 It's my pleasure to introduce our next speaker, Alice Fan, who's an assistant professor of oncology and a colleague of mine in our medical oncology division. Alice came to Stanford. She did her medical oncology training here at Stanford. And we were, again, fortunate to have Alice be interested in kidney cancer research. And she's now part of our clinical faculty. Alice spends a big part of her time in her lab looking at how best to study kidney cancer and the various drugs that we use. So I think one of the questions were about how can we detect from our tumor cells which therapy is right for a given patient. So Alice is going to tell us about her work and how the technology that she's developed in order to be able to get some answers from very little tissue. So again, pleasure to introduce Alice. Thanks for coming on a Saturday afternoon and sharing your work with us. Thank you, Sandy, for inviting me. And it's so great to see everybody here. So it's my great pleasure to tell you today about a burning question in my mind and in many of your minds. How do we actually know if a treatment's working? We've heard a lot this morning about how can we predict from a biopsy, from our surgical specimen, from a drop of blood? How can we predict how long we're going to survive from our cancer or if it's likely to come back? But I'm going to ask another important complementary question, which is once we've actually chosen our therapy based on the best predictors, how do I actually know it's working? Another important complementary question, which is once we've actually chosen our therapy based on the best predictors, how do we diagnose with Sunny's talk this morning and how we can do surgery and how that's important? And a bit about choosing our first treatment. Well, for our patients and for many of you in the audience with advanced dramatic cancer, we know that this is a tough decision. We have a menu of treatment. Then we choose something, and then it tries to do something against the cancer cells. And then only eight to 12 weeks later, and you're tired of hearing this from me and Sandy, how long do I have to wait before we can see if it's working? We have to do a CT scan, but we have to wait eight to 12 weeks. That's when we measure the clinical response, and eventually we'll know if we've cured or relapsed. So just to go over a country recap, some of the things that we've talked about earlier, and then to launch into what I'm going to focus on. We know that a diagnosis, you want to go a standard evaluation, and that's determining your stage with CTs, imaging, in some cases an MRI, bone scan to see if it's gone to the bone. And then if it's advanced disease and you require systemic treatment while you would see the medical oncologist, me or Sandy, then we choose for you the best systemic treatment we can based on all the information that we have. In some cases, it's now increasingly involving additional tests that we get. But it's important to think, OK, well, what are these treatments that are the first ones? And Sumit just gave you a very beautiful overview of especially Neville about one of the newest ones. OK, well, what are these treatments? Oh, this is an old slide. It's supposed to be systemic therapy in 2016. And but you know it's important because in 2014, all we had were the ones in black. And in the past year, the three that I've added are the three in blue. But you know, if you think about it, we've heard a lot today about immunotherapy thanks to the fantastic talk that I've had before me. And you heard about Nevolomab and Avdevo being the newest immunotherapy that we have. And we also talked about mTOR inhibitors. These are inhibitors to a cell and an infinitor that are pills or given IV treatments that actually suppress tumor cell growth and survival signals in those cells. But if you look at this list, by far, the biggest category are pills and IV treatments that are inhibitors of blood vessel formation. And again, this is really important because even the last two that have been approved, Khabazantinib and Linnvatinib, these are inhibitors of blood vessel formation. And again, this is really important because even the last two that have been approved have been inhibited in Linnvatinib and Linnvatinib. I just talked about all these targets that we're trying to do with all these specialized therapies. How do we know that this targeted therapy is working? How do I know that you're tumor? I just talked about all these targets that we're trying to do with all these specialized therapies. So from the time of first treatment, we know that we're supposed to be inhibiting the blood vessel formation that feeds the tumor cells if we give you one of those seven. Or if we're giving you a nevolumab, we think we're supposed to be activating the immune system. But how are we measuring that? Right now, the standard of care is our CT scan. And these are diameter measurements. The problem with diameter measurements, even though that's our gold standard, this is the best we've got right now. But it's billions and billions of cells in every square millimeter of tumor. We think we're trying to hit cells in immune cells that are going in there or hit blood vessels that are in the tumor cells. But we don't have ways of measuring those yet. So this is what we're going to be talking about. Again, the standard reevaluation scan is measuring the size of tumors and how that's changed. But this is why for kidney cancer, that's not always the best way. And we're looking for better ways. So we know that a lot of our treatments don't necessarily shrink your tumors. For a tumor to shrink, there has to be a change in balance. Either the tumor cells are dying faster than they're growing, or they've all stopped growing and it's just not getting bigger. For it to actually shrink, something has to change in the balance. So just a diameter measurement of how big it is isn't telling us as much information as we really want to know for a change in the balance. And the other hard part is that it does take 8 to 12 weeks for a treatment to actually halt tumor growth. So by the time we can see it, we've done a measurement with a ruler. We've had to treat, and you've had to have all the side effects for 8 to 12 weeks before we can actually make that standard measurement. And to make things even tougher, we know that with nevolumab, you just heard that there's a small percent of tumors that actually look bigger at the first scan. And how can we figure out if that's bigger one that's going to shrink later because it's due to tumor cell infiltration with immune cells that are actually attacking the tumor cell, or if it's actually progression? So we have a lot of work to do to try and get better ways to immune the cell. And so I'm gonna tell you about what we're doing at Stanford as well as beyond. So a more direct approach would be let's measure not only the size and how things are changing based on a ruler measurement as beyond, but let's quantify how active the cancer pathways are in your tumor. We think we're knocking down these activity pathways. Let's see if we can prove that in you, and let's try and do it sooner than the cancer pathways are in your tumor. So I'm gonna spend quite a bit of time talking about the seven out of 10 targeted agents that actually suppress growth of blood vessels that feed the kidney tumors. So these are the seven listed here, Votrient, Cetan, Nexivar, Avastin, and Lida, and the two newest ones, Cabometix and Lenvina. And these suppress the growth of blood vessels that feed the kidney tumors. So you can imagine if you've got a tumor, imagine the tumor mouth is in green, and some normal tissue near it. Oh! So you can imagine if you've got a tumor, and if you've got normal tissue near it, the tumor mass, in order to keep growing bigger and bigger, it needs to get oxygen and blood. So you've gotta have growth of blood vessels that go into the tumor and feed it. So we know that kidney cancer is especially dependent on antigenesis, on this growth of blood vessels feeding it. So, and in fact, I don't know if you remember from Dr. Lepper's talk, he talked about the number one genomic hit that we see is in the VHL gene. That's the mutation that actually makes tumors really oxygen-hungry, and they want blood vessels to come feed them. So that's why one of the major targets in kidney cancer is suppressing the growth of blood vessels, suppressing antigenesis. And if these drugs are working, we know that in preclinical studies, you actually see less blood vessels, and the tumors may stabilize, or they may start to shrink, as they lose their oxygen and blood supply. Blood vessels, and the tumors may stabilize, but they may start to shrink. So how can we quantify antigenesis better than just a ruler measurement with our CT scans? Well, this is a special CT scan, called a dynamic profusion CT, and it's a special scan that we're set up to do here at Stanford, and we're studying if that can really help us measure these antigenesis factors better. The things that we're set up to measure are tumor blood flow, tumor blood volume, and how weak the blood vessels are. And it requires very special scanners and software, and we do have this at Stanford. Tumor blood volume, and how weak the blood vessels are. And the hypothesis is that if we're doing an antigenesis treatment, we should be decreasing the tumor blood flow, something that we can't measure with our scan scans. We should be decreasing the tumor blood volume in your tumors, and we should be decreasing the leakiness of vessels. We should be decreasing the tumor blood volume. So we do have a clinical trial that offers you this profusion CT imaging, and the way it works, and it's for patients that are getting any of these anti-angiogenesis inhibitors. We do a scan before you start your treatment, so we see how vascular it is before you start. And then after one week, we do the next scan. Now this is still research, so no matter what we find at one week, we can't make any clinical decisions. We still have to wait for that eight to 12 week scan to decide if it's working or not. But what we're hoping to see is a hint. At one week, if we can see decreased blood flow, decreased tumor volume, and decreased leakiness of vessels, hopefully that will predict what we actually see at 12 weeks with our standard scans, and a repeat profusion CT. So the goal of this study is to determine if blood vessel measurements, not just size, but blood vessel measurements, can change as early as one week. As we know in preclinical studies, things start to change within days, but right now a size measurement can't find it. So we wanna see if the one week measurement with a special profusion scan can predict the 12 week response. So this is very early, but we are offering this participation to any of our patients that are starting these drugs with better angiogenesis inhibitors. So this is very early. And in fact, I think I see a few patients who have actually been on the study. Any of our patients that are starting these drugs with better angiogenesis inhibitors. It is an additional CT scan, and it takes an extra 10 minutes for each one of these scans, so you do have to come back at one week and do this, and it's being run by myself with a radiologist, Dr. Ayak Maya, and you've probably met our study coordinator, Yori, who helps facilitating this. And it's being run by myself with a radiologist, Dr. Ayak Maya. Well that's not the only approach. There are other ways to try and figure this out. So some of you have probably had PET scans. PET scan, or standard PET scan, is when we inject radioactive sugar into you, and radioactive sugar is taken up by tissues that are very active, and dividing quickly or metabolically active. And radioactive sugar is taken up by tissues. The problem with the regular radioactive sugar PET scan is not all kidney cancers take up the radioactive sugar. So one of the radiologists at Stanford, Dr. Iaguru, has a new probe. It's called F18-RGDT peptide. This is a probe that specifically binds blood vessels and it's radioactive. So theoretically what it can do is, if we inject that instead of radioactive sugar, this probe, the RGD2 peptide, will go to all the blood vessels, especially the very antigenic and vascular blood vessels in your tumors. And we can measure, similar to the other study, before starting treatment, how much there is vascularity. And then after one week of treatment, how that vascularity has changed based on this radioactive probe. And then there's a third scan that's done 12 weeks after treatment. This is an example of the type of data we could get. This is a regular glucose FDG scan on a patient with lymphoma, because as I said, the regular scans don't necessarily light up the kidney cancer. And all the red spots, the hot spots, that's where there's active tumor based on the glucose scan. So what we're hoping is we can localize your tumor with this FDG-RGD2 peptide, sorry, the F18-RGD2 peptide, that we can see a similar picture of your kidney cancer. And after we start, again, these angiogenesis inhibitors as early as one week, we're hoping that the red stops glowing. And after we start again, we have had patients that have participated both on the perfusion CT scan, as well as the special PET scan study. So we have had patients that have- Well, how can we do this even more directly? I've just talked to you about several imaging studies, but wouldn't it be much more direct if we could see what's happening in your cells? That's what we want to know. Are the cells dying? Are they growing really fast? Are they slowing down? But wouldn't it be much more direct if we could see what's happening in your cells? Are there blood vessels? Are there immune cells in your tumor? Are they growing really fast? Are they slowing down? If we could even get these cells magically without having to do a big surgery to see what's happening and get a movie, what's happening once we start treatment, what should we even look at? Well, there have been a lot of efforts, and you hear a lot of stuff in the news about measuring changes in DNA, looking at mutations. Also, there's a lot of great research going on with RNA, and in fact, I think you're going to hear more in the next talk with Dr. Alchin about ways we're doing this for DNA. Also, there's a lot of great research on RNA. Well, what I'm focusing on are proteins, because if you think about it, DNA is like a blueprint for building a house. It tells you how things are going to be built, and then RNA is kind of the lumber that everything's made out of, but then it's proteins that are actually the house with the lights on and the lights off, and what we're trying to do with our targeted therapy is turn the lights off, so it doesn't necessarily get at the blueprint. We want to see if the lights are on or off, and that's where the proteins come in, and it's a really hard thing to study, and that's why I've spent so many years here trying to figure this one out. We want to see if the lights are on or off. And the problem is, you need a big biopsy to measure protein in the tumor. And that's why I've spent so many years here trying to figure this out. And so, serial biopsies, if you wanted to look at one week to see what we're doing at the molecular level in your tumor cells, you'd have to get another surgery to get a big biopsy, and that doesn't make any sense. We're not going to put you through that, so it's just been a big black box where you've simply not been able to look. You'd have to get another surgery to get a big biopsy. And the solution may be that we can get away with little tiny biopsies, or maybe you can get away with cells from your blood if we use super sensitive nanotechnologies to analyze tiny numbers of cells. So I'm going to tell you about one specific nanotechnology that I helped develop to do this in cells, but also put it in the picture of a bigger thing. So Stanford for the past 15 years has had a center for nanotechnology excellence. It's run by Dr. Sam Gambier, who's the chair of radiology, and these are some of the projects that are ongoing. It's actually unbelievable, if you think about it. Here in the news, oh, we can inject little tiny nanorobots into your blood. Well, imagine this. Dr. Rao's a chemist here, and what he's doing is part of the center, is he's working on visualizing your tumors by injecting little tiny nanoparticles that go through your blood and get taken up by the tumor. And if you inject just the right cocktail, your tumor can take up these little cocktail things and in the tumor cells assemble into something we can image. And not only is he working on having them self-assemble in the cancer cells and only in the cancer cells, once they're done giving off their signal, whether it's a light signal or whatever, imaging signal and we've seen it, then they disassemble and go away. So this is actually something we're working on right now in mice, and it's my job as leader for the clinical translation of the center to start thinking about how is this going to apply to you guys, how can we use this in our patients and link these technologies to our patients in clinical trials. So another project is using nanotechnologies with Dr. Shan Wang and magnets. Magnets are incredibly powerful. We know from MRIs that's all based on magnetic technology. But if you can attach little magnets into little nanoparticles, they might be a way to hunt out the cancer cells and show us which cells we need to analyze and get them back out. So Dr. Wang is using magneto nanotechnology to analyze cancer cells and signals in the blood and I'm partnering with him. So some of you that have donated blood to my tumor biomarker study, we're using magneto nanotechnologies to fish cells out of your blood. Hopefully they're your cancer cells and study how they're changing early after your treatment. We're using magneto nanotechnology to fish cells out of your blood. Project three, Dr. Gambier is running it himself. He's using smart nanoparticles to image tumors using sound waves. And every time I've heard him talk about this, he said, basically you yell at the tumor and with these nanoparticles, they yell back at you. So now you can say, all right, how are you doing today? And it can say, oh, I'm growing, and looking at all the tumor. And with these nanoparticles, they yell back at you. This is kinda amazing that it's coming. So now you can say, all right, how are you doing today? And it can say, oh, yeah, I'm growing, I'm growing, so hot, hey, this is kinda amazing. But I'm thinking really hard with the teams one and three to figure out when and how we can bring this PC, guys, to figure out when and how we can bring this PC. So one specific nanotechnology that I helped develop is something that's now called the peggy sue instrument, and I didn't make the instrument, but I figured out how to use it. So one specific nanotechnology to think about, I'll tell this thing. now called the Peggy Sano technology is because we make measurements in tiny, tiny capillary tubes. And we can run 96 tubes at the same time, it's automated so the robots do it so it takes out all human error because a lot of steps we can introduce error ourselves. And we get a result in four hours. And what do we do with this? Well now, because it's a nanotechnology and it only takes a little bit of input, it's feasible to either just get an IR guided biopsy so you've all probably had biopsy done in radiology where they stick a needle in and suck some cells out, or theoretically we can start getting cells from blood and you don't have to even poke with a needle. So can we use nanotechnology to measure proteins in tiny numbers of kidney cancer cells? Yes. To determine protein signatures of kidney cancer, probably many of you have participated with me and John Leppert's study, where we're collecting and profiling tumor tissue at the time of surgery from nephrectomy, as well as at the time that our patients are getting radiology guided biopsy. And so far we've had more than 200 participants, so thank you all for being a part of this. And the things that we're looking at are one, the DNA genomic mutations, but also I'm really passionate about trying to figure out if the lights are on, what proteins are actually out of activated in your tumor, and then once we start a treatment, how they're changing over time. So are we really hitting the targets that we think we're hitting or not? And so far, we've been able to sample tumors directly in the tumor, as well as adjacent non-tumor tissue, and see that the nanotechnologies give really high definition of proteins and patterns that are different in the tumor versus your own normal. And see that the nanotechnologies give really high definition of proteins and patterns. So I've talked about trying to analyze the biologic response. And Peggy Sue, this is a nanoproteomics, is one approach to measure and predict response in real time. Wouldn't it be wonderful if we could then either get a sample before you start treatment either by a radiology biopsy or ideally by blood, and that's the direction we're heading. And then a week later, get another sample and be able, at the protein level, to see if we turn the lights off or not. And then a week later, get another sample. So I think there's a question earlier about how do we get drug companies interested in this, because the standard is to get a drug approved right now, we're still using the size measurements. And that's important. That is our gold standard. So we'll never get away from that, but we're trying to think out of the box and figure out what other things can we add to that to make our targets more clear to us. And so ideally we can use nanotechnologies to help define protein signatures that predict therapeutic response and tell you if you're actually responding in use nanotechnology to help define protein signatures. So we can envision that maybe we can do this with an invinably invasive way. We use the nanomino assay, the Peggy Sue, to profile changes in cellular pathways in small numbers of tumor cells, either by a fine needle aspirate, the IR, the radiology procedure, or from blood, that occur after administering a therapy. And it is hard to get drug companies to do this, because, one, it's a lot of money to do these kinds of studies. And so one approach we've had is we apply for grants to do this, so we partner for a clinical trial, we get the study drug, and then we build a whole thing of biomarkers around it, and we have managed to get a grant from the Stanford Cancer Institute and also grants from NIH to fund the things that drug companies don't. And that way we have a really great partnership to try and figure this out. Because we can figure out which patients early in drug development, which patients really do benefit, we can see if it's the one patient out of 20, that's a drug that would traditionally fail if we couldn't pick out which one it was going to be. But with the right biomarkers in the early development process, if we can find that one patient, that's a drug that might get approved if we know that 90% of those patients respond. So everybody's hunting for these biomarkers, and this is one of our efforts to do that. So if you've been approached in my clinic or in Sandy's clinic to participate in our biomarkers, and this is one of our efforts to do that, so if you've been approached in my clinic or in Sandy's clinic to participate in our biomarkers, and for this, we have enrolled over 100 patients so far. So again, thank you for participating in that. That just entails two extra tubes of blood at routine visits. So I'm going to give you one example of how we're doing this in a clinical trial setting. We want to obtain direct tumor measurements when we're testing a new drug, not just the approval of how we're doing this in a clinical trial setting, but also earlier in the process. And as I said, to develop biomarkers to determine response earlier than eight to 12 weeks, we want to accelerate the development of new drugs and select early which patients are likely to benefit, and help personalize the therapy for patients with advanced disease, so not only predicting based on before you start, but early on, figuring out if you're actually responding at a molecular level. And this is really important. In a lot of drug development or clinical trials, if it doesn't shrink the tumors and patients don't live longer, we never know why the drugs fail. We literally have to go back to the drawing board and take just the next best candidate and put it through the pipeline again. Well, if we can figure out at the molecular level, you know what, the drug didn't actually get to the cells, that helps us, that we know to modify the drug so it can get in there. So this is a really important piece that's been missing, but we're really hopeful that we can start answering these questions to really make the whole process much more efficient. So this is a really important piece that's been missing, but we're really hopeful that we can start to analyze changes in tumor cells for a specific drug, CB839. This is a brand new first in man drug, which is a glutamate inhibitor. Glutamate is like glucose. It's an alternate energy source for tumor cells, and we know that kidney cancer is one of the tumors that tends to rely on glutamate, almost as much, if not more, than glucose. So we at Stanford have a Phase 1-2 study that's testing this brand new drug, CB839, a glutamate inhibitor, for its ability to, one, be tolerated, and two, testing if it can control tumors. And wouldn't it be great if we can actually measure the protein that CB839 is supposed to be inhibiting? We want to measure the protein that's producing these energy molecules and see if that's changing over time. And then measure if the energy molecules themselves, the glutamate, are actually decreasing over time. So patients that are eligible for the clinical trial are almost any RCC patient who's switching treatment. It's not a first-line study, so you have to have one thing first, but if you're considering treatment, Sandy and I are always trying to figure out, okay, what this study makes sense for you. This is run by Dr. Telly at Stanford, and I'm kind of running the RCC on with the study here. And the study coordinator, actually, oh, this should be updated, this is Karen Lau. And this is run by Dr. Telly at Stanford, and I'm kind of running the RCC. And what we built into this is not only the blood test that I told you about using the nanotechnology that I'm working on, but also we built in a novel imaging modality to image that pathway of interest, and this is F-18, F-S-P-G, which F-S-P-G is a glutamate probe interest. And let me show you on the next page what that is. Interestingly, so it makes sense. I told you that a regular PET scan is actually imaging glucose. Well, for this clinical trial, we're trying to change glutamate levels, so it doesn't make sense to use a standard PET scan. So we're using the F-S-P-G glutamate radioactive tracer. But that's a very specific thing, and only a handful of patients across the country are going to get this glutamate inhibitor. Could this particular imaging glutamate radioactive tracer have implications? Well, this is getting back to the whole immunotherapy that we were talking about last hour. Is there a way we can better image response to nevolumab, the PD1 inhibitor? Well, you know what? Glutamate is also a molecule that's used in activated T cells. So when your immune cell is really revved up and it's doing stuff, they might glow with this tracer. So what we're doing is we're offering F-S-P-G imaging to patients that are about to start nevolumab here for kidney cancer, or this is also nevolumab is also approved in kidney, in long cancer melanoma. So those patients are also eligible for this kind of imaging. And this kind of gets that we're going towards molecules. It doesn't necessarily matter what kind of tumor you have. But if you're getting a therapy that's tidying something specific, we want to try and make it more cost-disciplinary. So this study, the F-S-P-G study is run by Eric Mitra, and his study coordinators are Sonia and Omar. So I think many of you in the audience have talked to them as well. And again, this is just the glucose image of a glucose scan. But what we hope to see is the hot spots, actually, if nevolumab, we want to see more hot spots. We want it to get more red, showing that there's immune activation. But what we hope to see is hot spots, actually, if nevolumab, we want to see more hot spots. So to summarize, what I've talked about, we can now use new technologies to measure molecular changes in tumors over time. Almost everything I talked about is still in the research stages. So we can't use any of these studies yet to make a clinical decision. Almost everything I talked about is still in the research stages. So we're going to switch. But that's what's coming. This is the very first step. So I talked about profusion CT scan to measure tumor profusion. So we're going to switch. The RGD2 blood vessel probe and the F-S-P-G immune glutamate probe and how we're making nano measurements in blood. And they're not mutually exclusive. You can participate in several of these at once. I gave you an example, how we're incorporating these technologies into clinical trials, including the CB839 study. And you can envision the studies that Samit and Sandy are coming up with with immune combination therapies have this sort of approach to be really helpful. And we aim to develop bioparkers to help personalize treatment. Immune combination therapies have this sort of approach. I will close and just acknowledge so many people that make this research possible, including our study coordinators, Tommy is here in the back. And he's probably talking about drawing teams of blood. You are Asia main, Jared, Denise, as well as our whole clinical team. I don't know if you've noticed, but we have a lot of nurse coordinators sitting in the back who are really dedicated to making sure each of us can get you the care that you need. And you can get all the things we've done. So thank you to everybody, especially to making sure each of us can get you the care that you need. And you can get all the things that you need. Thank you, Alice. Any questions for Dr. Finn? With the glutamate inhibitor, can you use those in conjecture with other drugs? Are they being used with nevolumab and with? That's a perfect question. Yes, I didn't go into it. But they were first studying it as a single agent. And there was some activity, but now we're pairing it. So the specific flavors that we have going, we're pairing it with the mTOR ebrilymus and RCC. And there's a new amendment to now start pairing it with the angiogenesis inhibitors as well. So yes, in fact, they might be most effective in combination. And it is still phase 1, 2. It's phase 1, 2. It's very early. Have you seen any positive results yet? It's been presented at ASCO this year that we do see in kidney cancer and breast cancer some efficacy. So it's promising. And this may be a whole new thing. There's a lot of excitement about immunotherapy. But we're always thinking about what the next pathway is going to be to target. And metabolic pathway is a big one that's coming. I think this is not the subject of your, but you just kind of addressed this. I wanted to ask, I think I read somewhere that cancer cells have a less efficient way of using sugar. Is that something that you're, is that what you're talking about metabolically? Like try to stop glycolysis or some other kind of? Exactly. So cancer cells are incredibly smart and resourceful. One, they have very high energy needs. So just the usual ways of getting a breaking down sugar or making sugar for energy are not necessarily enough. Some patients who have cancers actually have mutations in the sugar Krebs cycle pathway that makes them especially dependent on alternate energy pathways. So studying this balance of energy that's used by tumor cells is definitely a hot area of research right now. And being able to target those is something that we're also actively pursuing. So did that answer your question though? No? Yeah? OK. OK. Any other questions? So you mentioned three different areas of nanotechnology treatments. Now if someone's a relatively new patient and doesn't know much about getting on clinical trials, how does one keep track of what may be taking applicants for trials and deciding if a certain technology might be appropriate for you? That's a fantastic question. Yeah. So for RCC, me and Sandy actually are all over everything that we can offer to you. And in fact, my patients are kind of tired of hearing me talk about it in clinic sometimes. So for kidney cancer, it helps to have somebody that's got a foot in the lab as well as connections to the nanotechnology world. For clinical trials in general, including some of these diagnostic and imaging studies, we do have the Cancer Center website is actually pretty good at Stanford. And all of them are also listed on clinicaltrials.gov. So what I always encourage my friends and patients to do is if there's something that looks interesting to you, bring it to me. And I can help you figure it out if it does make sense for you, whether it's worth traveling to Florida to try this new nanotechnology or therapy even or not. The ones close to the home, we definitely are always thinking about each of you. So it's incredible. We never want to stop till we really continue to find new drugs, new ways to detect this disease, and new ways to treat this disease. So I think Alice is a great example of how that pursuit continues. So thank you so much. Alice.