 Thank you all so much for coming today and I am really excited to have a conversation with you today about some new ideas in oncology which are sorely needed as we all know that I hope will pique your interest and perhaps put some ideas into your brains and you will help us move these ideas forward and get some traction with treating a very specific area of oncology and that's patients with currently incurable metastatic cancers now what I'm going to talk about is is very theoretical at this point it's not ready for prime time but still I think it's important that you hear about it and I think it's important also to know when not to apply these ideas and we'll talk all about that in this talk so here we go so we're going to journey today through the evolutionary landscapes of cancer and we're going to talk about how cancer arises through evolutionary processes in between species how it how cancer rates vary within species why fertility and cancer risk go together you don't get one without the other how current models of cancer treatment can sometimes make things worse and how a branch of mathematics called game theory may help us move cancer treatment in the right direction so cancer rates vary between species large species and long-lived species tend not to get as much cancer so elephants don't rarely get cancer the title of the talk is why elephants don't get cancer they actually have a lifetime cancer rate of about 5% it's very low mice however have a rate of about 100% at their lifespan of two to three years and humans are in between at about 50% and the reason for this is evolution that's the reason for most that's the answer to a lot of questions in biology the definition of evolution that we're going to use here is change in the heritable heritable characteristics of biological populations over successive generations there are other definitions but this is what we're going to work with here there are some principles of evolution that I'll review for us natural selection fitness and adaptation natural selection is officially the differential survival and reproduction of individuals due to differences in phenotype and I would argue that it's really the differential reproduction because natural selection if you forget the the fancy formal definition answers the question who gets to reproduce and what I was practicing this talk one of my colleagues said hey you switched the names on there I didn't do that this was a this is a movie poster so what allows selection you have to have variation if you want to make a selection and phenotype not genotype phenotype is what is selected and that allows epigenetic variation to to play a role in cancer and other evolutionary processes and these variations can occur within species an individual or within a cancer a single cancer harbored by an individual will have variations that allow for selection of certain we'll call them species in that realm to fitness I want you to throw out you know you this is the ancestral health crowd you guys are all so fit it's kind of scary but I'm not talking about the kind of fitness that you exhibit I'm talking about the ability to win at reproduction doesn't necessarily mean you're strong it means that you're well adapted to your environment that's it it means that you are able to extract resources from the environment you accidentally find yourself in and we all accidentally find ourselves here on earth and if you have any other ideas about that I love to hear it but and we have to adapt so fit organisms are able to adapt because they have the right tools if you do not have the right tools to reproduce in your environment you will not be fit we have we think a last universal common ancestor here she is this is grandma for all of us this is a bacterium most evolutionary scientists believe that the last common universal common ancestor of most creatures on earth today was a bacterium or a bacterium like creature what do these creatures do they have two imperatives they eat and once they've eaten enough they divide eat divide eat divide they are immortal this is a paramecium this is a slightly more advanced but single celled creature it eats and divides eats and divides this is a didinium I think it's really pretty and delicate lacy it looks like a lampshade to me but it eats and divides and that's all it does so the one celled organism has a pretty easy task it has to stay alive and it has to divide it never dies as long as it doesn't get eaten but a one celled organism is very very edible this is our paramecium this is our didinium and this is what happens when they meet this is the didinium our beautiful delicate lacy little lampshade eating a paramecium it thinks it's going to get all of that in I don't not sure how but they apparently they do this is a yeast this makes your beer and they divide they reproduce by budding these are little buds that you can see on our yeast here in a scanning electron micrograph yeast have figured out that there's safety in numbers so sometimes they don't completely separate when they divide Hydra has gone a little bit farther it's a fully multicellular creature with division of labor and all sorts of new interesting things multicellularity is a good deal for cells they it's evolved separately at least seven different times it allows variations that can complement various niches and it allows sexual reproduction and all the goodies that come along with that the variations it also changes the predator-prey relationship you're a better predator if you are multicellular and you are less good as prey you are better off if you're multicellular if you are prey but multicellularity has a dark side all of those cells that were previously driven with a program to eat and divide and eat and divide still have that program that program has to be shut off it's hard to shut off the eat divide eat divide program if you don't completely shut it off in a multicellular organism you get cancer this is a mushroom what's what's called rose comb disease this is a tumor on top of an ordinary mushroom hydra here's a normal hydra on the left here is another normal hydra and on the right is a hydra with a tumor you can see that asymmetric symmetrical bulge there with the t next to it that's a clue here's a normal saguaro cactus here's a saguaro cactus with the tumor is growth at the top so we've talked about how unicellular organisms divide then the current organism becomes the next generation there's no death involved in multicellular organisms only one cell makes it to the next generation the germ cell the rest of the body is disposable the only job of the rest of the body which we're going to call the soma here is to transport the germ cells to the next generation so what you consider yourself you are a vessel for transporting either ovum or sperm to the next generation so again we've contrasted germ cells and somatic cells the soma let's spend a little more time on this again the soma transports germ cells to the next generation usually via sexual intercourse not always there are some variations on that theme with some different types of moss and other plants with very complex reproductive cycles but in general the soma only needs to hang around long enough to make sure that the offspring will survive and then it can die so these are the only intergenerational travelers in multicellular organisms these are the only ones that really get to reproduce ad libitum and go on to the next generation so multicellularity requires cooperation you have to have division of labor you have to transport resources and allocate them you have to maintain the tissues and the extracellular environment but again multicellular organisms are composed of cells that have all descended from unicellular organisms that want only to eat divide eat divide they still want to do that they have those programs in the background those programs have to be shut off in favor of the newer programs that fulfill the goals of the larger multicellular creature so wayward cells if a cell decides hey I want to go back to the way it was when I was a bacterium it's executed and if that execution fails for some reason cancer can result so let's talk about something called pedos paradox pedo was a biologist I believe in the 1970s he noticed that large animals with all of their cells and their long lives should always get cancer because they're at risk and small animals should rarely get cancer but as we've learned elephants rarely get cancer mice usually do and humans are in between so why is that you may know that large dogs are very prone to cancer and most will succumb to cancer between the ages of five and eight where small dogs do get cancer but they usually have a long life and live to be you know anywhere from 12 to 20 years old same in people these are from a family in Ecuador that have a genetic variant called laron dwarfism they do not get cancer they do not get diabetes they don't actually live any longer than anyone else their life spans are normal 60s 70s 80s but they don't succumb to those two diseases the reason for this is that within a species is that smaller body sizes and fewer cell divisions lead to less opportunity for DNA replication errors and we'll talk more about this in the in the future but this is only within a species so within a species a large specimen is worse off in terms of cancer than a smaller one and that goes for humans as well and the reason for that is part of the reason for that is so we think a hormone called IGF one this is the link between cancer risk and size within a species and there are different versions of this in Chihuahua's and Great Danes there are different versions of this in humans with laron dwarfism and other humans and oops there we go sorry so again pedos paradox just to review again why is there a lack of correlation between body size and cancer incidence between species and not within species and the answer is that the soma deteriorates with age the soma requires constant surveillance communication the wayward members have to be executed the intruders have to be expelled or murdered or contained there's got to be transportation of resources throughout the soma waste has to be removed there has to be eating and metabolism there's landscaping the pH has to be kept nice and comfortable the hydration oxygenation the microbiota have to be kept in check the specimen has to be prepared and beautified for courtship injuries have to be repaired DNA has to be repaired this is so expensive that it is kept up only until reproduction has been completed or the reproductive age has passed and all chance for reproduction is over so by that time the question of who gets to reproduce who is fit has been answered and the soma maintenance or lack thereof no longer influences the next generation does that make sense if you're not reproducing and the soma deteriorates with age you cannot have that effect the evolution of the species so there are ways to slow this process down it's mediated mainly by things like inflammation and intermittent fasting caloric restriction maybe metformin these things are all being looked at I think by a lot of you folks to see if these might help cancer however is pretty much a given for an organism that's aging once the soma gets old enough and that's because cancer is a disease of gene genes and gene expression so DNA can be damaged it can acquire inappropriate epigenetic tags or lose epigenetic tags that it should have this can happen with external factors or internal factors so just living breathing metabolizing eating causes DNA damage so I want you to take a look we're going to talk we're going to spend some time here on DNA repair so DNA damage is usually repaired pretty quickly there are a million DNA damage events per day per cell by some estimations now the this varies by tissue and by organism and by all sorts of things but this is a you know this this is a reasonable number for a lot of tissues and the there is an error rate in the repair of DNA or just plain old division and it's 10 to the minus 8 to 10 to the 10 minus 10th and if the repair is incomplete the cell is either executed or put into a dormant non dividing state so I'm going to bring you back to fitness again and fitness has nothing to do with strength or muscles or health or longevity it has to do with the ability to reproduce in our definition of fitness in evolution so the more fit a cell is in a tissue compared to others in the tissue the more likely it is to cause a cancer in other words I'm going to say that in a different way the more able a cell is to divide within a particular situation in a tissue the more likely it is to be able to cause a cancer so in an adult organism once growth is over with increasing the fitness of a single cell is not necessarily a good idea and any mutation which does this is something to worry about so an organism as it's or a species as it's evolving can decrease its cancer risk by decreasing the mutation rate or increasing its repair capacity now you can decrease the mutation rate by having a short lifespan which requires that you reproduce very early because you've got to get your child bearing in you can have a you could decrease the mutation rate by having being small you can decrease your metabolic rate by eating less decreasing your body temperature and you can avoid mutagens well humans can do a lot of these things animals don't necessarily do these things but we're going to get back to elephants and I'm going to give you a hint here what if you increased the activity or number of your DNA repair genes or their accuracy now that would improve the mutation rate so that's what elephants do they actually have 20 copies of the TP 53 gene which is a tumor suppressor it's involved in the repair of DNA damage humans have only one copy of this gene and mice only have one copy so of course one of the first things when this was discovered one of the first things that was tried was to insert artificially into mice several copies of the TP 53 gene it did work it decreased tumor formation but it also increased aging and the mice didn't live any longer so that still needs that strategy needs some work apparently so life strategy is involved in cancer risk and the life strategy of the mouse because it has such a large short lifespan is to reproduce fast and massively and hope some of the young survive and then to die elephants have a different life strategy they grow very large they mature late they have very few young and they take exquisite care of them so most of them do survive so the elephant requires a lot of p53 because it has to maintain this huge soma over a long over many decades so who gets to reproduce or can I divide now is a question each cell in your body is always asking its neighbors is it my turn is it my turn is it my turn well it's not their turn unless they're the germ cells and there's only you know not very many of those so it's a bad lottery and you know on a certain level there is a pressure within each cell to escape from the constraints of being part of this multicellular organism go its own way and go back to being a happy little immortal bacterium so in youth this process is heavily suppressed there are a lot of checks and and blocks and obstacles to unwanted division in young multicellular organisms and that's good because most of the DNA mutations that are going to occur when does when does DNA mutate it mutates when it's dividing when our cells dividing when you're a fetus mainly I mean there's this huge you turn from you know one cell to organism to an egg and a sperm into you know however many cells there are by the time you're born and in in 50% of all mutations occur by the time you reach maturity age 20 all 50 behalf of the mutations that you're going to have in your lifetime are there then and most young people don't get cancer there are cancers in in children even babies and that's a whole that's a whole different talk but that's because so many of these mutations can occur very very early in life so aging permits the emergence of emergence of fitter cells and remember what the definition of fitness is it's the ability to reproduce the propensity to reproduce so aging tissues have decrease in their tissue oxygen levels blood flow there are important changes in the glucose and insulin levels with aging and maintaining and suppressing these changes is very expensive what also I want you to take away from this if nothing else is that tumor suppression decreases fertility and that is why these tumor suppression genes mutations in tumor suppression genes that cause cancer remain in the gene pool it's because people with some of these mutations actually are much more fertile and reproduce more and an example of this is the BRCA mutation which all of you have heard of the mutation results in decreased activity of a DNA repair gene related to the TP 53 gene that we saw in the elephants it's called p53 and studies have shown that carriers human carriers of this both male and female have more children and have them earlier we have no idea why that is but cancer as you know is very frequent in BRCA mutation carriers cancers of all sorts although it was first discovered in breast cancer so what oncology needs to do is to drive the fitness of cancer cells in the direction that is beneficial to the patient and we can learn a lot from what's called integrated pest management in agriculture where the ecology is engineered to a certain extent to increase predators of a pest to decrease food supply of a pest rather than just blanket blanketing the pests with some sort of pesticide which can engender resistance these maneuvers will often be much more successful in the long term so what is resistance I'm talking about resistance it's the ability to survive an intervention designed to kill you okay so we have insecticide resistance antibiotic resistance and bacteria herbicide resistance in plants resistance is produced by selection pressure it can evolve naturally because of spontaneous mutations we can cause it and we often do when we treat cancer so we do that by exposing a cancer cell population to a large continuous dose of treatment so in the wild in a situation when we're talking about cancer now but it would also work with with insects any resistance that you carry around you're dragging around if you're a cell and you're dragging around a resistance machine that's expensive that's going to take away from your ability to reproduce you're going to need resources to build the machine you're going to read need resources to maintain it it's basically a drag and prevents you from reproducing as quickly it's one of the proponents of this theory says that an umbrella is a burden unless it's raining so you can think about resistance as an umbrella it's great when it's raining and it's horrible when it's when it's dry and sunny so resistance cells are always in the minority in a cancer and that's important we'll get to why that's important later so let's talk about a very common cancer metastatic prostate cancer not prostate cancer in general I'm talking about metastatic prostate cancer here is incurable with current treatment so evolutionary approaches which don't provide a cure but might keep the patient alive and without symptoms of cancer are now being looked at and I think that's a wonderful thing to really change our goals from curing and killing all the camp curing the patient by killing all the cancer cells or treating the patient so that the patient remains healthy and lives with cancer basically most of us are living with cancer our entire lives and we just keep it suppressed if the patient needs a little help keeping it suppressed from the outside I think that might be worth looking into so the prostate gland sits just below the bladder in the male it's about the size of a walnut you'll note that the urethra goes straight through the prostate gland so if the prostate gland is ill and swollen the patient will have trouble urinating and they will complain of a full bladder and slow stream it's not always a sign of cancer but it can be this is a dissection of a normal two normal prostate glands they've been removed from the body but they haven't been cut in two you can see the urethra going through a potential space for the urethra right there you can see the open urethra here in this specimen that's what a normal prostate looks like this is a prostate that's been sectioned and has a cancer on the right side of the screen and you can see it that yellow yellowish tissue there and you can see the urethra in the middle so so you can stay oriented so a cancer in the prostate gland is not fatal the prostate gland can be removed what kills patients is metastasis prostate cancer tends to metastasis first to bone this is a patient with a metastasis in several areas of bone those black spots there this area down here is just the bladder filled with some of the contrast that's not a cancer so prostate cancer patients can be monitored with a blood test called the PSA it as the blood test goes up and down that tells us whether the number of prostate cancer cells in the body is going up and down respectively so here we have again the cancer we want to avoid resistance when we treat this patient with metastatic prostate cancer if we wanted to engineer resistance what would we do we give the patient the biggest dose as often as possible and for as long as possible and that is what is currently done in most prostate metastatic prostate cancer cases now I want to take a segue here and a detour and say that maximum tolerated dose is important in curable cancers and I've listed some of the curable cancers is not an exhaustive list but if your oncologist says hey we've got treatment that can cure this cancer and it requires maximum tolerated dose please please listen to them and I want to especially say in pediatric cancers 85 percent of pediatric cancers can be cured even if they're advanced so you don't want to miss out on on a cure but in general the common cancers of late adulthood are not curable when they're metastatic and maybe we should be abandoning curative attempts in this situation because in this situation we're usually making things worse so I've mentioned that the standard treatment of metastatic prostate cancer is is a treatment at maximum tolerated dose what's done is testosterone is removed from the body used to be done by removing the testicles it was called castration and now we give drugs it's still called castration we call it chemical castration I it's a horrible term but I guess it's true so the goal is to remove all the testosterone from the cancer ecosystem because a lot of prostate cancer cells will grow in the presence of testosterone but not all of them some of them have a resistance mechanism because that resistance is expensive when there's no treatment they're in the minority but they're there so if we treat a prostate cancer patient that at first the PSA goes down the bone scan gets better things look great this and we've gone with the idea that we're going to just kill them all this is Xena warrior princess this was one of her favorite sayings and what do we actually have happening here we have the sense treatment that testosterone dependent cells are purple okay you see that they're in the great majority at the before we start treatment there are a few little green resistant cells there then we give some treatment and this is called M.T.D. stands for maximum tolerate dose we give treatment wow the tumor shrinks the PSA goes down we're really happy but what's really going on there if you count the cells even though the whole tumor is smaller the resistant cells the green ones have expanded in number things are getting worse in terms of resistance and the same as you go along toward the right you can see that the treatment is given at regular intervals and the resistant cell population continues to grow and eventually we've wiped out all of the purple cells all we're left with is green cells and the therapy stops working oh looks like I've got one minute I missed my five minutes huh okay so what's worse than treatable prostate cancer cells well untreatable ones so what if we use game theory theory game theory is a type of branch of mathematics that utilizes strategies to maximize the desired outcome in a competitive situation if we give adaptive therapy small doses infrequently and only as needed to remove or decrease symptoms we end up we hope with a healthy patient who's alive but does have cancer theoretically here's what it looks like you notice that the purple cells remain throughout this treatment schema there's only two treatments given and at the end the tumor is no bigger and most of the purple cells remain so this actually worked in do you want to questions now I have about three more minutes sure I could carry on okay so it actually worked those were mathematical modelings but it actually worked in a real trial 11 patients were given adaptive therapy for metastatic prostate cancer 16 patients were given standard high dose therapy and the adaptive therapy worked only one of the 11 patients had worsening disease while in adaptive therapy and 14 of the patients of the 16 patients on standard therapy got worse and more studies are planned so this is a real my favorite equation in mathematics this is a tic-tac-toe board and tic-tac-toe can be described as a combinatorial game and the idea is to force a double bind so that wherever you put a treatment the resistance development actually makes you more sensitive if you're a cancer cell to the next treatment so there have been double bind attempts in human cancer with alternating of estrogen therapy and estrogen deprivation and metastatic breast cancer there have been the similar trials with testosterone giving testosterone and then withdrawing it and blocking testosterone activity and metastatic prostate cancer with limited success it's promising and research needs to go on so I will everybody gets these slides right okay so I will let you read the summaries here at your own time but basically what I want to say is that increasing fitness of a cell in old age is bad because it allows it to reproduce and that can lead to cancer this SOMA is not maintained very well anyway after reproductive years and so you want to take special care of it you can fast you can try some drugs metformin exercise we don't know but things like hyperbaric oxygen therapy may have a role if you end up with an incurable cancer you might want to seek out some adaptive therapy approaches and the ultimate goal of evolutionary cancer therapy is to create a therapeutic double bind wherein the development of resistance to one drug confers susceptibility to a second drug thank you very much there's references and things on there great job Don thank you so much it's 10 25 we have to wrap up at 10 30 so we have five minutes we can get a couple questions in hi thanks for that so my name is Andre Angel Antoni and I'm the project lead for the vaccine course I have a poster I'm inviting you to come see on vaccine induced auto immunities I'd love for you to come see it but my I asked someone on the team to go through all the section 13's of all the product inserts of the vaccines we did that for 73 of them and we found that none of them had been tested for long-term carcinogenicity and that about 60 percent of the vaccines contain aluminum salts so we tell people not to use antiperspirant because as aluminum because that might cause breast cancer but we're using we're injecting the aluminum in all of us why is the FDA not requiring long-term carcinogenicity testing of these drugs so that's a really good question I'm not a vaccine specialist and long-term carcinogenicity testing is extremely expensive it would take probably several generations and more than the gross national product so that might be a reason but again that's not my area of expertise so I would defer to maybe to you to help answer that question okay would you recommend we remove the aluminum from the vaccine again I'd have to look at the the whole situation I'll come and take a look at your poster okay great thanks hey how you doing thank you that was very interesting talk can you elaborate on why you would potentially see an increase in aging with increased tumor suppressor genes in the mice yeah so if you have increased tumor suppression one of the mechanisms of tumor suppression is apoptosis program cell death so you're ordering the execution of a lot of damaged cells so a lot of these cells are damaged but still functioning somewhat in the aged individual killing them off would decrease you know would eliminate that function which could decrease their viability you antidote on a point that you you made twice increased health equals increased propensity for cancer which makes me increased fitness not increased health fitness and health are different okay fitness has only to do with the ability to reproduce has nothing to do with health okay okay then there then there's I might be saved after all then is my my nutrient smoothies that my wife reminds me I'm perhaps doing myself harm may actually be doing myself harm making myself more fit perhaps so again fitness in this the definition of fitness as used in evolutionary context has nothing to do with with general health of an individual it has to do with their ability to reproduce well I'm trying to bring this down into a practical statement for me to consume and take action on so if you could maybe give some actionable advice but sometimes when practitioners discover things in the lab you ask the practitioner well what are you doing now that you have this information so ma'am what are you doing so I'm a big proponent of intermittent fasting and I think that's probably important I also use in my clinic drugs like metformin and cancer patients with incurable metastatic cancers in in hopes of improving the tissue landscape make a rejuvenating it a bit we use things that decrease inflammation there are drugs that do that intermittent fasting helps with that things like fish oil can do that in some people now fish oil will increase cancer in certain Norwegian men who have a particular genotype so you want to look into that before you start taking fish oil to decrease inflammation if you're worried about prostate cancer but things have to be individualized to a certain extent but the main point I want to make and I hope I've made it here is that fitness in the evolutionary sense does not equal health and they're different and they're you're asking a different question you're asking what will make me healthy and I'm talking about what will make a cell reproduce no not in the evolutionary terms so I want to separate again the the evolutionary definition of fitness has only to do with the ability to reproduce so if you're talking to a PE teacher fitness means something different than if you're talking to an evolutionaryist an evolutionary scientist physical fitness is not evolutionary fitness though yeah yeah okay let me let me say that physical fitness is good okay physical fitness is good evolutionary fitness is sometimes good but not if you're an aging cell in an aging tissue then it can be bad we're talking about the fitness of an entity in its environment so we are at our time so I think if you guys want to you know continue discussing the details of that you can after thank you Don