What tumors eat -- and how to poison them | Dr. Christal Sohl | TEDxTulsaCC

about the time i first started researching how tumors grow and develop my aunt lizzie was diagnosed with breast cancer i'm sure probably all of you have been in my shoes where a loved one receives a cancer diagnosis and you want to do everything you possibly can to learn about all of the available treatment strategies the breast cancer subtype that my aunt had which was her2-positive this actually represents one of the earliest and really most famous examples of a cancer subtype that has a precision medicine associated with it in case in this case herceptin and so the difference between precision medicines and traditional chemotherapies which do often work very well is a little bit like spraying a field with a crop duster in order to get rid of weeds instead of going in and spraying just each individual weed in order to get rid of it and so the challenge though in cancer is that we can't always tell the difference between the weed and the crop or maybe we can tell the difference but we don't have an effective pesticide yet or maybe like in the case of my late aunt lizzie we can tell the difference between the wheat and the crop we have an amazing pesticide but ultimately the patient stops responding and relapses so in my lab at san diego state university we're interested in understanding how these weeds work though we call them tumor drivers and these tumor drivers can happen as as a result of any random genetic mishap a mutation deletion amplification imagine for example you're a protein and your job is basically to be stationed right outside the cell and you are constantly scanning scanning scanning looking for clues about the health of the environment whether there's a lot of resources around and if you determine that times are good you change your shape in just such a way that you signal to inside the cell that times are great and that cell now knows that it can grow and divide and grow and divide but imagine that you pick up a mutation and so now you're stuck in that grow shape so times could be bad very dark indeed but you're still sending that message of grow and divide grow and divide grow and divide or imagine you can still make the right shape at the right time but maybe instead of 10 of you surrounded around the cell maybe now there's 10 000 of you lining that cell and so now you're screaming that message instead of just saying it that's a little bit like what happens in the case of her2 positive breast cancers so we're starting to think about tumors less in terms of their tissue of origin breast cancer lung cancer prostate cancer and more in terms of their drivers egfr positive or too positive p53 mutated because these drivers it is true that they can represent essentially a superpower for the tumor but it's really important to know that these tumor drivers can also represent an achilles heel because these tumor cells become so reliant on these pathways so addicted to these pathways that if you can go in and strategically shut down just that pathway well you're going to harm the tumor cell way more than you're going to hurt any other cell in the patient and of course that's always what we're shooting for in precision medicines in cancer one of the most interesting examples of achilles heels is tumor metabolism or how tumors eat so let's say for example you look inside a cell and you see a protein that's catalyzing hundreds and hundreds of reactions in a second which is extraordinary they can do this and it's not just that one protein but there are thousands and thousands and thousands of proteins that are catalyzing a variety of different chemical reactions at any time so cells often have a decision that they have to make are they going to use that delicious carbon that you just ate whether it's chocolate cake or burritos or salad are you going to devote basically all of that delicious carbon towards driving these chemical reactions or do you need to save some of that carbon towards making stuff making the protein and the dna and all the cellular components that you need for a cell to grow and well even though it sometimes feels like this is not true when we stand on the bathroom scale in the morning most of the cells in our body are not actively growing and dividing all the time and so this is really um an important factor in tumor cells that they are having to balance these two needs to grow and divide and power reactions and so we've known for a very long time that tumors eat differently than non-proliferating cells they do this in a couple of ways they might simply take on a lot more glucose which is cells usual favorite dish or they might be a bit more open-minded about what food is and i don't mean this in the context of trying to psych yourself up to eat protein in the form of bugs but instead of just glucose maybe these cells are using glutamine or serine or some of these other small molecule building blocks to allow these cells to rapidly grow and divide in my lab at san diego state university we're interested in understanding how these changes in tumor metabolism occur and one of the proteins that we're really interested in is called isocitrate dehydrogenase or idh and this is a really important protein that basically helps balance levels of important metabolites or small molecules that are needed in the cell to power a lot of these different metabolic reactions and so unfortunately you can develop a mutation in idh that well for one breaks the protein it can't do the reaction that it's supposed to do but it gets worse what also happens is that these mutations allow this enzyme to perform a brand new chemical reaction that it was never before able to do a superpower and this superpower is making this metabolite that is kind of like a carcinogen if it builds up to too high levels in the cell it basically creates a pro tumor environment it helps cancers form and so in my lab we're interested in understanding how to shut down this particular reaction because this can be an important therapeutic so it may seem like going after cancer metabolism is too dangerous in the context of precision medicine to be fair most cells in the body need to grow and divide at some time and it's true sometimes we can't get the selectivity that we need in order to shut down strategically just cancer metabolism but in the case of idh that single mutation that one change out of three times ten to the ninth size genome that we all have that single change changes the shape of the protein just enough where it can perform the new reaction it gets a superpower but it also changes the shape just enough where you can design a small molecule therapy a drug that can strategically go in and just shut down the mutant that's extraordinary and in fact there's a drug company here in the united states that has actually successfully designed a brand new drug that does just that selectively shuts down that mutant activity and there are many aunt lizzie's in the clinic today that are benefiting from this important new drug so what do we know so far well in my lab at san diego state we have found a particular type of idh mutant that's kind of a troublemaker gone wrong what happens is this particular mutant makes buckets and buckets and buckets of this dangerous metabolite and not only that it doesn't seem to to bind these therapies particularly well now it's absolutely true that this particular mutation is extremely rare in patients but that's still somebody's aunt lizzy this still means we have a lot more that we need to learn about idh and tumor metabolism in order to help every patient that has a cancer that has this type of of problem in the genome a graduate student in my lab that was helping perform some of these experiments was doing so while his own father was dying of colorectal cancer it is absolutely true that as scientists we are motivated by our love of discovery and our fascination with how humans and other organisms work but it is also true that we are very much motivated by our own stories and the personal narratives of those in our lives that we love we know that finding new ways to combat cancer is an urgent charge indeed thank you you

Channel: TEDx Talks

Views: 1,494,888

Keywords: TEDxTalks, English, Science (hard), Biology, Cancer, Cells, Medical research, Research, Science

Id: F2pC3Ty_L78

Length: 10min 15sec (615 seconds)

Published: Wed Dec 16 2020