What tumors eat and how to poison them

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