 So first of all, I want to thank everybody for coming and I'm very happy to be here to share with you what we have done and the field have accomplished and what we can do for the future. So the reason I am kind of mentioned that this disease is in the past was very very bad very very lethal disease, one of the worst disease, but kidney cancer has become a disease that's much easier to manage and currently for the metastatic clear cell kidney cancer, they will talk about it most of patients are contracted with the metastatic disease in the past, the medium survival is about a year now it's almost three and then I think we we are moving towards that in the next couple years I think we will move it to almost five years with all the other trials including immunotherapy or complex, more compound targeted therapy. So I think this disease is actually I think it's a poster child of what we can do for cancer and not just kidney cancer I think hopefully we can actually share the success with other disease time and people can start to think about not just so afraid of cancer in general and really think about how we fight it and how we get rid of it. So my name is James and I work at Memorial Sloan-Catering. I speak not for myself, I always speak they present the group that I work with and I'm very fortunate to have many people working with me at Memorial Sloan-Catering it's a group approach in team science and that we really try to understand the disease better I'm a physician scientist I see patient half a day a week as well around the laboratory having to you know Dana-Farber, Washu, Hopkins but I never crossed the midline so I never just came here about four years ago and the reason I came is really I really want to deal with this disease and that the I think I want to bring your attention to this is and I want you guys to be aware of this that kidney cancer although is like eighth most common disease in them in US but you can see that the funding from the government for kidney cancer is four into this other part okay and this other part maybe like maybe 10 percent of that other part belongs to 10 20 percent of the other part belong to kidney cancer research that's why the kidney cancer research kind of didn't move too much but but but for the past couple years I think we made a lots of a wave and and lots of progress and I hopefully that you know or some of you can you know be aware of this and then hopefully we can get more of the research funding for this disease so so think about it you know to me I feel like if you really want to cure cancer the first thing you have you know the patient most of the time nowadays go to radiology and they find something and then if they find something that it you know the surgical oncologist you know can take it out and try to take a look at it and that's so so now the where am I so this is double screen so I need to figure out okay so so there's small pieces or big pieces got cut out and be visualized by pathologists and pathology would make a diagnosis about what kind of disease that you have and once you have disease if you localize disease will be operated and cured fortunately and if for the patient that have a metastatic disease disease spread out then you make start to see medical oncologist and the radiation oncologist any any working with surgical oncologist hopefully that we can still make a cure or at least extend the lifespan or change improve the quality of life of cancer patients so this is all good and well and the death thing to this need to kind of all thing together you need to you know have scientific based studies and really understand the disease and really under in the past the trials all based on like okay in real life five thousand if a thousand patients and I try to see whether you respond or not nowadays I think this is totally irresponsible behavior if we really want to conduct of meaningful trials you need to know what patient to select first and that's why precision medicine personalized medicine I think that's very very important otherwise we're missing the big boat okay so today is what I want to talk about is from you know it's from the pathologist standpoint medical oncologist standpoint and the scientific standpoint of this part I want you to kind of help you kind of guide you through this and hopefully you can understand cancer a little bit better in a very very simple sense why do we develop cancer so so this is just a single cell so our body is made of like about 30 point 37.2 trillion cells in our body every single cell has the same DNA okay has three billion base pair of one copy and there's another copy of it what is this chromosomes so it's about six billion base pair in our DNA and I think about it and then the DNA make RNA RNA protein protein and then our structure and it make metabolites and that with all these they build up our body so the bodies consist of 37.2 billion cells they have like every single cell actually it's showing sharing the exactly same three billion base pair obviously six billion base pair because you have two copies of it and the reason why just Jen has talked about why this is so difficult to deal with for the past you know with the beginning of the human history is because it's just part of us and the reason it is part of it it's not coming it's basically we go through evolution then everybody you know evolves different ways and DNA is very very stable but if it evolve if we don't have the capacity to evolve we are not evolving okay so we'll be the same a couple hundred millions years ago so that's the that's the the capacity we inherit then we have the capacity to mutate unfortunately if the mutation go crazy go too fast and take on take a wrong route then the cells become try to be the host and that's proliferate like crazy without further control and that's taking over and it's that's from your body the cancer is from your own cells and that's why it's so difficult to to take care of it and the other layer of complexity is not just because it's all you is the other thing is really it's because it's you know everybody you know different people they have different genetic makeup and people get different kind of cancer even within the so you can see that different people they could have different cancer and the other thing I will try to show you that is within the same patient this is a kidney cancer of mine so he has cancer here this is the kidney and he has metastasis here this is spleen this is liver are they are they the same disease it is a big question has been puzzling for us but no kidney cancer it just taught me a lot is many of them even you take from here to here from here they look they start from the same origin but they start to mutate and acquire different mutation and the truth acquiring different mutation they become behave a little bit different so that's why disease it is a layer of complexity and heterogeneity that that make disease is very difficult to treat and again so as I said that we start with cells and then we start with DNA so the you know so-called you know analysis analysis of big wholesale analysis of DNA is called you know genomics and then wholesale analysis of you know the RNA made from DNA is transcriptomics and then it you know RNA the purpose of it mainly is to make protein and protein is proteomics and then proteins mainly try to kind of build up our body conduct or an enzymatic reaction every time I'm moving my hands my consuming as lots of ATP and those kinds of that's all the enzyme is doing it so so this is complex it is very very intricate of phenomena so but the current focus in the past we all saw our focus on transcriptomics because the transition is easier to obtain but but it's flexible but generally a lot of noise so nowadays because we sort of go back and because of the sequencing technology available to us at this moment in in past in 1995 when this whole human genome was sequencing cost of billion dollars to sequence 20 times of your genome every single base pair sequence 20 times now it's about thousand dollars so that's a million times difference and that's why enable us to understand the disease is at life speed now compared to five ten years ago that's the major difference and that that's not only it and that's what we will build on it and we'll start to understand the other thing like proteomics and metabolomics hopefully by by knowing from DNA and through this we start from the genotype and the ultimate phenotype we can understand how cancer is built and how do we deal with cancer so this is a for for a cancer biologist it would you know everybody will know this so-called cancer hormones have been proposed for many but 10 20 years and it's been highly cited it's just because cancer is a cell within our cell try to be you know dominant dominant and try to gain all the capacity that we have by the differentiated and and by acquiring multiple activity and and causing a disease so so this is just a pretty a background information for you guys to understand it has changed so much from very beginning when I was seeing cancer patient when I was an intern trying to to help them and it was just like horribly disheartened because the only thing I can say that you have cancer I cannot do anything about it okay so things change a lot so in terms of kidney cancer the you know the most known kidney cancer and most of the people contracted it's so-called clear cell kidney cancer and and is it we notice a BHL disease and for suggesting me BHL disease for a long time but now with all the genomics I can tell you this is really really a BHL disease and and we make most progress of kidney cancer treatment on this disease and that's exactly what I say one year to three and then likely in five years and then the goal of my and and I was talking to Dr. Moser was that we should try to actually cure a significant amount of this disease before then we can actually say we make some progress then the other part of the disease sorry so the other non-clear cells so we'll call non-clear so because it's just so many different of them they have papillary and they have papillary type one type two they have chromophore they have a TFE3 tumor they have medullary type they're collecting type and there's something that we actually classifying so unclassified so these are all based on histology these are non-molecular characterization these are all just based on histology and there are other disease these are based on molecular characterization so this the kidney cancer is fascinating that's because that I'm studying and you know the patient I'm taking here it's just because it's a disease of many many many other diseases not like prostate cases one disease maybe a few disease long maybe three four disease this is like a disease of maybe 10 disease and in individual one of them we involve many many different kind of a mutation like SDHB patient I've seen of three of them for the past two three years they're only like maybe 20 family being identified in the whole world so you know so and the problem is that we we know how to treat this disease and it you know just genus talk about you know in old days the chemotherapy was the only way that I can that we can treat patient and that that you know some patient you know we need to know better how to use them but at a time the medium survival for five it's about a year and now it's much better we move the curve and it passed the clear silk disease is the bad disease but now you can see here the non-clear silk become a bad disease because we remove this curve from here and here and this disease the other 25 percent then basically left no trial and no meaningful trial and try to understand that but but hopefully by understanding the molecular makeup of the disease hopefully you can figure how to treat them more specifically instead of just say okay you have kidney cancer even you are non-clear silk kidney cancer but we just treat you as clear silk kidney cancer because we have no drug for it okay so that's the problem that we are facing so the the genomic studies now has been very clearly suggested clear-sealed type kidney cancer the majority of you know the patient here are patient or family and the type that they involve is called clear-sealed and it is a one-up the key feature is a chromosome 3p loss and the chromosome loss is because the first event is a loss of a gene called VHL and this and VHL is on 3p so we need to lose both good copies of the so-called tumor suppressor so that cancer can cancer take place and the key feature of these complexes regulate a phenomenon a protein it's called hip family school hypoxia inducible factor and these family proteins mainly induce hypoxia vessel formation and think about it this is it's part of our body responses if you have under hypoxia condition this gene need to be stabilized and they stimulate blood vessel formation that's why clear-sealed kidney cancer is full of blood vessel and that's why the drug they work not a chemotherapy agent they work the best they change the way we treat kidney cancer is the targeted therapy targeting blood vessels okay so that's what changed the practice and then the other thing that we know is about m-tore inhibitors it's been proposed maybe working here maybe working there nobody really understand what's really going on I think we may start to learn more about this and as you got kidney cancer clear-sealed kidney cancer very interesting for some reason it has to go to some reason to activate Torah pathway that's why Torah inhibitors are important and that's why Torah inhibitors is the first is the the kidney cancer is the first in a proof indication for m-tore inhibitors so we have made a lot of progress and these are the type nine that you can see from you know from 2005 or after they approved to 2012 accidentally to prove we moved the curve from one to two and half almost three but the problem is that we lots of it's about 20 to 30 percent better patient like this tumor strength about 50 percent of patients are stabilized for like a year or so then start to progress but it has about 20 percent of them even within a clear so they behave pooling in some way they die very very fast and then these are the patients that I try to learn more and and try to make them look like this and instead of they are dying like within three to six months but haven't said that that's why the first layer of heterogeneity and complexity and I think they are genomic determinants to determine which one is this which one is that which one is this I think I have some evidence for that but I don't want to bring it up to you guys kind of complete you could eat everything's way way too complicated but one thing I can tell you about is two real genomic studies now we begin to understand kidney cancer it clear cell kidney cancer is a VHO disease because VHO is mainly mutated and there are some other genes you know also mutated at high frequency like PBI 1 said D2 but these are all names one of the two 20 000 genes that we have in our bodies and the reason they are important because they when they mutated they make the cell give them more power give them more of the unwanted phenotype for our whole organism and they become try to become they differentiate they're probably afraid they don't die and take over the host it's a lose-lose situation because the cancer never probably get become another human being they all died so anyway so so we know much more about this and they actually tell us who will do better who will do worse because the problem that the issue what I have was maybe like 60 70 percent of patients will be cured by just surgery the problem is maybe maybe 20 percent of them will develop you see 20 years later or some of them what is it two years three years four years five years so spend millions billions of dollars trying to figure out who will recur who or not and then we develop all kind of the nomogram try to predict but here but I did study that we have done and it's not included here you should we should be able to kind of build a molecular feature and try to understand who will likely develop recurrence who will not instead of monitoring everybody exactly the same and that's that's to me that's um I hate to say that I kind of say this so in the past and I think it's very I don't want to say it's stupid but but it's exactly what I'm trying to say um because and then because it's the reason it's stupid is because you spend billions of dollars you will take 10 000 patient and you are not going to get the answer because it's just not the right way to do it and that's why the that's what health cost is so much because you don't select out the right patient to do the right thing and that's cost that's why it's so expensive okay so the you know I talk about you know the genomic studies that you know I talk about clear cell a little bit but now you know we we actually started to learn more about you know chromophobic type uh kidney cancer you know and and it's it's another type of kidney cancer it's very fascinating because this disease has multiple chromosomal loss it lost chromosome you know one two six ten thirteen seventeen it's kind of very very defective tumor by the point why would it this so defective tumor losing chromosomes so it should be a very wimpy tumor how come they if some of them about five to ten percent of this disease actually develop metastasis so we have some idea about maybe what's happening and and and and so on and so forth so the other things like you know papillary you know TCGA efforts has been trying to study this disease and we you know we like we'll be publishing this this year in 2015 and then it's some other disease I think I began to know more about this disease and then we have classified this we think this is about three to four different disease at least molecularity and these disease we have sort of pretty much better understand molecular handling of what these are these two are the one that at this moment really don't know much and this one happened imaginary happened in most of the African American who has a sickle cell trait and those patients always come if a patient come to see me it's about 20 some years so early 20s or early 30s and an African American patient before they came working at all I said this patient most likely have this bad disease is super aggressive okay and the most of the kidney cancer treatment nowadays that we have do not touch it so this is again so this is the genomic studies that was telling you that you know the kidney clear cell is losing 3p but the chromophore is losing 1 2 6 10 13 17 it's it's very crazy that you it's very effective how come you've come so you know so that's something that that needs to be studied in the future so the the cancer is it's genetically a Darwinian way where to think about a star which is exactly the single cell but it started a quite a different mutation and if you develop you know evolve a quality of mutation you can consider is a tree and maybe a different kind of tree but it before even they are evolving if they are it's within you know it's a localized disease you know surgeon can just sort of cut it out cut the tree whatever the tree to come whatever complex the tree is they cut it out you know then the tree is gone why do you need more about the intertumor heterogenesis of the primary side there was a big paper published by Charlie Rohmaston 2012 and triggered this whole wave of understanding the the heterogeneity but to me the heterogeneity of the primary tumor is it's it's important in predicting who is going to respond or who is going to relapse down the road but it's not as important in terms of do we really know you know how complex it is if you if you see many many mutations they are these these are passenger mutations have nothing to do with the pathogenesis of disease why would you care so surgery can take care of it the problem is that when the disease spread then it started then we started in color problem we need to deal with the heterogeneity and in the past it's very you know treating cancer is really you know old days like before even before immunotherapy is chemotherapy just just like a new period of war like bomb and everything did normal tissue get hurt tumor tissue get hurt then hopefully that you know normal tissue can recover better tumor tumor tissue get killed more and that's the that's the the way of treating cancer in the very beginning and then they'll target this therapy that you know if you try to find out where the the problem is and target it and hopefully you can get rid of the disease and now that the immunotherapy and something else that they're in a pipeline so this is the paper I was talking about that you know if you take kidney cancer it's like half fascinating disease if you take this is one patient and if you take tumor from there here different region of the primary or from the metastasis you're going to figure out it are carrying different kind of mutations and the problem is that interesting thing that is trying to teach us it diverge out crazily but they actually for example in this tumor this this different regions they all start with VHL mutation and this guy here branched out they mutate 32 and this totally different tumor also mutate 32 but different ways to mutating it so it's kind of fascinating right but we use always one mutation why would why would you acquire mutation but it also on the same gene suggesting there is a reason that you need to do that so it's not really just like a tree and I'll try to illustrate this way the way I think about cancer that is you know genetically it looks like a tree but phenotypically as I said the end output is like you need to acquire all the cancer phenotype that is they need to acquire different mutation on gene and gene translate into the phenotype that the cancer phenotype but once you started and actually you need you have for some disease for kidney cancer like for example they want to go through VHL but they don't they have to go to some gene to gain additional activity but it's wondering honestly started it has to go through the pathway it has to go through the same river and it is already predetermined it's not it's complex but it's not complex it's complex to a degree that we think is just too too bad we cannot do anything because they have to converge on certain genes and the reason I come around genes because they want to converge on function the reason I want to converge on functional pathways is because they want to gain common additional tumor phenotype okay so the easiest way I see it is this is my own personal you know view of cancer is I think it's it's it's a river you start with something and then you know you start to branch out but you don't have to converge and then converge against a gene level it can be on a pathway level but ultimately it is the phenotype level and that's why if you take if it's a clear cell cancer you start with the BHL mutation you deal with the BHL it works if you you know you started you know maybe it converts at mTOR somewhere so if block mTOR it works but whenever it gets too late I call you but later they start to acquire all kinds of way of mutation that's why you cannot even deal with it and because lots of them start to replace the the activity that you know rendered by the early mutation and it's become very difficult but that's the the opportunity of immunotherapy the immunotherapy actually does this maybe actually give you an immune system more target to deal with that's why immunotherapy is part of the game and I always you know and the reason immunotherapy is kind of interesting is you know we have our own immunity we were we born with our immunity and the immunity is really trying to tease out what use yourself so it's called tolerance I own okay this is my I don't want to attack it and if it's from foreign is a viral infection or bacterial infection you get rid of it so the strongest infection is acute infection you get rid of it and and then you live with your body right every single cell but you need to live with them through your lifespan so you need to develop a lot of tolerance and the cancer cell is it's part of it but it's just a little bit different because they may have cryolis mutation or that you have mutation maybe a little bit different it's a little bit dysregulated so so the immune the the immune checkpoint basically is just dialed down the activity okay so now you really try to recognize this by increasing your immunity and decrease the tolerance so the toxicity you can imagine is autoimmunity so it's very simple you think about you dial down your immune system and what happened what you're going to see is the immune autoimmunity autoimmunity disease so you know I will talk to about a vehicle and and and and then like I can say they all facts immune therapy is great it's important and I think it is correct but but I almost also reminded them that that we need to take all things into consideration you know therapy you know targeted therapy maybe even chemotherapy and treat figure out who should get what then get and then you are in the trial that way would be much much more meaningful and then the last thing I was trying to tell you that in the future there's another another thing that that people start to explore and then and that maybe actually contribute to future treatment is some of the metabolic pathway so again you start with DNA RNA protein metabolize and then this is basically trying to do something build up the DNA building DNA building protein building all those kind of things so some disease especially kidney cancer I think will be very range kidney cancer and pancreatic cancer very very metabolic driven disease I didn't know it's time to talk about it but it's really really a metabolic driven disease so I think metabolic treatment will be kind of interesting thing to look into for the future for some kind of cancer type just like immunotherapy will work on some cancer type not all cancer type you know the therapy work on smoker alone because it mutated heavily work on uv melanoma because it mutated heavily that generated a lot of new antigen the way you work on kidney cancer I've been thinking so much recently so it be really could be kidney cancer is really a very immunogenic disease it's not the mutation we know it's not a mutation because mutation is not that high but anyway so so that's my take on it and so so that's my 25 30 minutes