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