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

When I started researching how

tumors

grow and develop, my Aunt Lizzie was diagnosed with breast cancer. I'm sure all of you have probably been in my shoes when a loved one receives a cancer diagnosis and you want to do everything you can. to learn about all the treatment strategies available, the subtype of breast cancer that my aunt had, which was her2 positive, this actually represents one of the oldest and actually most famous examples of a subtype of cancer that has precision medicine associated in this case. herceptin case and therefore the difference between precision drugs and traditional chemotherapies, which often work very well, is a bit like spraying a field with a fumigator to kill weeds instead of going and spraying just every individual weed to get rid of it, so the challenge in cancer is that we can't always distinguish 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 my case late aunt lizzie we can tell the difference between wheat and crop we have an amazing pesticide but in the end the patient stops responding and relapses so in my lab at san diego state university we are interested in understanding how these work weeds, although call

them

tumor drivers and these tumor drivers can occur as a result of any random genetic mishap, a mutation, deletion, amplification, imagine for example that you are a protein and your job is basically to be parked right outside of the cell and it is constantly scanning, scanning, scanning. looking for clues about the health of the environment, if there are a lot of resources around and if you determine that the times are good, you change your shape in such a way that you signal to the inside of the cell that the times are good and that cell now knows it. it can grow and divide and grow and divide, but imagine you acquire a mutation and now you are stuck in that form of growth, so times could be bad, very dark, but you are still sending that message of growing and dividing, growing and divide, grow and divide or imagine that 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 are 10,000 of you lining up that cell and now you are shouting that message instead of just saying it, it'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, prostate cancer, and more in terms of their drivers, egfr positive or p53 too positive mutated because these drivers, it is true that they can essentially represent a superpower for the tumor, but it is really important to know that these tumor drivers can also represent an Achilles' heel because these tumor cells become so dependent on these pathways so addicted to these pathways that if you can strategically go in and shut down just that pathway, you will damage the tumor cell much more than you will damage any other cell in the patient and, therefore, Of course, that's always

what

we look for.

In precision cancer medicines, one of the most interesting examples of Achilles' heels is tumor metabolism, or how tumors feed. Say, for example, you look inside a cell and you see a protein that catalyzes hundreds and hundreds of reactions in a second, which is extraordinary. 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 to make a decision: are they going to use that delicious protein? carbon that you just ate, whether it's chocolate cake, burritos, or salad, are you going to basically devote all of that delicious carbon to powering these chemical reactions or do you need to save some of that carbon to make things that make the protein and the DNA and everything? the cellular components you need for a cell to grow and grow well, although sometimes it may seem 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 or dividing all the time and So this is really an important factor in tumor cells, that they have to balance these two needs to grow and divide and generate reactions, so we have known for a long time that tumors feed differently than cells that do not proliferate.

In a couple of ways, they could simply consume a lot more glucose, which is the cells' usual favorite dish, or they could be a little more open-minded about what food is, and I don't mean this in the context of trying to psych yourself out. . eat proteins in the form of insects, 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 grow and divide rapidly in my laboratory at the state university from san diego. We are interested in understanding how these changes in tumor metabolism occur and one of the proteins that we are really interested in is called isocitrate dehydrogenase or idh and this is a really important protein that basically helps balance the levels of important metabolites or small molecules that They're needed in the cell to drive a lot of these different metabolic reactions and unfortunately you can develop a mutation in idh that well, if you break the protein, you can't do the reaction that you're supposed to do, but it gets worse.

What also happens is that these mutations allow this enzyme to perform a new chemical reaction that it has never been able to perform before. A superpower is producing this metabolite that is something of a carcinogen. If it builds up to too high levels in the cell, it basically creates a pro-tumor environment that helps cancers form, so in my lab we are interested in understanding how to stop this particular reaction because it may be an important therapy, So it may seem that pursuing 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 point and it's true that sometimes we can't get the selectivity we need to strategically shut down cancer metabolism, but in the case of idh, that single mutation changes From the three times ten to ninth size genome that we all have, that one change changes the shape of the protein enough so that it can perform the new reaction, it gains a superpower, but it also changes the shape enough that you can design a small molecule therapy, a drug that can strategically go in and simply deactivate the mutant, that is extraordinary and in fact, there is a pharmaceutical company here in the United States that has successfully designed a new drug that does just that, selectively deactivates that mutant activity and There are many Aunt Lizzies in the clinic today who are benefiting from this important new drug.

What do we know so far? In my lab at San Diego State we have found a particular type of IDH mutant that is kind of a troublemaker gone wrong. What's going on? This particular mutant produces buckets and buckets and buckets of this dangerous metabolite and not only does it not seem to bind particularly well to these therapies? Now it's absolutely true that this particular mutation is extremely rare in patients, but it's still someone's aunt, Lizzy, this one. It still means that we have a lot more to learn about IDH and tumor metabolism to be able to help every patient who has a cancer that has this type of problem in the genome.

A graduate student in my lab was helping to do some of these. experiments he was doing 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 motivated by our own stories and personal narratives of those in our lives who we love know that finding new ways to fight cancer is an urgent task, indeed, thank you