanna thank from the bottom of my heart the patients who are here, who are listening, and who help us advance cancer. Thank you. Thank you. Thank you.