New Strategies for Cancer Treatment and Prevention in Sub-Saharan Africa

New Strategies for Cancer Treatment and Prevention in Sub-Saharan Africa



Corey Casper, MD, MPH, is Founder and Director of the Uganda Cancer Institute (UCI) / Hutchinson Center Cancer Alliance. He is also Associate Professor, Medicine, Epidemiology and Global Health at the University of Washington. Casper spoke about his global cancer work at the Duke Global Health Institute this week.

[Music] uh today I have the pleasure of introducing our speaker Dr Corey Casper Dr Casper is an associate professor of medicine um with adjunct appointments in epidemiology and Global health of the University of Washington he is the associate director of the University of Washington Fred Hutchinson um Center for AIDS research he is the director of the Uganda program on cancer and infectious diseases at the Fred Hutcherson cancer center and the director of their scientific program on AIDS Associated malignancies and infections Cory has been very active as the principal investigator he is the pi for AIDS malignancy Consortium Granton Seattle and he's the chair of the AMC capy saroma working group he is the principal investigator on an R1 that's studying hhv8 and HIV Associated malignancies and today he's going to tell us a little bit about a supplement that he's received to focus on Burkin lyoma um he also is the principal investigator for their d43 training award in kalala so you can see that he's quite accomplished in terms of his Global cancer work uh it's really a pleasure to have him here and he's going to talk about new strategies for cancer treatment and prevention in subaran Africa so welcome Cory thank you for the kind just to okay perfect well thank you all for coming I appreciate it and uh the columns present that interesting challenge for I content there's anyone hiding behind that I'm looking at you anyway uh so welcome and I I have a whirlwind presentation I'm from New York so I've been told I talk quickly um but I'll try and talk a little less quickly but I did really want to give a flavor of a lot of the activities uh that uh I've been uh involved with in Seattle uh really trying to sort of uh start a new discipline in what uh what many would call Global oncology so today what I'll describe is a series of things um I'll go into the research activities and my research Focus has been on viral Associated malignancies so I'll talk a little bit about that um and then I'll also talk uh quite a bit about some of the other cornerstones of our program which I frankly feel are very important for a global program and they include education and capacity building as well as clinical care so that's a lot to get through in an hour and I'll uh try and do that but if you have questions please feel free to stop me um so if you uh if I lose you I know that there's someone who's just off the plane from China and if I lose you right now and you don't remember anything else from this talk I just want to impress you uh press upon you three facts um so the first is that I'm going to try and make an argument today that uh really cancer is an increasingly important problem in global health I think that um for many Global health is a something of the purview of infectious disease doctors or way back when I started training tropical medicine um but the argument I'd like to make is that cancer is probably up there with the world's greatest Global Health threats um the statistics would tell us that more people die of cancer in low and mle resource countries than of HIV tuberculosis and malaria combined so clearly cancer deserves to be a global health issue um I want to tell you that cancer is not only a problem of resource rich countries so when I first started doing this work everyone said why are you working on cancer in a place where no one is wealthy enough to afford to get cancer um but 70% of new cancer cases are in low and middle- inome countries and so clearly this is a problem of of lower resource areas and really probably most importantly if you forget both of those things what I would like you to remember um is the argument I'll try and make is that by studying cancer and by studying it smartly um in international settings we can make rapid and meaningful benefits against cancer both for people living abroad but also for people in the United States so those are what I'll try and sort of impress upon you uh in the next 40 minutes and I'll try and tell you a little bit about the model that I've used to get at this issue and really a model that's based on close Partnerships and again on not just research but on capacity building and clinical care so the first part of the talk I just want to sort of acquaint you with what uh the burden is of cancer around the world so these are not my work these are slides that are uh or these are my slides but they're from work from uh uh from uh collaborators and from The Who so first what you'll see here is that um these are where I make the statement that more people will die of of cancer than of HIV tuberculosis and malaria combined and these are the numbers so it's expected by 20 20 um of the uh more than 10 million uh Global cancer cases that will happen uh in low and middle resource countries you can see that that will dwarf HIV tuberculosis and malaria combined um you can also see that these curves are very much Divergent where that the number of new cases in industrialized countries uh is growing at a a steady Pace but certainly one that is uh a fraction of the pace of the increase in cancer cases and resource limited settings so based on this I would say this is a strong argument to think about cancer in places other than just here in the United States um this is not a a slide that you were meant to see in any great detail but what it's meant to show you is that there's a wide world of cancer and so when you talk about studying Global oncology it really depends on where you're standing so here in the United States our most common cancers are not the most common cancers that we see in East Africa um when I speak with trainees and other students in global health and they I ask them why they're interested in global health I always asked them uh they asked me how I got interested in it and my interest in it comes from the fact that the disease that I studied kosi saroma you'll see is the most common cancer in the region of the at least in the general population in East Africa where I work so I think a strong motivation for studying cancer internationally is if the particular disease that you study is of extremely high incidence in an area that is not where you live and I can tell you that in 2012 the place to study kosi saroma one of the things that I study is not Seattle there were five new cases of in Seattle last year whereas there were 2,000 in ugand so clearly I think geography is important and the motivation for a global oncology program in my opinion should be based on where you want what questions you want to answer scientifically um so not only is cancer common in resource limited settings but it's very morbid so this graph is from a paper in the Lancet a few years ago and it looked at the association between Cancer incident and mortality so what you can see on the left is that in lowincome countries so each of these bars again the lines of different color you don't have to read carefully but these are all different types of cancers and for each type of cancer essentially across the board when you live in a lowincome area the number of new cancer cases approximates the number of annual cancer deaths so essentially one to one whereas as you look to the right in the United States about for every 10 cancer cases there are only two cancer deaths so what this tells you is that across the board not only is cancer common but in low resource settings it's very morbid um so uh that would tell you that Global cancer should should be a priority for researchers and one of the questions I get asked is well is it actually a priority for the National Institutes of Health now I don't pretend to be able to speak on behalf of the National Institutes of Health I wish I could I might explain some of my scores or other things like that um but to the extent that I do understand them I did have the opportunity of spending a week with Dr Harold varis um in Uganda when he came for our groundbreaking of our new facility last year um and these are taken uh uh he said a lot of things that would probably be off the Record uh but of things that he has said on the record um there's two quotes that I'll give you here so Dr varas said that few problems are more daunting or more tempting than alleviating disease in poor countries and Dr Neer Huber his predecessor a lot of people we've been talking a lot about the elections coming up all of you probably know that the director of the National Cancer Institute is the only of the National Institute of Health directors that is appointed by the president so clearly uh Dr varus's job might be in Jeopardy come the results of the election uh next week um but nonetheless even the previous NCI director uh his comments were for us to make true progress in cancer research we must address cancer as a global phenomenon and extend our efforts to emerging and developing countries so what I would say is that I think this continues to be a priority in NIH there's now a new office of global cancer uh that's been established and again they've been very supportive of the work that we've been doing um so I'm going to tell you about our work in Uganda um Uganda I'm just this is a model of of uh what I think could be done in many different places um so the question that I always get asked is why Uganda a lot of times I also get asked where is Uganda U but I won't answer that well I'll answer that question later but right now I'll answer the why Uganda so uh I study infection related cancers Uganda has the highest incidence of infection related cancers anywhere in the world and it had a single cancer treatment facility which although it was somewhat run down um and in need of some assistance when I first saw it in 2004 had a long established track record it had over 200 scientific Publications in cancer over the last 40 years it was the first place where combination chemotherapy was given to treat cancer anywhere in the world and it was the place where epan bar virus was first identified um there's also a very large community of international researchers in kalala and in Uganda in general uh so when I wanted to propose doing things like isolating peripheral blood monuclear cells or uh placing tumor biopsies in liquid nitrogen this was one of the few places where I thought that that could actually happen um so another reason why Uganda and I'm sorry that these are so graphic but um you know I uh I'm not an oncologist I'll say that as my dis although my child tells everyone that I am but um but I feel like I play one on TV I do see a lot of cancer cases um and these are five clinical presentations of cancer that I have never seen in seeing thousands of cancer patients in Seattle um so the top left is a young boy with lymphadenopathic kosu saroma uh the middle picture on the top is a patient with fungating kosu saroma a morphology that's never seen in the clinics in the United States uh on the right is a woman with kosu saroma which again are as rare as hen's teeth uh in the United States uh the bottom left is a child with burket lymphoma um and the woman the girl on the bottom right also has berket lymphoma but an abdominal presentation so um cancer the point of these is to show you very graphically that cancer looks different in different parts of the world and if it looks different there has to be a different biology that's my premise and so the question is what is the difference in this biology and what does that tell you about the pathogenesis of malignancy and I'll tell you about some of that work as I go through this um so the equation of heard that I found when I started working in Uganda in 2004 was a pretty dire equation there was a population of 34 million people so essentially the population of Canada uh highest rates of cancer in the world one oncologist uh one Cancer Clinic Center and no chemotherapy pay medications or diagnostic equipment so I summed that up as a cancer crisis but there were a lot of opportunities and so the question is how do you balance this crisis with the opportunities for cancer research um this is the history the program that I started in 2004 and I'll take you through this history but uh it took basically eight years to get to this point so in 2004 I established a collaboration with the director of the Uganda Cancer Institute uh to in principle study infection related cancers in 2005 I was awarded a grant from the darus duom foundation to actually study infection related Cancers and that's what kicked us off in 2008 our institution signed a formal memorandum of understanding and also signed them with the Uganda Ministry of Health and McCary University and those are very important because they actually hold all of these stakeholders to distinct promises and we all try and keep those promises as we move ahead um in 2008 we began a training program which I'll tell you some more about in 2011 we broke ground on our new training uh Cancer Clinic uh training center and research facility and in 2014 that facility will be done so that's the timeline and I'll take you through some of these things now so again what I say about this program is that it's about the research it's about clinical care it's about training and capacity building and it's about building an infrastructure to do all of these things so today in my talk while I might not go as deep as you might like to see for some of my research activities I will at least go wide and I'll certainly tell you about all of these things if there are additional questions or concerns about the research I'm happy to go into those as well um so now I want to turn to my research and again I mentioned that my research was on infection related cancers so this on the left is what I call probably the most ignored article ever published in Life Magazine um from 40 years ago uh so you see that the title on the left is new evidence that cancer may be infectious but on the right it says Marilyn Monro the pictures you'll never see on the screen and it's full of a spread of her in bathing suits so I'm pretty convinced although I wasn't alive to read this article that it was widely overlooked um but nonetheless this was uh the recognition 40 years ago uh indeed that uh cancer had an infectious ideology um and uh it's only slightly less ignored now but uh but I will tell you a little bit about about my view on this now I'm trained as an infectious disease specialist um and then you know there's an expression that to a hammer everything looks like a nail uh so to me I think everything's an infectious disease um but the evidence would suggest that up to a quarter of human cancers are attributable to an infectious disease it's actually about 22% now but I think that there is a large percentage of cancers that have not yet been attributed to an infectious ideology so I'm going to go with 25% um but when I look at the pieces of this pie of the broad CA of cancer um what I would say is that it's very hard to do something about the environment that genetics are very helpful for helping us to identify uh you know what the causes of cancer are but we're not so good at changing your genetics and the unknown that's not very helpful so of this pie uh right now I would say that we have the technology to eradicate prevent or better treat about 25% of the cancers worldwide so that's you could look at that as half empty and say that's not very many cancer or you could look at that as half full and say what an opportunity to make a meaningful difference on 25% of cancer worldwide so that's where where our Focus has been um if you're curious about the types of cancers that are caused by infectious diseases this is a table from the lanet oncology that was published last month and it uh lists the different types of cancers that are caused by different infectious pathogens and you can see that hepatocellular carcinoma attributable to Hepatitis B and C viruses is the most common uh closely followed by human pathoma virus related cervical and anogenital Cancers and helicobactor pylori um so this is the list the other thing that you'll notice is that the preponderance of these cases are in resource limited settings so another reason uh why to be in Uganda and why to be working on infection related cancers in Uganda I like to quote Willie Sutton so Willie Sutton robbed banks uh around the turn of the century and they caught him he wasn't the most intelligent guy and they said really why do you rob banks I mean you just Rob One Bank after another and he looked at them very quizzically and he said well that's where the money is um and so not to be so crude but if you want to study infection related cancers you need to be where the money is and that really is in places where these diseases are endemic and that includes Africa um so when I make a pitch for Global oncology what I like to say is that um there are lots of reasons to study cancer in places other than the United States and these are the main arguments why I would say that a uh you know a a a cancer researcher in the United States should even be remotely interested in studying cancer in places other than the United States so I would say that in places like Africa there's a high incidence in concentration of cancer cases so the Uganda Cancer Institute is the only Cancer Center in a five country region and so every Cancer case from a five prin region comes to one place anyone who's done clinical cancer trials in the United States and has fought with 2% participant in you know patient enrollment and clinical trials this is a very different situation um there are opportunities by studying very Advanced disease and I'll show you in a minute but over 80% of individuals present with endstage cancer um there's an ability to Target unique tumor Pathways such as the MC tumor enogen um there is an ability to investigate infection related cancers and also the impact of immunosuppression on cancer biology and then I think that there's a lot of interesting opportunities for comparative cancer biology so I've been telling some people today that we just saw our first case of a 13-year-old girl with widely metastatic triple negative breast cancer not uh you know uh the youngest case that's been reported in the literature in the United States I think is 20 and so um this is a very unusual disease and I think that clearly by studying that Pat you would be able to make meaningful inferences about the biology of triple negative breast cancer even here in the United States um this sort of graph on the top is what I use as kind of my way home I think any of us who are involved in research let alone Global Research can sometimes have their heads spun around and can really say you know what am I doing here I've been through you know every study we do has to go through seven irbs and so you know there are days where you just feel like you're mind numbingly defeated um and I always look to this slide U unfortunately these aren't the same girls but this is Susan on the left and Olivia on the right and essentially what we're trying to do is take a patient who looks like the left and make them look like the right um and so the way we've done this is through several distinct areas epidemiology cancer prevention clinical trials and translational science and in the next few slides what I'll try and do is just give you a very broad overview of the type of work that we've been doing in each of these areas it's not meant to be exhaustive about the research hypotheses or scenarios but it's meant to show you what I think are some of the opportunities that are afforded by doing this work in resource limited settings so first a snapshot so we have enrolled over 7,000 participants uh in over 25 studies um at our site in Uganda over the last uh six years um we have collected over 150,000 bios specim in a bios specimen repository um and the types of studies have ranged a broad range of cancers and that's what you see here and also a broad range of types of studies from randomized clinical trials to cancer registry studies to prospective cohort studies um first I want to start a little bit with the epidemiologic studies and the reason I want to start with these is because I maintain that unless you know where you are right now you're never going to know where you're going so right now there is very poor data on the incidents and Trends in cancer survival and resource limited settings especially in Africa so many of you may have heard this but there are two cancer Registries serving 6 million people that service all of 1 billion people in subsaharan Africa now there are other cancer Registries but they are not yet certified is comprehensive by the uh by the World Health Organization and I think that we have more data than than than that but really what the point is that there's a poity of data on what's going on out there so one of the things we've really tried to do is lay a foundation for knowing Trends in cancer incidents and survival in Uganda so that in the event we actually come up with something that actually changes those tends For Better or For Worse we can actually measure those and actually put metrics to the program that we are building so I want to show you one example um this is an example of um a study where uh so remember you know we all sort of take a lot of things for granted in the United States such as having a unique identification number although there's problems with ours at least you know people have social security numbers there's ways of identifying individuals in the United States and when they participate in population-based cancer Registries in Uganda there is no National identification number and so it's very hard to link data about cancer incidence Trends and any other Factor so one of the things I've been very interested in is how anti-retroviral therapy may change the incidence of cancer and places in the United States there was a 10-fold decrease in AIDS Associated malignancies within a year of initiating anti-retroviral therapy question is would you see that in places like subsaharan Africa so essentially what we did was we were able to link the cancer registry in Uganda to uh Records that are maintained by pepar about the Countrywide use of anti-retroviral therapy and what you can see is we're here for the three AIDS defining cancers kosi ciroma cervical cancer and hutkin lymphoma what we saw is that even though now uh between 2000 and 2008 40% of the people who need anti retral therapy now have access to it still not close to 100% the incidence of these cancers has changed very minimally there's been a 4% decrease with each 10% increase in art coverage for kosis there's been an increase in non- Hotchkins Lymphoma and no impact on cervical cancer so certainly the dramatic effects that we saw on cancer incidents um in this country we are not seeing in Yukon although granted there are very much differences in amount of population covered but these are some of the registry based work that we are doing to look at Trends in cancer incidents and how they maybe depend on another Factor like art use um in the United States we spent a lot of time um we don't even know uh much about survival of cancer in the setting of HIV in the United States so we spent some time trying to characterize this and this is a paper we published last year looking at the 2-year overall survival of cancer and the setting of HIV in the United States across the board this is generally worse uh than patients without cancer but we wanted to know this so that we could begin to compare this to what is the impact of having cancer and HIV in Uganda in Uganda at the Uganda Cancer Institute 60% of the patients with all cancers have HIV co-infection so HIV and cancer are a combination that go almost like peanut butter and jelly um in Uganda and so the question is how what's the impact of these two comorbid diseases well again when you think about how you would get at that these are how we've done it this is records room at the Uganda Cancer Institute and this is Hong win uh a former epid doctoral student who's now at the CDC who basically went through all of these records by hand and what I'll show you are some of the results of what we know about survival after a diagnosis of cancer in Uganda again really the First Data that I'm aware of that really start to look at survival after a diagnosis of cancer in subsaharan Africa so first one of the things you'll notice this is a graph that looks at the stage of cancer at presentation um and you can see that here it is divided between HIV positive and HIV negative easy take-home messages that there's no difference in stage based on your HIV status but what you'll see is that over 80% of individuals present with Street stage three or stage four cancer across the board and so this has clearly got to be an effort of global oncology programs downstaging cancer um the observation of the head of our oncology unit at the University of Washington when he came to the Cancer Institute is that 90% of the patients who were in the hospital at that moment wouldn't dbb candidates for therapy in Seattle be sent for paliative care so this is something that really needs to be done is downstaging cancer and here you can see the data are quite striking um here these are the first data on Survival so over uh over 3,000 charts were abstracted to get data on Survival for various cancers and again you're not meant to read these data but this is oneyear survival and this is a pretty standard cap Meer curve and you can see that even among patients who manage to make it to the Cancer Institute to get therapy one year overall survival is universally pretty poor surprisingly it was best for breast cancer which you can see up top uh it was about uh over 80% uh and it was worst actually for Non-Hodgkins Loma which you see at the bottom with uh a one-ear overall survival that was about 60% but again these are the First Data that actually looked to see what is the survival after a diagnosis of cancer and important not so much in themselves but to see when you change an intervention how this may change or improve over time um another question that sort of exists is is the biology and the response to treatment of these diseases similar this was a study where we looked at response to treatment for kosi saroma and we looked at all patients who presented with capos saroma our clinic in Seattle there were about 200 patients over a couple of year period and in Uganda where there were several thousand patients over a couple of year period but what you can see is that the red line and the blue line the red line represents Cala and the blue line represents Seattle and the top bars are overall response and the bottom line is complete responses but what you can see is that if you actually were afforded access to care your response to therapy was very similar in both settings and the reason I like these data is they get over this myth that you can't do anything about cancer and resource limited settings it's too complicated of a disease to treat these actually suggest that if you can get people to treatment then actually there's some efficacy there's also novel predictors of response to efficacy so we found for instance that having a low body mass index was associated with a five-fold increased risk of not responding to therapy we found that the type of anti-retroviral therapy you were on made a huge difference so whether you were on a proteus inhibitor compared to a proteus non Proteus inhibitor regimen was associated with a 16-fold increased odds of responding to your therapy and finally um this is obvious but with each 10% increase in the ideal dose of chemotherapy that you received and we looked at this because access is such a problem your odds of resolving your cancer increased twofold so again what that means is that we really need to work on strategies to downstage cancer and also to make sure that people get complete forces of therapy so adherence is a key issue um we also wanted to look specifically at non's lymphoma and here we found actually that the the bottom line for this study was again that there were novel factors which predicted outcome all of the factors which we use in the United States to predict outcome of lymphoma were not predictive of outcome at all so the international prognostic index and the LDH were not predictive of survival in Uganda what was most predictive of survival was actually your hemoglobin level and again I'm not sure why that is but now this has come out of three other studies that we've done now with breast cancer esophageal cancer and kosu saroma as well so clearly there's something about anemia that is predisposing these patients now whether it's causal or just merely Associated I can't tell you but again these are things that I think we really are seeing now by doing detailed studies of survival in the setting of cancer uh in Uganda um we've also looked at pediatric malignancies these are things that I think are not really well established so again kids with kosi saroma just don't exist in the United States but the left are survival curves for kids with different stages of copos I'm sorry the left is with kids with burkets and non- burkets Lymphoma survival curves and the right is kosi saroma on the top overall and on the bottom with with mild or Advanced disease so again what you're seeing is that even among kids these are very morbid conditions but that again they are very frequent in Uganda and these are things that again I think we need to spend more time looking at um I'll step away from the epidemiology studies for a moment and I want to talk a little bit about uh the more translational work that we've been doing um so this is from my favorite medical journal the New Yorker um and it says it's a picture of someone standing in the sun it says just don't stand there looking Prett cancerous and if it were only that easy um but a lot of the work that we've got done is to look into cancer biomarkers and so the reason I think that this is a very fertile field is that with infection related cancers you don't have to be so smart you have generally many many years between the acquisition of the infection and the development of the cancer and so we have a lot of opportunities over that time period to make uh meaningful observations and interventions to prevent the development of cancer so I'll tell you about a couple of things on this pathway um I'll tell you a little bit about some of the work we've done to identify how these viral enens are acquired and transmitted and then I'll tell you a little bit about some work that we've done to both inhibit these uh these viral infections from replicating and a goal to prevent them from developing malignancy and finally I'll talk a little bit about biomarkers so what is happening in this intervening time period between when someone acquires the infection and when they develop a malignancy that may inform cancer prevention strategies um so this was a a body of work that I had done in Seattle to develop a Ser diagnostic test for human herpes virus 8 infection and what I can tell you is that after eight years of trying this I'm done um it is a very difficult uh uh virus to make a Ser diagnostic assay against I've gone from being mad uh I've kind of gone through all of the stages of grieving um but now finally an acceptance um and I think that what is really interesting is that I I've been ignoring a very important message with that this is really telling us something about the biology of kosi saroma associated herpes virus that I actually now think it's immune evasion that is making it so challenging for us to detect certain humoral antibodies and we've learned a lot from this but all I wanted initially when I did this was to tell someone who was infected with this virus from someone who wasn't and I still can't do that to this date um but a large body of work in Seattle to really identify how this how we can identify an infected individuals and begin to look at novel risk factors for transmission of the virus make a long story short although we did develop an essay it's not the most sensitive or specific but it was good enough for government work and we used it to make inferences about transmission and we found that human herpes virus 8 was probably transmitted through saliva um in doing that work we then sort of put the serologic antibody tests aside and wanted to look at direct virologic tests so what was happening in these individuals uh who were infected with human and could we make inferences about those that went on to kosi saroma versus those who remained asymptomatically infected in their lifetime so this graph that you see on the right is a very complicated graph I call it my Admiral's uh you know lapel uh uh diagram um but essentially the way to read this diagram is that each row of the diagram is a participant that we followed for anywhere between 1 and 360 consecutive days and on each of those days we collected blood and saliva um the color of the bars that you see so each of those individual cells within the row is the amount of virus that was detected in saliva and these are ranked in order of these 70 individuals from days when the virus was frequently found and the color of a bar is the quantity of virus so red bar is virus that's found in over a million copies per milliliter a blue bar as no virus was detected and a gray was that the sample went missing but what you can see is that there's a dichotomy I think with your naked eye you could pretty much be able to draw a line and say that there are some P patients above which they have the virus detected almost on every day that you look and at very high quantity and then there's a group of people that really almost never have the virus detected even though we know that they are infected with the virus so what this tells us is that we think that there are different measures of how One controls these chronic viral infections um and maybe it's if we can identify those factors associated with the control of these viral infections we would be able to identify those factors that predisposed uh to development of kosi saroma and indeed what we found is that these individuals on the top are the indiv idual who went on to develop kosi saroma or multicentric castl disease and other complications of human heres virus a infection so um we repeated this study in Uganda this was actually my Doris dupan and although the graph is displayed differently here here each column is an individual and what you find is the proportion of days on which virus was detected in blood or in saliva and the cells are broken into patients who have uh who are HIV negative on the left I'm sorry on the top and HIV positive on the bottom uh and folks who are with and with without kosi saroma so one interesting thing about Uganda is that there are patients who have endemic or HIV negative kosi saroma and essentially the take home message of this study was that the virus was detected in both blood and saliva in almost all of the days that you looked in individuals with capos saroma um and that it was found very frequently in both HIV positive and negative individuals in Uganda which was very different uh than what we see in Seattle so essentially in Uganda there is a much higher prevalence of vmia with human her virus a something that's almost never seen in the United States and again whatever is controlling the dissemination of virus from this from the Oro fings to the central compartment is probably a key pathogenic mechanism for why you go on to develop kosu ciroma so I'll tell you a little bit more about what we're doing to try and look at that another concept that's very very important with these viral outages is when you acquire them um so the question was um is the timing of acquisition associated with how well you control these viruses and the answer is yes um and the way we sort of tried to look at this is that we went to the anti-natal clinic at malago hospital it's the larest anti-al clinic in the world they have the highest fertility rate in Uganda and so um we took women before they gave birth and we enrolled them in a study uh where we collected samples from them and then we were at the delivery collecting samples from the cord blood and from the infant when they were firstborn and we followed the mother the infant and all members of the household weekly at home for 5 years and in doing that we tried to characterize patterns of viral replication and we've done this now for all seven human herpes viruses and several other DNA viruses so it's a wealth of information that we're still sorting through but this is a very representative picture of what you see so what you see here is in the blue bars um those are um the one of the siblings in the household and you can this is for human herpes virus a and each of these is a week and the bar height is a quantity and you can see that every day that every time we sampled this sibling saliva they had very high quantities of human groupes virus eight in saliva um what you can see is that the red bar is the mother and she was shedding at Sal hhv8 from saliva at the time of delivery of the infant and then sporadically throughout the rest of the 5year period and what you see is in the green bars you see the probably the time at which that child acquired human herpes virus Aid infection now correlating that with the mother or with the sibling might be a challenge we're working on that molecularly but we also now can study all of the events we have peripheral blood monuclear cells as well as viral isolates from that time period of initial acquisition and what we're now looking to do is to sort of characterize the immuno maturation of the immune response to these viral enogen over time so these are again the type of studies that we found but what we found is you can see on the next study is this is the prevalence of evv detection in plasma by age in the cohort looking at um again all of the siblings and all of the primary kids combined and you can certainly see that the frequency with which you detect evv and the quantity in the peripheral blood is dramatically Rel proportional to or inversely proportional to the age of the infant or the child so again we think that there is a lot to be learned here about the timing of acquisition of these viral enogen the control of their replication and then how that eventually will again we're following all of these kids perspectively although these cancers are rare we do think that we will see incident cancers in some of these kids and be able to make inferences about pyrodynamics and immune maturation um uh I think that the other thing we've been very interested in is how replication is really important and if this is the key step along the pathway to development of malignancy can we inhibit viral replication and prevent the development of malignancy so this was a paper I published in blood several years ago where we had a group of patients with an hhba Associated disease called multicentric castus disease and we showed for the first time that you could treat hhv8 infection with an antiviral drug an cycler and when you inhibited their replication the patients felt better this was a disease that's traditionally treated with conventional chemotherapy so it suggested that for some of these viral enogen by inhibiting their replication you can inhibit some of the clinical manifestations of disease um we expanded this to do a randomized trial and indeed even in a randomized trial there was vast inhibition of replication of human herpes virus 8 with an antiviral drug and actually this is the first and only randomized control trial of an antiviral drug against human herpes virus a um this was interesting but you know gyl is a somewhat toxic medication it's not something that we could give widely in a population so so we were looking for other opportunities um we looked at uh we wanted to look at the effect of anti-retroviral therapy and although all of the current HIV anti-retroviral drugs shouldn't have an effect on most of the viral enens we actually found that there was a pretty dramatic effect so what we did was we took 10,000 patient days in which we had clinical samples uh either saliva or blood um from individuals who were infected with human herpes virus 8 and we compared the amount of virus that was detected in their saliva on days when they were on a specific anti-retroviral drug or when they were not and looking across the board again that diagram may be a little too small for you to see but what we found was that essentially on all of the proteas Inhibitors there was essentially no virus detected on any days that an individual was taking these proteas Inhibitors and that was more than 1,00 days of observation so clearly these prus Inhibitors were having a very potent effect on human herpes virus a replication when we looked in vitro and set up an assay system to monitor this we found that indeed the anti-retro drug nefir had a very strong anti-human herpes virus a effect and indeed we found that the in wasn't mediated by effect on the virus but rather on cellular Pathways that inhibited replication that means for the non virologists here that it's very difficult to induce resistance or mutations because it's a cellular pathway not a not a viral pathway um and it also means that there may be utility uh of targeting this pathway um in in studies where you want to prevent Baro replication um so so indeed now there's been uh nefir has had a number of other effects it's been shown to have strong proapoptotic and anti-neoplastic effects there's actually 16 clinical trials of n interview right now being used in HIV negative individuals as a treatment for solid tumors and the results have been somewhat mixed but nevertheless I think that it could clearly have a role um in the prevention of viral Associated malignancies so the question is how would you study that um and U maybe I'll skip this slide um well I'll come back to it but there's a slide later where uh I'll show you a study that we have ongoing we're actually about to launch in the field um where we are comparing the addition of nelfinavir to a standard HIV regimen to see whether that's effective in reducing the incidence of AIDS malignancies so I'll talk about that in a little bit um I have two slides here on what we're doing to try and look at the human immune response I've talked about it very broadly to say that the immune system is controlling these viral infections this was a study where we looked at neutralizing antibodies to human herpes virus 8 and indeed we found that in patients with capos c neutralizing antibodies were completely absent um whereas in other asymptomatic forms of hhv infection there were very high tiers of neutralizing antibody this study was done in Seattle and one of the confounders was that all of our patients with kutu saroma had HIV so uh we didn't have any endemic kosi saroma in Seattle but in doing the study in Uganda we' repeated it and found that even in endemic kosi saroma neutralizing antibodies are absent and again we think that there is clearly a role of neutralizing anti antibodies and the prevention of these malignancies but how much they contribute is unclear so we're trying to assemble a more comprehensive picture we're looking very closely at te cell immunity and we published recently that Gamma Delta T cells a cell line that we were attracted to because they have they're intimately involved in the control of viral replication at mucosal sites and that's where these herpes viruses tend to replicate um we found indeed that a deficiency in Gamma Delta T cells the the V Delta 1 subtype was associated with poor control human herpes virus a replication so again we're trying to put together a comprehensive picture I think we've shown that replication is associated with progression to malignancy that there's a phenotype in individuals where there is poor control of replication and now we're trying to look at what is the association between specific components of the immune response and that replication phenotype um I also want to just mention that we've done a lot of work with tumor genomics um so one of the things I mentioned is that the the what you see the morphology of cancer looks very different in ugand than where it looks elsewhere and so here are two very unique morphologies of kosu saroma you see on the right there's a patient with plaque-like Kos saroma and on the left there's a patient with nodular Kos saroma and what we did was we looked at the expression of latent and litic human herpes virus a genes and found that the macular phenotype was associated with a preponderance of litic gene expression and that the nodular phenotype was associated with uh more latent gene expression so so again what this means for the pathobiology of the tumor is not clear one inference is that perhaps by T targeting nodular kosi saroma with antiherpes RS8 uh drugs you might be able to make a contribution to the clinical care but it also may suggest why there's different morphologies of this disease I think that this model and looking at what is the gene expression of viral Gene products um with different subtypes of non hodkin lymphoma and evv and with different uh presentations of HPV Associated disease may also lead to observations about the biology of these Cancers and again I would say it's it's this application of what we're seeing at the bedside uh to the bench uh that that we're actually being able to make these observations um this very confusing diagram shows a little bit about um what what other things we're doing with tumor biopsies so we've established a system by which we can uh take a piece of tumors that are established from the operating that are obtained from the operating room and send them off for detailed genomic and also proteomic analysis and essentially the take-home message of this proteomic study that we've done for Kos saroma shows that almost all of the uh of the proteins that are overexpressed in the Kos biopsies compared to normal skin um or to peripheral blood mat back to the interferon gamma pathway we know that interferon gamma is very important um in the control of human herpes virus replication now what this led to is that it led to the identification of 11 proteins that are secreted and widely abundant in peripheral blood that we're now looking at and evaluating it biomarkers so our thought is is that because these these 11 secreted proteins are highly abundant they may be very useful for the early detection of kosis saroma so could you use that in HIV clinics to identify patients who are have sort of subclinical chaos that then you would Target for more aggressive anti retroviral therapy or could they be used as prognostic biomarkers to suggest those patients who do poorly but again it's this proteomic approach of chaos biopsy material that's allowed us to do this um fin we just uh were awarded a grant from NCI to uh to work on the tumor genomics project and we have been isolating uh tumor tissue from about 600 individuals uh where we will try and understand whether the basic genomics of four Sentinel tumors differs between what we see in Uganda from what is seen in the United States and I think that that comparative genomics especially with the well annotated clinical phenotypes that we will have will lead to important inferences about cancer uh both in the US and in um this has also led to another grant that I just got which is one of the nci's provocative questions grants um this grant hypothesizes that there is an infectious cause of many cancers that don't yet have an identified infectious ideology and so myself and Denise Galloway at the hut will actually be looking to identify viral ideologies for lung cancer HPV negative anogenital Cancers and evv negative so more to more to follow on that but we're very excited about this new project which again will be based on tumor material and serum samples from the the cohorts um I mentioned again that I think that this work is very nice and it in understanding the biology of cancer but really can we do anything about it um and this study is a study that came out of these findings so by making these inferences about n we will be conducting in conjunction with the a malignancy Consortium a 1400 person trial to see whether the addition of nelfinavir to Conventional anti-retroviral therapy prevents the development of malignancies in individuals with HIV and so that's a real example of taking an observation that was initially made to clinical cohorts to the Ben to the bench and then from the bench back into the implementation science Arena so we're excited about that as well um finally where all of this is culminating is that um because of the work that we've done in Uganda NCI has asked us to to see what it would take to uh to set up a network to study burket lymphoma um and so uh we've just embarked in a project to set up a network to study Burk Loma in 23 different countries uh 23 different sites I think it's only 18 different countries but they're in uh subsaharan Africa as well as Central and South America and over the next several months we'll be evaluating these sites for their Readiness to participate in both clinical and translational studies and for those sites that have a high incidence of burkus lymphoma that are deemed to be not ready we'll be working with them to build the infrastructure to participate in clinical care and clinical research so it's a project that we're very excited to kick off uh this month um I want to turn my attention now just in the last few minutes of the talk after that sort of dizzying head rde through what the translational science was to talk about some of the other initiatives that I really think are cornerstones to the program and those are the clinical care and the educational and capacity buildings um so to date in the last 8 years we've trained over 200 ugandans and Americans um in cancer research um and we've had this through three NIH training grants but um it's been um a wide variety of disciplines um I mentioned that there was one oncologist when I first came to Uganda Cancer Institute we've trained 12 in Seattle so now there is a total of 13 oncologists still not enough for 34 million people um but that type of capacity building has been very very important to doing the type of work that we are very interested in doing and for allowing ugand to develop the capacity to care for their own cancer patients in country um the training program has been very successful the Ugandan Physicians have all of the rights and privileges of our medical oncology fellows you can see them here in the clinic with myself and oi press and they're in the clinic with Dr GR but it's been a very successful program and I would also say it's been extraordinarily successful for people in the United States who haven't seen a way to get involved in global cancer research so we've sort of opened that pathway um we have now uh the first NCI k23 Grant uh to be awarded overseas uh and again we see that as being a pathway uh to allowing Independence in our Junior investigators um clinical care capacity I think is really key as well um you know again it's very clear that coming to Uganda Cancer Institute in the past has largely been a death sentence and so how do you get around that so I mentioned that we've increased the number of practicing oncologists we've also uh We've started a pilot project where we've come up with a standardized protocol for treating every patient with burket lymphoma it's not a novel agent protocol they're all getting the three drugs that were first investigated in the 1960s but we're administering them uniformly and with optimal supportive care and essentially the question we're asking is how good can care get based on the current resources before you go and invest in additional resources um we now have uh nine uh meetings each uh each week that are attended by uh by both sides of our uh you know teleconferencing sort of setup I think much like you do here um and that's been very uh it's been actively attended by our clinicians on both sides of the pond um and we're very happy to say that we're starting we started construction on a new uh facility which I think will really be the first of its kind the first training facility uh research facility and Outpatient Clinic devoted to cancer in subsaharan Africa we've also developed clinical guidelines for the three most common cancers uh in adults and kids and looking to see whether the implementation of those guidelines leads to better care this is a a projection of what the new cancer institute will look like in 2014 we're all very much looking forward to that um and finally I just want to end with the slide that I call the the benefits and so if you look at the slide very closely even though it doesn't line up perfectly what you'll see is essentially that the benefits for participating in a program like this are the same for people in Uganda and the United States so on both sides I think that this leads to the earlier diagnosis with cancer through biomarker Discovery the cheaper and more effective treatments for cancer and again developing treatments specifically for ugandans and Americans based on similarities and differences in cancer biology that we observe in these two settings so um I want to stop by by thanking uh my collaborators um so all of these Studies have been done in collaboration with the Uganda Cancer Institute uh we have a staff of 40 individuals there that help us do these studies uh the work has been supported by a number of mechanisms uh Dar Duke foundation usaid and then both niid and NCI at the National Institutes of Health um and uh I thank you all for for listening so maybe I'll stop now take a deep breath and maybe take a few questions do we have questions for Dr Casper is anyone still with me do you want to comment on uh uh the issue of inflammatory biomarkers uh and predisposing to different types of cancer in uh in Uganda for example yeah so well I'm not exactly sure um you know I think that the um the issue really that I think is uh that's becoming increasingly clear is that um it's this interplay between the host genomics and the viral infection that is leading to uh the development of cancer and I think think that as I said with KS most of the biomarkers are mapping to an inflammatory pathway the interfering gamma pathway and we're also finding as I mentioned before that a depletion of some of these important you know Gamma Delta T cells um and as I mentioned to you these uh these mdscs which are cells that are really important for shutting off inflammation are important um in these malignancies I would say that the work to date has been somewhat mixed I think if you look in the literature um a lot of people are sort of looking in the peripheral blood at inflammatory cyto kindes and trying to correlate that with a cancer phenotype and I think that that's probably not the best place to look and I think it's very hard to measure these these uh these inflammatory biomarkers in the peripheral blood so my hope is that as we improve our ability to look at gene expression arrays and proteomic acids of these tumors we actually get a better signal of what's happening with the inflammatory sort of biosphere Within These tumors um and as we have perspective cohort studies where we have individuals where we can have intra individual sort of dampening down so we can measure someone's inflammatory biomarkers maybe in the periperal blood before they develop cancer and after and how each person act as their own control I'm hoping that the signals will become a little bit more clear but for right now I would say it's clearly got to be important but the inflammatory signals to focus in on are getting lost and I think a larger picture yes Nelson is it be looking at the gut microbiome of these to the population or the skid microbiome of these people yeah it's an interesting question so the question is is anyone looking at the microbiome so I would say that I think up until now a lot of the work on infectious diseases and cancer has been looking at a single microorganism and a single malignancy and I think that that's probably a little naive I mean we know very much that there's an interplay for instance between the herpes viruses and HIV and so why is it not possible that the either microbial community of bacteria fungi or viruses as a whole is actually contributing to the incidents uh to the manifestations of these diseases the place where we're starting to look at that is in Burkin some foam so there's a theory and I admit I think it's a little bit you know out there but it's at least a place to start is that uh it's actually as you know the the burket tumors in Uganda frequently present in the jaw and so and there's been an observation at least that there's an association with dental eruption so certainly shortly after the kids their some of their initial MERS come in they start to develop these per lymphoma now I think it could just be coincidental timing but one of the explanations that's been offered is that there may be a change in the oral microbiota that then leads to a permissive inflammatory environment for the development of malignancy so to get at that we actually have now been obtaining uh you know fresh frozen saliva uh and then inter Dental uh samples uh to look at how the microbiota changes in these kids from birth to the time that they develop their Dental eruptions and hopefully we'll I mean I hate to say this but hopefully we'll see a number of cases of burkets in this highly emic area that will allow us to look at how that changes and predisposes to the development of the berates but that's the only work that we're doing I think that clearly more globally there is a lot more work that's being done on gut microbiota and how that's influencing things like gastric cancer um but I think that's a very important area that is one that's very right for investigation but we are not doing very much in that at the moment yes Mike Cory is incredible body of work uh clearly you've worked very hard to get funding opportunities to to get these programs initiated could you comment on sustainability you know how do you TR how do you transition these from the initial funding and research opportunities to uh the local governments uh picking these these kinds of activities up so that they'll have a long-term impact yeah that's a really important question so um I think that there's a couple of principles so I mentioned Theseus that we've signed memorandums or understanding and you know at first I was sort of like this is just you know I have a long list in my whiteboard in my office of the things that I was never trained to do despite having three degrees um that I do all the time I'm sure we all feel this way um but one of those is negotiating memorandums or understandings um but they're really important actually in the end and the reason I think that they're so important is that our memorandum of understanding with McCary University says that for every person that we put in a long-term training program they will be bonded for five years of an academic appointment at McCary um the memorandum of understanding with the with the government of Uganda is that all of these individuals who receive long-term training will actually be be made Ministry employees and that in Uganda is sort of has a number of things that are you know that go along with that as benefits um all of those things though don't ensure a sustainability of a research program or a research career so what do you need to ensure that well you you know I think there's a vaccinology there's this concept of the push and the pull right you can either mandate that every you know vaccine maker in the world makes a vaccine at prices that you know the low resource you know countries can obtain it or you can actually say that they'll come up with a way to develop a market so low resource regions can actually buy these products that's the poll model at a way that the market can bear so what we say is that we can mandate that you know someone goes back to Uganda a lot of programs I don't know if you guys do this but they make the trainees sign a statement saying I will go back to my home country for five years well to me that's almost like a prison sentence like what's the point of sending you know you train someone you invest all of this in them and then you send them back to an environment where they can't use their skills so although we do make our traines do that um we also try and back that up with support and we try and make that support come from the local government so again by having the ministry and the medical and the and the medical school U provide commitments to faculty positions that's one way the second way is that um when we sort of the goal of our research lab so we do 75,000 of these molecular biology assays and about 50,000 of our other assays in country in Uganda and so we have a laboratory there we have it staffed and operated by ugandans and so what we ask the government to do is to use that as a contract lab by which they do their clinical work and then we use that as well as our research grants to help maintain it and offset the operating costs so that it's perpetually available so I think that this sort of model of having a Synergy between um using a shared set of resources um making the government and the local community sort of buy into this um and then frankly for me it involves a lot of planning to try and make sure that when we sort of put in a technology or a piece of equipment that I can see a long way into the future a way how this will be the back bone of of the work that will the researchers will want to do so you know recognizing that what people what the researchers want and need in country is thermocyclers and floms and so those are things that we make investments in other things that people have asked us to invest in we haven't because they're not sustainable so it's not a complete answer it's a problem I mean I think you know um I was told by the minister in Uganda the previous minister of Health that um Uganda couldn't possibly you know do you know make any investments in you know in cancer cancer research or Cancer Care and it was ironic because the day that I was told that by this person the Ugandan president announced that $720 million of Russian fighter jets were just purchased so you know I went back to them and very politely I said is it can't or won't you know so I think that um I think that um they came back to me and said you know um we've never been told that cancer is an important Public Health priority we're not seeing that you know no one from our own country is telling us that and frankly when Bill Gates comes and sits at my desk he says you have to go do something about HIV tuberculosis and malaria So my answer my long answer to your short question is that I think that by raising the literacy of the importance of cancer as a public health impact in that region um that makes more Focus from the government when I started in Uganda $10,000 was the budget from the Ugandan government Ministry of Health and Cancer Institute last year it was 1.5 million now 1.5 million for you know over 20,000 cancer cases is not nearly enough money but that shows that I think when you shine a light on this that you will find sort of a bilateral support so the model I would say is generate the data to show that this is an important issue generate the data to show that a dollar spent is actually well spent and actually returns that investment and then be very shrewd about how you ask your partners to commit with not just words but with dollars or Shillings uh to to the what you're trying to do so you know I'm not I'm not standing here saying that I that this has been future proofed for the next 20 years but I do think that there is an ongoing commitment by our program and by the Ugandan government that I think at least for the next decade you know things are in a pretty solid form other questions Cory and that cohort of 300 families that you're studying do you have hepatitis B data so we do um yeah and that's actually launched another interesting area um it's I mean know so we do have some data on the incident of he we find that there is about 40% of these kids who acquire the infection sort of around the age of two um but the other thing that's interesting is that um we have another cohort that we've been looking at of adults with HIV infection and right now in Uganda as I'm sure this is in Tanzania Universal Hepatitis B vaccination is at Birth but there's no catchup vaccinations so HIV infected adults who are hepatitis negative are thought to not be a risk for it because you only get it as a child inic areas we're actually finding a very high incidence of hepatitis B in adults with HIV infection in incidence yeah interesting so again that suggests that um although the Pediatric cord is very interesting for these 40% of cases that are required at a young age there is continuous acquisition at an older age as well interesting yeah well Cory thank you for traveling here it's been a pleasure to have you with us [Music]

#Strategies #Cancer #Treatment #Prevention #SubSaharan #Africa

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