 me to speak today and tell you about some of the things we're working on to find new ways to determine if your treatment is working. And I think my talk was set up beautifully by Dr. Mitra, and I'm going to pick up kind of right where he left off. So if we think about kidney cancer and all the different steps that happen, we need better answers at every step for kidney tumors. And a lot of the talks that you've heard about today are really our attempts to do exactly that. When kidney cancer starts, something happens in a cell population that makes a normal cell become abnormal. And then the cells start to grow out of control. Normally cells that are out of control just die off and they don't survive. But these kidney cancer cells start to accumulate additional mutations and things that make them hungry for more oxygen, hungry for more energy, hungry for more blood vessels, and the tumor gets bigger and bigger and it grows out of control. It's really hard to detect as Dr. Mitra said, when it's really small like this, so there's certainly need to try and detect things earlier and smaller. Well, eventually it grows large enough that you get a diagnosis. For some people, it's because they're having blood in their urine. For some people, it's because they went to the ER for some other reason. And they found a mass on the kidney on a CT scan. At this time of diagnosis, the standard evaluation is to try and determine all the places that you do have tumor, to determine your stage. And CT scan is definitely the gold standard to really understand anatomically where these lesions are and how big they are. MRIs are sometimes used and to look at the bones to see if you have metastatic disease to the bones, we can do bone scans or PET scans. So based on this, we select our first treatment. If you have an early stage cancer, kidney cancer, then you go to nephrectomy, just as Dr. Leppert discussed. But me being the medical oncologist, I deal unfortunately with a lot of advanced cancers and we deal with systemic therapy. So when we see a patient that has metastatic kidney cancer, we have to choose what systemic therapy that'll go to every cell of your body to try and deal with that. And this year in 2014, this is kind of the state of where we are for the approved therapies for systemic treatment. These are kind of older treatments and tougher treatments, immunotherapy, and we don't really use them so much except for very select patients. You're probably more familiar with these, the blood vessel inhibitors, and I've kind of grouped them by how they work. These five medications, which is Suthent, Nexivar, Votrient, Avastin, and Enlita, are really targeted at inhibiting the blood supply of your tumors. So these are therapies that we give that should cut off the blood supply to the tumor and therefore stop its growth. There are other ones, Torosel and Affinitor, that are approved that work in a slightly different way and they're trying to target the tumor cell growth and turn off the survival signals in the tumor cells. There are five of these that are approved for first line treatment and we have to just pick one. We don't really necessarily know for you which one is going to be the best one until we try it. So we choose one. Dr. Surnivas and I, if you see us in clinic, we think through all the best things we can with you and what we know about your tumor and we select one of these first line agents. And then you think to yourself, and I think to myself, how do we know that this targeted therapy is working on your tumor? We can give you numbers and say if we try it in 100 people, 50 percent it should keep the tumor from growing, maybe 25 percent it'll shrink, and 25 percent it might not do anything. But how do we know what's happening in your tumor? And this is the question that I'm really passionate about, helping us answer in different ways. And what we really want to know is what's happening here. What's happening at the tumor cell level, the tumor response, when we start our first treatment. Because the minute we start the treatment, the molecules of the drug start going through your body. And early in the few days you might even start getting some of the side effects. Sometimes you will get diarrhea from some of our first line treatment, sometimes fatigue and sometimes if it's working you might feel a little better. But how do you know? Because sometimes you're more tired just from the medication. And we basically tell you you're going to have to tough it out eight to 12 weeks and we'll do our gold standard CT scan and see if you've had a response, if it's shrunk or if at least it stayed the same size. And this reevaluation scan measures the size of the tumors and that's how we decide whether or not it's helping you and whether we should keep you on it or not. Well CT scans are a measurement of the size of the tumor but they're not telling us anything, as Dr. Mitra said, about what's actually happening in the tumor cells themselves. We have all these fancy treatments that are supposed to decrease the blood vessel supply and we don't know if it's done that based on our CT scans. So we'd like to take a more direct approach if we can to make these measurements and really quantify how active these cancer pathways, like the blood vessel pathways, how active they are in your tumor and how quickly they're changing. Because they should be changing quickly. We shouldn't have to wait eight to 12 weeks to know what's happening to your tumor cells. So the first question is, well, which cancer pathways does it make sense to study? For kidney cancer, we should look at the pathways where we have drugs that we think we're targeting these pathways and this is the angiogenesis pathway. These five drugs target pathways that are associated with the growth of blood vessels, as I mentioned, that supply the kidney tumors. So we would love to be able to figure out if we're turning off angiogenesis, if there's any evidence that the blood vessels are actually decreasing. So Dr. Mitra has already mentioned a couple of ways and I'm going to talk about another one. There's something called a dynamic perfusion CT, which is a special CT scan. And it's done by injecting contrast in a special way, and it measures the tumor blood flow, the tumor blood volume, and how leaky the blood vessels are that are feeding the tumor. Now this is not necessarily something that can be done everywhere, but at Stanford we do have several of these special scanners and software to enable us to make these kinds of measurements. And this is particularly useful for the kidney where PET scans really are not as helpful. And this is the topic of a clinical trial that's opening this month here to offer perfusion CTs to our patients before we start our standard treatment, one week after we start the treatment because we really think that as early as one week or even a few days, we should be able to see changes in the blood vessels. And then we should compare it to the standard 12 weeks and see if we could have predicted it much earlier. We'll specifically determine if blood vessel measurements change at one week. And if this predicts the 12 week response with a standard CT. A couple of things to know about this is it takes an extra 10 minutes because of the contrast in the scans. And because it takes a little longer, you have to be able to hold your breath for 25 seconds. So we'll keep that in mind and we'll screen our patients for that ability. Well, even that is indirect because it's kind of taking an image. And it would be great if we could really more directly look at your tumor cells themselves and see what's happening. Then the question becomes, well, okay, say we could even get your tumor cells out, what would we look at in them? You guys have heard probably a lot about sequencing all these incredible sequencing efforts that are going on looking at mutations in the blueprint, the DNA that makes up all the cells. Well, that's really incredible work and is giving us a lot of insights. But what I'm going to propose to you is that it's also useful to look at proteins. And here's why. DNA is the blueprint that kind of is for the machinery that drives a cell, but it's just the blueprint. DNA is then transcribed into RNA, which are kind of like the little workmen that put together the machines from the blueprint. But finally, the machines in your cells that actually carry out all the activities, these are the proteins. And sometimes you can imagine you have something going wrong with the machine that you couldn't find from the blueprint. So looking at the proteins themselves that are involved is very could be much more direct. And in fact, all of the five therapies I talked to you about are targeting proteins, they're not changing your DNA blueprint, they're not even changing RNA, they're changing how your proteins can act. So there are many reasons that it's been hard to study the proteins. First, you need a lot more tissue to analyze proteins than you do for DNA. And so you would need serial biopsies to provide enough tissue to analyze proteins. And of course, we're not going to do that, we're not going to put you through serial surgeries just so you're gonna get enough tumor cells to be able to make these measurements. But now we don't necessarily need large biopsies because we're in the technology era and nanotechnologies can really help us analyze tiny numbers of cells because nanotechnologies are either tiny little instruments themselves that can do things, or they're big instruments that can measure tiny amounts of material. And that's what I'm talking about today are these instruments that can help us measure very, very small amounts of input. So instead of needing a scalpel to take enough tissue, now maybe even a needle poke is enough to get enough tissue. So I'm going to spend just another minute talking about developing the use of a specific new nanotechnology, which is called the NanoPro 1000 or we call it NIA for short, to quantify panels of proteins in patient cells. The NIA allows for really rapid profiling of proteins. And here's a picture of one of the tubes in which the measurements are made. It's really tiny, you can barely see it and barely pick it up. So the measurements are made in tiny tubes, which means the amount of stuff we need to put into that tube is very, very small. And that's why we can now get away with poking a needle into the tumor. And that's enough to make this analysis. And we can run 96 tubes at the same time so we can get lots of measurements at the same time. And it's an instrument that makes this measurement because you can imagine if I tried to do this by hand and tried to poke it stuff your tumor cells into that little tube, and then tried to wash everything through, it would not be very precise because our hands are not very precise, but instruments and nanotechnology instruments can be very, very precise. So they can give us very high quality, very highly reproducible data, and they can be fast. So one of the issues we talked about today is being able to get an answer in real time. It's really tough to have to wait. Sometimes like foundation one testing can take weeks to look at genetic testing come back. But this could give us a result in four hours. So that could be useful for kind of a same day decision. So can we really use NIA to measure proteins in tiny numbers of kidney cancers? The answer is yes, we can. We are and we have been and we're continuing to collect and profile tumor and adjacent non tumor tissue from nephrectomy specimens. Our first test was let's go to the operating room when we know we have plenty of tumor cells, and we can poke a needle directly into your tumor. Not only that, once it's out of the body, we can also poke the needle into other areas of tumors if you had another one there, and also the adjacent normal tissue to see what's different about your normal tissue compared with your tumor and how different regions of your tumor are different from one another. So we've been using this to start determining protein signatures of kidney cancer by sampling both the tumor and the non tumor nodules in our individual patients. So how we can now apply this is to determine the biologic response to determine how our therapeutic agents are working in you. Our standard 12 week tumor reassessment CT MRI is something we want to push back this timeline so we can get a much earlier treatment response. And NIA is one approach to doing this because now it's feasible to get a needle stick of your tumor before the treatment and then a needle stick earlier on and get an answer closer to real time at the protein level, so a much more direct measurement. And so this is all very, it's still in the early stages of our research, and we have a clinical study to apply this to patients who are getting standard therapy to see if we can get earlier predictions. We're using the NIA nanotechnology to define protein signatures that can predict the response much earlier than the CT scan. And we have a couple of approaches. One is, as I mentioned to you, a minimally invasive approach where we're using NIA to profile changes in cellular pathways of small numbers of tumor cells that we can get by a fine needle aspirate, which is that needle poke, or we're really pushing the envelope and we're trying to get tumor cells out of your blood. So that's just a blood draw. And we want to see these changes that occur early after administering the treatment. So this is the minimally invasive way and to do it by blood it just requires two extra tubes of blood at your visit. And so you may have met our study coordinator, Tommy Metzner, and he's always coming through and saying, oh, would you be willing to let us draw two extra tubes of blood? Well, this is what it's going for. This is the kind of research that we're really trying to move forward. And we've enrolled more than 50 patients and we've got blood and we're starting to get results so far. And the next goal is not only to do this for drugs that are already approved, but to do this earlier on as we're developing new drugs early in clinical trials when we're testing the new drugs. And this could be helpful because it'll help us develop biomarkers to determine response to the new drugs in less than eight to 12 weeks and to accelerate development of the new drugs and to select which patients are likely to benefit so we can help personalize the treatment for you, our patients with advanced disease. And importantly, this is something that we're not good at right now is in clinical trials, if we give somebody a new drug and it doesn't work, we really don't have any idea why. We can't learn from that and kind of make a new iteration that overcomes the reason it didn't work. But now, by taking a sample before and after, we're going to get a lot more information to try and understand that. So I'll just give you one example of how we're able to do this and how we're applying this and it follows right up on the talk from just before me. And this is in a minimally invasive way to analyze changes in tumor cells by blood or FNA that occur after administering a new therapy. At Stanford, we're really excited to have open one of the very first clinical trials that's inhibiting the enzyme that makes glutamate. So you heard about glutamate imaging. This is actually a target because it's an alternate energy source for kidney cancers in general. They particularly like to use glutamate instead of glucose. And so the hypothesis is that if we inhibit the generation of glutamate with this new drug, it should help the tumor cells to regress because we're cutting off their energy source. So what I'm setting up to do is to measure the protein that produces these glutamate molecules and measure if the glutamate levels themselves are decreasing soon after starting the treatment. And in addition to this minimally invasive way where it's with blood and finital aspirates, we've also in the same clinical trial built in a totally non-invasive way to do this through imaging with the F18 FSPG that you just heard about. So we're doing that at serial time points during the study as well. So that's just one example of how we're starting to apply these novel technologies to try and figure out how therapies are working and sooner. So I hope I've convinced you that we can use new technologies to measure changes in tumor cells themselves over time. Two examples I talked about are perfusion CT scans and FSPG scans, as well as nano measurements of proteins using the NIA. And we're incorporating these technologies into clinical trials that are going on right now here for kidney cancer and really aiming to develop biomarkers to personalize treatment. And so I would like to acknowledge this huge team that's really required to do this kind of work. Many of the people in the room have been a part of this work. Either as investigators, Sandy and Eric and John Levbert and our study coordinators who are here too, as well as collaborators in pathology, other medical oncologists and radiologists. And of course this couldn't happen without you, our patients. And the kidney cancer association has been really, really supported for all of these efforts as well. So thank you for listening.