Ivan Zamorano

Acupunture Treatment

Cancer Metabolism: From molecules to medicine

Cancer Metabolism: From molecules to medicine


Hello. Good evening. I’m Gina Vild. I’m the chief communications
officer for Harvard Medical School, and I am thrilled
to welcome you here tonight. This is the 19th year that we’ve
been offering Harvard Medical School’s Mini-Med School
to those in Boston, and more recently, to
those throughout the world. So to all of you here
in the auditorium and to those of you who are
watching us on the live stream, thank you for joining us. Over the past two
decades, this program has allowed many thousands to
learn about science and health issues from Harvard’s
expert faculty. Think of this as your
classroom, and we will think of you as students. So you’ll have an opportunity
to both learn and ask questions from our expert faculty
about the latest research and medical breakthroughs. The people you will
be learning from are on the front lines
of science and medicine. I’m happy to report
that last year, we had more than
120,000 students. Viewers from 84
countries participate in our Longwood seminars. Would you raise your hand if
you have attended a Longwood seminar in the past? Many, many repeat attendees. If this is your first
Longwood seminar, would you raise your hand? Wow. Thank you. Well, we hope you
enjoy them, and we hope you’ll be back next year. Because the topics are
chosen through crowdsourcing and surveying you, you are
also the course director for the Longwood seminars. And so as part of
our alumni, we are asking that you
participate in planning the programs for next year. And so if you have
any thoughts, please email us on our website or
talk to a member of our team. So these are the topics for
the upcoming Longwood seminars, so we hope you will join
us for the next three later in the next month. So we do ask you to silence
your electronic equipment, but please do not turn
it off, because we are inviting you to participate
in our Twitter conversation. So please join in. The hashtag is #HMSMiniMed,
and we have it on the podium, should you forget. So whether you’re here
or watching from afar, please join our
Twitter conversation. You may know if you’ve
attended in the past that we offer certificates
to those who’ve completed three
or more seminars, and we also offer teachers
professional development points. For more information on
how to receive these, please check our website or
talk to a member of our staff. On the website, you’ll also find
the seminars from past years. Our speakers will be taking
questions– your questions– at the end of the program. So if you are here
in our audience, you were given an index card. A member of our staff will be
walking through the aisles. Please hand them–
pass your question in. If you are watching
from around the world, please post your question in
the comment box on Twitter, on Facebook, and on YouTube. And please also indicate where
you are from, because we’d love to share that. So now for this
evening’s seminar– Cancer Metabolism, from
Molecules to Medicine. Did you know that there were
17 million new cases of cancer worldwide in 2018? Worldwide, there will be
27.5 million new cases of cancer each year by 2040. That’s astounding. And so this evening,
you’re going to learn from some of the
leading scientists at Harvard Medical School who
are working to tackle this devastating disease. By illuminating
molecular pathways, researchers have discovered
that cancer metabolism actually changes the activities of cells
when compared to normal cells. Research is now
underway to figure out how metabolism becomes
reprogrammed in cancer cells, and then to find new and
effective treatments to stop the disease from spreading. I’m delighted to introduce
you to our panel of experts who will share their
insights with you. Brendan Manning is Professor of
Genetics and Complex Diseases and Director of the PhD
program in Biological Sciences and Public Health at the
Harvard T.H. Chan School of Public Health. Nabeel Bardeesy is Harvard
Medical School Associate Professor of Medicine,
Assistant Geneticist in the Center for
Cancer Research, and the Gallagher Endowed Chair
of Gastrointestinal Cancer Research at Massachusetts
General Hospital. But first we’ll hear
from Marcia Haigis. Dr. Haigis is Professor
of Cell Biology at the Blavantnik Institute
at Harvard Medical School. She is a member of the
Paul F. Glenn Center for the Biology of Aging
and the Ludwig Center at Harvard Medical School. Her lab continues to
work on understanding the role mitochondria plays in
human aging and age associated diseases. So thank you for
being here with us. We’re just thrilled to
see so many in attendance. And please welcome
our first speaker. Thank you. [APPLAUSE] Thank you very much
for coming here today. Thank you for that
wonderful introduction. And I am so thrilled to
be here and share with you all tonight’s program, Cancer
Metabolism from Molecules to Medicine. And so 2018, the World
Health Organization reported that cancer remains
a leading cause of death globally. And, in fact, in 2018
one in six individuals had cancer as the
cause of death. So these remarkable
statistics really highlight the urgent need to
further study cancer biology with a hope to identify
improved therapies to improve patient care. So today I’m going
to talk about fuel. And these are some of
the fuels that I think about when you consider fuels. And fuels are important. They need to be harvested. They are delivered. They need to be processed. But in doing so, burning fuels
to generate their energy so that they can do the work
that needs to be done also has the side product
of generating byproducts. And, in fact, it’s become
a major and very important dialogue today to consider
alternative fuel sources that result in a cleaner,
more efficient fuel utilization, maximizing ways
to process fuels efficiently, and also generate
less byproducts. And think about how do we
deal with these byproducts. But you might be asking
yourself, what does this have to do with cancer. So I’m going to talk about a
different kind of fuel today. And this is a picture of a salad
that I had last week in Italy. This is the kind of fuel
that our bodies use. And so when we consume
foods, these foods are broken down
into metabolites. And here’s a metabolite cartoon
of a sugar and an amino acid. And these metabolites,
or metabolites similar, are taken up by cells,
and they’re also delivered and processed by cells. And as a side reaction of
this cellular metabolism, metabolic byproducts
are also generated. And understanding how fuel
metabolism is processed in cells and how that
affects cell biology has really blossomed into this
new field of cancer metabolism. And it makes us wonder,
is cancer metabolism an Achilles heel that will lead
to a new class of therapies. And I think to fully
understand this point, we need to discuss
a few questions. And so in the field we have
several driving questions, and I’m going to talk
about mainly the first one. And you’ll hear about the
second and third points today from Brendan and Nabeel. But we’re interested
generally in understanding how do tumor cells
differ from normal cells in their metabolism
of cellular fuels. How do tumor cells
integrate growth signals and nutrient metabolism in
order to proliferate and survive different environments
and promote tumorigenesis? And this coordination,
you’ll hear, is really critical
to tumor cell growth. And what is the
metabolic communication between tumor cells and their
surrounding environments? And understanding how all of
these influences interact. And the bottom line is
we want to understand, can we actually exploit the
unique metabolic properties and vulnerabilities
of cancers in order to improve patient
care and therapy. And so what are fuels
and why do we care? Why do we care about
fuels in cancer biology? So if there are lots
of different fuels that our cells can use,
and a few are shown here, sugars, fatty acids, amino
acids broken down from proteins. And they’re taken up by cells
and converted and processed in order to make molecules
important for providing the cell with
energy such as ATP, and also for
generating molecules that contribute to
the essential building blocks of macromolecules
important for cell life. And these macro molecules
include DNA, RNA, proteins– I can’t really reach
way up there but– membranes to form lipid bilayers
to form membranes around cells. And so you might think how do
they actually help contribute to building a cell. So these macromolecules
are actually the building blocks that
form the physical components of a cell. And so you might imagine that
a cell that proliferates a lot needs a lot of these
macromolecules. And so it’s apparent, so you
need genomic information, you need RNA in a cell. Cells are full of proteins. And cell boundaries and
organelle boundaries are framed by membrane layers. So all of these components are
absolutely critical for cell growth and cell proliferation. Now normal cells need
these components, too, and they use fuels to
generate energy and maintain homeostasis. That’s important to their
specialized function. So if you consider the
specialized or normal cells in our bodies, our brain cells,
our heart, our muscle cells. They need to metabolize fuels. But a lot of the fuels
are used to make energy so you can do
muscle contraction, or also to provide
homeostasis and maintain repair and the health and
viability of that cell. But by contrast cancer
cells are kind of punctuated by their unique
ability to proliferate. And they have unchecked
proliferation, in part because of mutations. There are many causes of cancer
and mutations and unchecked growth signaling pathways
and coordinated upregulation of fuel uptake and metabolism. And the fuels are used in cancer
cells not only to make energy, but tumor cells
upregulate the fuel usage in order to make more of
the macromolecules needed for the building blocks to make
the mass and the physical form of the cancer cell. And we see evidence of
this in patient care today. So you can put a probe, a
label, onto a sugar molecule and administer that to patients,
an image where the tumors are through PET imaging. And that basically measures
where is the glucose taken up. And so you can see glucose taken
up in highly metabolic tissues like the brain and the heart. But you also see it here in
this patient with a lung tumor because it’s highly metabolic. And so we know that these
tumors don’t metabolize fuels in isolation. But instead there is this
really dynamic competition of fuels for the tumor cells
and the normal healthy cells surrounding it and
in other tissues. And so what we want to do is
know can we actually identify the precise molecular pathway
that tumors use in order to exploit metabolic fuel
preference to target the tumor cells, and maybe minimize the
side effects in healthy cells and also improve patient
therapy and care. And so the rationale
is really simple. And we know that signaling
and cell-cell interactions and immune cells
affect tumorigenesis. And we know that this synergizes
with altered metabolism, because tumor cells have to
take up more fuels in order to make the building
blocks for their mass. So standard of care historically
has targeted this one arm of signaling and
cell interactions to try to block tumor growth. And, of course, there has
been therapeutic success. But ultimately in many cases
there is emerging resistance. And not every patient
responds similarly. So we want to know by
targeting the fuel, by targeting the energy pathway
and the building blocks, can you synergize with standard
of care available in order to actually improve
outcome and maybe help to overcome resistance. And so in order to
answer those questions, we need to dig deeper. And so far I’ve told you
some of the big picture concepts of fuel usage and
how the fuels are taken up and metabolized by tumor cells. But in order to
design precise drugs, we actually need to identify the
metabolic pathways themselves that are altered between
normal cells and tumor cells. And this is showing
an overview schematic. And it is simplified
of the difference in how a normal
cell handles sugar compared to how a proliferating
cancer cell might handle sugar. And so in a normal cell, you
can see the glucose is taken up and it’s converted to
these intermediates through a process
called glycolysis. And then it’s
metabolized further in this round organelle
called the mitochondria. And in the mitochondria,
the glucose metabolites, namely pyruvate
metabolites, are further metabolized to generate ATP. Now in a tumor cell, they
have more glucose uptake. And in addition to more
uptake, the process of the handling of
the sugar differs. So you don’t just
have simple metabolism of glucose through
glycolysis to make energy. But instead many of the
carbons from the glucose are diverted into
pathways that you can see form these
critical building blocks important
for macromolecules that contribute to the mass and
physical properties of a cell. And so in understanding
some of those properties, we can also see that
burning fuels in cells contributes to metabolic
byproduct production. And so here is an example of
how healthy cells versus tumor cells metabolize an amino
acid called glutamine. And high levels of
glutamine breakdown generates this small
metabolite called ammonia. And what happens is that
ammonia really builds up in the tumor environment, called
the tumor microenvironment. And so we wanted to
know in our lab, what is the role of this metabolic
byproduct in cancer. And so there are two hypotheses. One hypothesis is
that it’s simply secreted from the tumor cells,
detoxified through the urea cycle, and thrown away
as cellular waste. But another hypothesis is
that a rapidly dividing cell would need those nitrogens
to form building blocks and support cell
proliferation and growth. So we actually
measure the effects of this metabolic byproduct
in tumor cell proliferation. And so first of all,
ammonia accumulates in a tumor microenvironment. If you use a mouse
model of tumorigenesis, you can actually measure
the level of ammonia in the bloodstream or in the
fluid surrounding the tumor and find that it does accumulate
to a high level in the tumor cells, in the fluid
around the tumors. Moreover, if you add
ammonia to estrogen receptor positive breast cancer
cells, it actually stimulates their proliferation. And so this shows that the
cancer cells actually use their waste, or metabolic
byproduct, to fuel growth. Moreover, if we
stop this process by inhibiting or reducing the
level of the enzyme that’s important for this metabolic
waste recycling, called glutamate dehydrogenase,
you can slow down cancer growth in vivo, in
an animal model of cancer. And so you can see
that here, if you look at ER positive
tumors that have normal levels of metabolic
byproduct recycling, shown in this blue
line, compared to the levels of tumor growth
in tumors lacking the ability to recycle nitrogen. And so in this simple study,
we found a new pathway where ammonia in normal cells
is known, as the dogma states, to be produced by cells
and secreted by cells. But, paradoxically,
tumor cells are able to kind of reharness
this additional ability to use this metabolic byproduct
which accumulates in that tumor cell environment. And then they kind
of start to eat it, and they can use that to make
glutamate amino acids that are important for
protein production. And so through this
pathway, they’re able to recycle their
nitrogen waste products. So going back to my starting
question, is cancer metabolism a new Achilles heel. Well, to really
answer this question, we still have more
questions that we have to work on solving
and starting to address. So what are the
metabolic signatures of specific tumor types? We know that different
tumors arising from different
cells of origin have unique metabolic properties. And so we need to learn
more about those in order to better target
cancer metabolism. We need to understand with a
rational, logical way, what are the best combinations
of metabolic inhibitors with approved drugs. We have to understand how
does tumor metabolism differ with tumor genotype
and signaling, and you’ll hear more about
this from Brendan Manning. It’s really critical to
understand which genotypes and which patient
populations might be more sensitive to
particular metabolic inhibitors and combinations. And so when I think
about cancer metabolism, I really think about
this as a field that’s at the tip of an iceberg. So this field really
started decades ago with the studies of Otto
Warburg looking at how glucose was handled by cancer cells. But now in the last
10 years or so, it’s really had this dramatic
and exciting Renaissance that has deepened our
understanding of how tumor cells use fuels. But I think also exciting to me
is that beyond cancer biology, these lessons we learned
from cancer metabolism have taught us simple
properties that are critical for
tumor cell biology, like understanding mechanisms
that let tumor cells survive, proliferate, and progress. Our understanding of
cancer cell metabolism has also created an open new
field of metabolic research in other biological systems,
and these range from immunology to stem cell biology. So these same
principles of how fuel use in macromolecule
building hold true when you think about immune
cell activation in response to an antigen, which triggers
massive cell proliferation, as well as in the
principle of stem cell biology, proliferation,
and differentiation. And so this is just really,
really basic science that’s kind of been uncovered
from these mechanistic studies in cancer biology. And, in addition, studies
of cancer metabolism are continually
pushing the envelope of technology development,
and I find that also extremely exciting. When we’re trying to map
these precise mechanisms and pathways, it always
pushes for further technology development. And that also just supports
a lot of other studies. And so I want to
thank my lab for doing the work, all the wonderful
collaborators that we have at Harvard and beyond. And some of the collaborators
involved in the breast cancer study are shown here. These are my lab members who
love to draw mitochondria, as you can see. And I thank you all
for your attention [APPLAUSE] So I’m pleased to introduce
our next speaker Dr. Brendan Manning. [APPLAUSE] Thank you. I’m very honored to participate. I’m very honored to
participate in this symposium to bring what we do every day
as scientists to the public as well as to those online
listening around the world, including my boys,
Garrett and Cameron. Hopefully, they don’t
ask any hard questions during the question
and answer period. So I’m going to drill down on
an aspect of cellular metabolism that Marcia touched
on in her talk, and that’s the concept
of cell growth. This is something that my
lab is very interested in. We have a laboratory across the
way at the Harvard T.H. Chan School of Public Health, just in
the back corner of the Harvard Medical School quad. And we’re very interested in
the concept of cellular growth, and in particular the metabolism
that underlies cell growth and how that metabolism is
controlled in cancer cells. So just as a take home– let me back up here. So cell growth is
really a concept that underlies cell proliferation. A cell must increase its size. It must double its cell size
before it divides in order to form two cells
of the same size. So this is a simple
concept, but it may not be one that’s
obvious to everyone. If a cell divides
without growing, the cells will get smaller
with each subsequent division. And this is why cells must
increase their mass in order to divide and create more cells. So it’s a very simple concept,
but how a cell achieves this is actually quite complex. Again, something that
Marcia touched on is that cells utilize
nutrients and energy. And they consume
nutrients and energy in a process of
anabolic metabolism in order to drive the
building of a new cell. Through the consumption
of nutrients and energy, you can produce
the macromolecules that underlie cell
growth, that underlie that the products
that are used to make, to double a cell’s mass. So we refer to this
as cell biomass. About 2/3 of our cells are made
of water, not surprisingly. But when I say cell dry
mass or cell biomass, I’m really talking about
the dry weight of a cell. So cells are really
comprised primarily of these four components here. 55% protein, 25% nucleic acids,
15% lipid, and about 5% complex carbohydrates, give or take
on each of these numbers. And so in order to do this
seemingly simple process, a cell must take
nutrients and energy and build these macromolecules. And it does that by driving
anabolic metabolism, by driving metabolic processes. So I think a good analogy of
how this functions is really in the concept of
building a house. So in building a
house, in this case– excuse me, keep– the materials
to build the house, rather than nutrients, are
building materials, everything from shingles
and lumber and wires. These materials are utilized
by specialized contractors that build different
aspects of the house. And you can view the contractors
as metabolic pathways. So each of these contractors
is using these building blocks to build different
aspects of this new house. Just like that new
house, metabolites are utilized by metabolic
pathways rather than contractors. And these metabolites are util–
and some of these metabolites include glucose and
amino acids, the things that Marcia talked about, the
fuels that Marcia talked about. These are utilized
through metabolic pathways and turned into those
macromolecules that underlie cell growth. So these nutrients are turned
into the protein, lipid, nucleic acids, and
carbohydrates that I talked about on that
first slide through these metabolic pathways. So, however, this process is– it doesn’t occur on its own. Cells in our body grow
only when they’re told. They’re very disciplined,
and they really only grow when they’re told to do so. So they really
only grow when they receive a signal from other
cells that it’s time to grow. And this is really in the form
of growth factors, hormones, and cytokines, which are in
our blood and circulating and are messages
from other cells to a cell that tell it
to either grow or not. Sometimes the signal
tells it to die. But a growth signal will start
this process of cell growth by stimulating the
processes, the metabolic processes that I was
just referring to. So what distinguishes
a normal cell and its controlled
growth that’s induced by growth factors
and a cancer cell is that a cancer cell grows
in an uncontrolled manner. It receives this growth signal
without the growth signal even being there. So the cancer cell,
through a variety of different cancer causing
mutations, and Dr. Bardeesy will talk about a
key mutation that’s very common in human
cancers in his talk. These cancer causing
mutations drive cell growth by manipulating the cell
growth signaling pathways to promote cell growth in
an uncontrolled manner. So this cycle doesn’t
occur just once. It can it occurs continuously
in an uncontrolled manner, therefore giving you a tumor. Looking more closely
at this, the way that cell signals
are propagated, and growth signals are
propagated within cells, most of the time initiates
at the cell surface by receptors that receive
these growth factors signals. Those receptors
are then activated to propagate a signal
into the cell that tell the cell to grow. And I’m going to tell you
about one key growth signaling pathway today. Cancer cells are receiving
that growth signal, and generally the mutations
that effect cancer cell and cause it to
grow uncontrollably affected these same
signaling pathways, these lines of communication
within the cell, and signal to the
cell to grow even in the absence of an
exogenous growth signal, so that you have
uncontrolled cell growth. So in thinking about what
this signal hits in the cell to tell it to grow,
it’s really useful to think about
this growth signal as being a general
contractor, if we go back to our house analogy. So these individual pathways
or specialists– the roofer, the carpenter, the electrician–
that helped to build the house are coordinated,
often coordinated, if you’re going to
build a house de novo by a general contractor. Hopefully somebody who
is more competent than this general contractor here. If you are a general
contractor, I apologize. This is not how I view you. So the general contractor really
coordinates the specialized workers that build the house. And this is really
what that growth signal hits in ourselves. It hits the general
contractor of the cell. And that is a protein called
mTOR that my lab and many labs are very interested in. This is a protein called the
mechanistic target of rapamycin The title, the name of the
protein, is not so important. But it is a key
downstream target of growth signaling pathways,
and it drives cell growth. And the way that it
drives cell growth is by programming the cell to
convert nutrients and energy through metabolic
pathways into biomass, into the macromolecules
to build cells. So it is a coordinator of this
variety of metabolic pathways to drive cellular growth. And what happens in cancer cells
is that mTOR gets flipped on, and it stays on. So it is receiving
that growth signal through cancer causing
mutations such as the one that Dr. Bardeesy
will talk about. And it, therefore,
is being turned on in an aberrant manner. It’s receiving a growth
signal that’s not really there and, therefore,
driving cell growth in an uncontrolled manner. It’s not surprising,
given that mTOR is activated in the
majority of human cancers, that there’s intense interest
in targeting the pathways that lead to mTOR activation
as well as mTOR itself in human cancers. And this has shown some promise. It’s certainly not
a magic bullet, and I’ll talk a
little bit about why that might be in a few slides. But of course, there’s
intense interest in targeting the
general contractor to stop this entire program. So let’s go back to that
general contractor analogy. This is the analogy of firing
the general contractor. If you fire this contractor,
basically work on the house generally stops or
at least slows down. So construction is halted. So this is something
that would be good if you’re trying to stop the
building of a cancer cell and stop the
building of a tumor. You want to at least slow
the growth of the tumor, if not completely stop
the growth of the tumor. Another strategy, which
may not be as obvious, is instead of firing
the general contractor, to fire a single
person within this, that is underneath the general
contractor that’s driving the building of the house. So in this hypothetical,
if you fired the carpenter, for instance, without telling
the rest of the specialists or the general contractor
that the carpenter had stopped working on the house, you could
create, in theory, a setting where you have a
structural imbalance and the house collapses. And this is really what
we want to do to a tumor. We want the tumor to collapse. We want to create an
imbalanced setting that causes the tumor to collapse. And this is really a concept
that my lab is interested in, and many labs that are
studying cancer metabolism are interested in, whether we
can create metabolic imbalance in a tumor. And I just want to
tell you a little bit about that concept here. So, again, if we
go back to our mTOR signaling driving
cancer metabolism slide, and we think about the
usefulness of targeting mTOR, again, the general contractor
in this case of the cancer cell. What will happen, and we do
see this in many settings, is that these metabolic pathways
will slow their function in the growth of the cell,
and the growth of the tumor will slow down. OK? Often, this is
frequently accompanied by another pathway being
activated, which turns mTOR back on, or other pathways being
activated that can then turn on these metabolic pathways. This is frequently
what happens, and you get the development
of resistance to those targeted therapeutics. Again, going back to
our analogy of targeting the individual
contractors instead. If we can take out a
single metabolic pathway that mTOR controls
without telling mTOR, and mTOR stays on
and is still driving the activation of these
other metabolic pathways, we might be able to create
metabolic imbalance such that we ultimately can
kill the tumor cell. And this is something
that we have examples of in the literature. I’m going to show you just one
piece of data from my own lab that demonstrates this concept. This is actually two
separate experiments, one done in cell
culture, and one done in a mouse tumor model. And I’ll take you through these. I’m sorry. Excuse me. In this slide here,
on this side here, we have two cells
that are basically identical to one another. The only difference
between these two cells– this is a normal cell,
which has growth factor control of the mTOR pathway. So you need growth
factors in order activate mTOR in
this particular cell. This cell has a mutation that
leads to uncontrolled mTOR activation, like one of these
cancer causing mutations. mTOR is just on, and it’s
fully on all the time. And what we’ve done,
you can see there’s a little bit of a difference
between these two cell types. First of all, they’re all purple
because we stain them purple. There’s not something
special about the cells. One thing you might notice
is that these cells have a different shape
and they’re bigger, and that really is controlled
by this uncontrolled mTOR signaling. But what we’ve done
here is treat either with a control compound or a
metabolic pathway inhibitor that inhibits specifically just
one of those metabolic pathways I showed on the previous
slide that mTOR usually drives to promote cell growth. Just one of those pathways. mTOR is still on, and
all the other pathways that mTOR is activating
are still on. So one pathway has
been eliminated, and we see collapse
of those cells. They die. We see the same
thing in a tumor. This is a mouse
tumor that’s caused by uncontrolled mTOR signaling. You can see that the tumor
is here in this tissue stain. If we stain mTOR
signaling, you could see that the mTOR signaling
is very active really exclusively in the tumor. The rest of the normal
kidney is pictured out here. And what happens when you
treat with the same inhibitor that we did on this slide is
that the cells within the tumor all die. Importantly, the remaining
cells still have activated mTOR. So mTOR is really still on. And this turns out to
be an essential element of this treatment. If you turn mTOR
signaling off, they lose sensitivity to this drug. So you need to be driving
this program in order to have this antitumor response. So with that, I want to
take a step back and just talk a little bit
about targeting cancer metabolism in general
and the cancer metabolism field. So targeting the key
metabolic processes that underlie cancer cell
growth is not a new concept. Really the first antimetabolite
therapy ever discovered was discovered across the
street by this gentleman here, Dr. Sidney Farber. He discovered, working with
children that have leukemia, he discovered an
antimetabolite that would kill leukemia cells that
otherwise were untreatable, thereby sending these
leukemias into remission. And what he did was
target a pathway necessary for
nucleotide synthesis. So nucleotides are
one of the pathways that I showed on
the previous slide that mTOR drives, drives
nucleotide synthesis. Nucleotides are used
to make nucleic acids. That’s the DNA and
the RNA in the cell. This comprises about 25% of
our biomass, give or take. Nucleotides are really made
from exogenous nutrients. They’re made from glucose,
amino acids, and vitamin B9, or folate or folic acid. And what Dr. Farber found was
that treating these patients with antifolates that
blocked the use of folic acid to produce nucleotides
could selectively kill the leukemia cells
and, therefore, send them into remission. And this is still a therapy,
this antimetabolite therapy, is still something
that’s in use today. So targeting cancer metabolism
is not a new concept. But it’s been re-energized in
the last 15 to 20 years really by modern technology,
our improved ability to measure metabolism,
metabolites, metabolic flux, as well as improved
understanding and a deeper understanding of cancer
biology in general. We’ve really started to
unravel many aspects of cancer metabolism that are targetable. And this is really
what we’re looking for is targetable
metabolic vulnerabilities. And the field of cancer
metabolism in general is inherently multidisciplinary. It draws on lots of different
aspects of biomedical research and also contributes a lot
back to various aspects of biomedical research. And so just in
closing, I want to say that I’ve really talked about
one small piece of cancer biology today. I’ve talked about
really the early stages of tumor development,
how a single cell that acquires a genetic mutation
can give rise to a tumor. But we know that cancer really
is a complex disease that– sorry, keep mixing
up the pointer. And so that as the
tumor grows, we see that various aspects
of metabolism kick in. And the tumor
undergoes a variety of different metabolic
adaptations as it progresses. At some point during
its development, the tumor will reach a point
where parts of the tumor may be starving for nutrients. And at this stage, the
tumor will send out signals that tell the body to
grow more blood cells, more blood, more blood vessels
going into the tumor, in order to resupply
the tumor with food, because the blood is really
the source of nutrients for the tumor. So this is a process called
angiogenesis, which I’m not going to talk about today. But basically what angiogenesis
does is refuel the tumor and provide nutrients
back to the tumor. And then finally one of the
worst aspects of tumor biology, one of one of the most daunting
parts of tumor biology, is the fact that tumor
cells will ultimately leave the primary tumor
and metastasize and move to another site in our
body and set up camp there, and therefore metastasize
and form a metastasizing tumor. And in that setting, there
are other metabolic challenges that that tumor cell faces
as it’s entering a new tissue niche and experiencing a
different nutrient environment. And so I bring this up because
I’m not rooting for the tumor cells except to
say that these are all challenges that the tumor
cell faces that are targetable and that we can take advantage
of as cancer researchers and clinicians to
target cancer metabolism and therefore eradicate
cancer by targeting these different
metabolic pathways. So with that, I
want to hand it over to Nabeel Bardeesy, who is
going to pick it up from there. [APPLAUSE] So I’d also like to thank
everybody for attending here in person and live streaming. It’s a real pleasure
for us to be able to give a public lecture. We’re so used to
speaking to each other, and it’s a bit of
a challenge for us to try to convey
things in a more broadly interesting manner,
but it’s also a lot of fun. Brendan and Marcia,
my colleagues, nicely laid out
general principles in metabolic
reprogramming in cancer. As Marcia noted,
individual cancer types use different strategies
to rewire metabolism that are often in keeping with
their specific environment of that tissue. As an example of this,
I’m going to talk about metabolic reprogramming
in pancreatic cancer, which is an area that my lab works
on in Mass General Hospital. The pancreas is an organ
involved in digestion, so producing enzymes to
digest food in the intestine, as well as the
production of insulin to control blood glucose levels. Unlike many other
cancer types, progress has been actually quite
limited in the therapies for pancreatic cancer patients. In the graph on the right,
pancreatic cancer survival rates over five years, five-year
survival rates, and how they’ve changed over the last
40 years are on the bottom. Whereas much more
promising advances have happened in
other cancer types, the cancers tend
to be detected late and respond very poorly to
conventional chemotherapies and radiotherapies. And so we really need
to understand much more about the biology if we’re
going to make clinical headway. The central, or one of
the central, bad actors in pancreatic cancer is the
gene KRAS, whose normal function is to be coupled very
closely to growth signals and to act as a
conductor to orchestrate a whole set of events
happening at once, regulating cell metabolism,
migration, modulate modulating the immune
system, but in a very controlled manner. And this is important in
the normal development of the organism, or
different tissues, as well as in repair
in adult tissues. In virtually all
pancreatic cancers, and 20% of all cancers
throughout the body, KRAS is mutated. And so there’s no need
for any upstream signal. The protein is
always on and always acting in an uncontrolled way
to drive all of these processes. Unfortunately, in one
of the great, let’s say, unmet needs in oncology is a
specific and effective KRAS inhibitor. In the absence of
such an inhibitor, and yet despite decades of
attempts to develop one, many scientists
around the world are trying to investigate
what KRAS is specifically doing within the
cancer cell in order to curtail what we call the
downstream effects of KRAS. And one particularly
promising area is in understanding
and exploiting KRAS mediated alterations
in cell metabolism. All cancers undergo
a gradual evolution, which is driven both by– excuse me, an
evolution as well as an adaptation to the changing
environmental context that they are growing within. And these are driven
both by genetic changes as well as by
nongenetic alterations. In pancreatic cancer,
the first genetic event is a mutation that
activates KRAS gene. And KRAS mutations
causing abnormal growth of the cell, the
pancreatic cells that incur that mutation
as well as damage to the local
pancreatic environment. And there’s a co-evolution of
the growing pancreatic cells as well as the local
environment which leads to a very disorganized
tissue structure, unlike a normal pancreas. And this happens, actually,
it can be over 20 years. These cancers slowly evolve. An ultimate consequence of
this disorganized tissue is that there’s a great
deal of fibrotic tissue within the tumor and a
reduction of blood vessels. Brendan mentioned it a
moment ago, angiogenesis. And, in fact, for
certain cancer types, there are a lot more blood
vessels that are recruited in. But a feature that’s
characteristic of pancreatic cancers is
actually a compressed blood vessel context. The consequences of
this, of evolution of a tumor within this very
disorganized environment, is ultimately a
limited availability of nutrients compared to
a lot of normal tissues. And the blood
vessels, who are again abundant in the
normal tissue and can be very abundant in
specific cancer types like kidney cancer, are required
for delivering nutrients as well as delivering oxygen. So
pancreatic cancers, by virtue of their unique, very dense, and
hypovascular microenvironment, have lower nutrient
availability, often quite strikingly than normal tissues. A second feature
of this environment is that there are
replete immune cells and other connective
tissue cells that could, in principle,
be competing for those scarce nutrients. But they could also
be appropriated, and they can collaborate and
offset defects in metabolism. So they can share
the metabolic burden. And both of those processes
are probably ongoing. And I should just say that in
the histological image below, the cancer cells, or the
tumor cells with mutations, are circled. And you can see that they
are embedded in, again, in this very dense noncancer
cell matrix that are all participating in the tumor. So ultimately how is
this cancer growth achieved despite this limited
nutrient availability? We’ve learned in the
last number of years that this balance between
growth and nutrient utilization is really orchestrated
very much in large part by KRAS mutations themselves. And they’re keeping
a close concert between growth cues and nutrient
acquisition and nutrient utilization. And, again, this
is leading to a lot of predictions for how there
can be imbalances discovered and exploited. So I said earlier
that there aren’t any KRAS inhibitory drugs that
are currently in the clinic. And on the horizon there isn’t
immediate clear opportunities for robust KRAS
inhibitory drugs. However, we can use
genetic tools in the mouse or in human cells. And we can switch
off genetically KRAS and demonstrate that,
in fact, KRAS is very important in tumor growth. So the images at the
bottom show a model for what’s observed in
experimental systems. Turning off KRAS
genetically leads to a very strong
regression of tumors as well as a lot of
death in the tumor. And we’re learning now
that a considerable portion of this death is due to
a metabolic imbalance, and I’ll lead you through that. So, first of all, what
is KRAS actively doing? One of the things that
it’s clearly doing is ensuring that there’s robust
availability of nutrients and enhanced ability to
acquire the available nutrients despite overall limited supply. And these include taking up
glucose and glutamine, which are generally
abundant in the body and very diverse in being
able to be interconverted to generate many of the
basic building blocks needed in the cell. There’s also specialized
scavenging processes that are normally
operative in starved cells. A normal starved cell
can start recycling some of its cellular
components or taking advantage of an improved way to
harness nutrients that are available outside the cell. So pancreatic cancers have
all of these operating in conjunction. And, finally, they’re also very
effective in taking up fats. And I’m going to
lead through some of these examples of
how they are controlled and how they might be
exploitable therapeutically. So Marcia introduced
imaging for glucose. You can see here in
images from a mouse model where on the left,
KRAS mutations are on. The tumor is actively growing. And the tumor is actively
taking up glucose. That’s contributing to
the biomass acquisition of the tumor. Very rapidly upon genetic
switching off KRAS, the tumors are losing the
ability to take up glucose. And this is a very
important contributor to their loss of
growth capacity. So that’s for one
nutrient, glucose. Another key nutrient
is amino acids. And, again, in this context of
limited nutrient availability, pancreatic cancers are
specialized at a process called macropinocytosis, which
involves capturing extracellular nutrients that could
be derived from dying cells or the available
serum proteins. And these are ultimately
degraded in an organelle, in a compartment
of the cell called the lysosome that contains
a lot of degraded machinery. And this active process
of macropinocytosis is an important source
of amino acids, again, one of the key building blocks
in pancreatic cancer cells. A related process that
dovetails with the lysosome is called autophagy. And this is a process of
recycling damaged organelles in the cell. And, again, both of these
are operating at high levels in pancreatic cancer cells. And current drug strategies that
are being tested in the clinic are inhibiting this
cellular recycling program and have shown some promise in
pancreatic cancer treatment. Here’s an example from
experimental models, where the lysosome, so the
degradative structure, is very actively
degrading material. And so on the left is a
pancreatic cancer cell, where there’s very
little material present in this lysosome because
it’s actively being degraded. Whereas if we use an
experimental approach to inhibit this
process, you can see this accumulation of a lot
of cellular components. On the right is a
graph showing what happens to that cell
growth or tumor growth when these degradative
process are inhibited, where you can see a very
profound inhibition of growth due to inhibition of recycling. So to really fully be able to
harness metabolic reprogram, it’s important to know both the
source of nutrients in a cancer cell but also what
are the ultimate fate of these nutrients. What are they being used for? What are those
essential functions that are supporting growth? And I’ve listed some here. Glucose uptake is particularly
important in fueling the synthesis of the
generation of nucleic acids, and therefore in the
production of DNA and RNA. Glutamine is very
important in the control of a damaging chemical in
the cell called oxidants, so to prevent oxidative stress. And I’ll return to
that in a moment. I’ve already alluded
to what autophagy does. So by understanding some of
these altered utilization of nutrients, we
can exploit this. And so Marcia alluded to cancers
as having a really revved up metabolism. They’re hypermetabolic. And so cancers need to be able
to both integrate a growth signal as well as mitigating
this kind of cellular stress. And one of these
cellular stresses is reactive oxygen species. A lot of you in
the room have heard of taking antioxidants as a way
to protect our body in general. But it so happens that
cancers are actually quite efficient at dealing with
the excess oxidative stress that they generate. And they’re, in fact, generating
their own antioxidants as a protective measure
for the tumor themselves. And this slide here
sort of brings together how KRAS coordinates
both enhanced growth coupled with enhanced
protection from damage. So KRAS actively
increases glucose uptake and the utilization
of glutamine. This on the one hand
increases the tumor growth and leads to an
oxidative stress. So this very rapid growth
can lead to inefficiencies. Just like the car that I showed
on the previous slide, where a very, very rapidly
driving car can lead to a lot of
inefficiencies in the way fuel is burnt and lead to
damaging for the car. The same can be
operative in a cancer. But KRAS, by acting as
this master orchestrator, at the same time
increases the generation of antioxidants, both by
utilizing nutrient metabolites to generate antioxidants
as well as to increase the production of enzymes that
are good at, again, enforcing this antioxidant state. Autophagy, or this
recycling machinery, also rids the cell
of damaged organelles as well as increases
metabolic efficiency. So by maintaining
this fine balance, KRAS is able to both drive
very pronounced growth, while avoiding would be
lethal damaging insults. And this gives us a
framework to think about where we can intervene to
cause imbalances that hopefully will be toxic to the cell. So with the last slide, I’d
like to sort of bring things back to how we can take this
basic science information and to apply it in
the clinic, but also what are the
remaining challenges. And, furthermore, what
are the opportunities that are emerging
from understanding cancer metabolism. One other thing
that’s very exciting addresses a key
challenge really that could be transformative
in pancreatic cancer. If early detection
were possible, patients who have
tumors detected early, often by chance,
in the clinic that might be detected for coming
in for another indication. They can be cured surgically. And so if we can
discover properties of these cancers
that are present very early before the
tumors metastasize, this might offer opportunities
for early detection. And there’s been some
very exciting work in the pancreatic
cancer field showing that a very distinct
metabolic production that can be detected in the
blood is associated with early pancreatic cancer. And this is being
actively explored for whether it’s a practical
way to increase the potential for early diagnosis. Another aspect is what
we call immunometabolism. So cancer treatments, a
diversity of cancer treatments, both those that
affect cancer cell metabolism but other
properties of the cancer cell. It’s now emerging
that we need to think of how the metabolic
properties of the immune cells are being affected,
because we want to be able to harness
and reactivate immune cells to
recognize the tumor. And it’s becoming
increasingly recognized that we have to consider
how our interventions affect immune cell function. A topic that many
of us scientists get asked a lot about
is how diet affects both the development of cancer
and, perhaps particularly savvy people, how it might
affect more specifically therapeutic response. And there’s been some
very exciting developments suggesting that, well, let
me turn to the first aspect. So certainly diet can
affect pancreatic cancer. We know that obesity
is a risk factor. We also are gaining
a more precise role of why that’s the case. But, secondly, what’s emerging
more recently, irrespective of obesity, is that
certain foods in the diet seem to be able to have
a very pronounced effect on therapeutic response,
again in model systems. And by dissecting this,
we’ll be able to both have a more integrated,
holistic view of how to harness cancer therapies. Marcia alluded to, and
Brendan alluded to, this crosstalk
between cancer cells and other types of
cells in the tumor. On the one hand,
there seems to be some sort of
symbiotic relationship between the nutrient
supply between the tumor and the noncancer cells
that we need to understand. And, finally, we’ve shown
a lot of experimental data that suggests that
you can really have strong antitumor
effects when you intervene in metabolism. And the public often
hears this laboratory data that sounds very promising. And it’s not always apparent
for why this doesn’t immediately translate in the clinic. In metabolism, one
extreme challenge is that metabolism can
be viewed as robust. And what we mean by
that is that there’s many ways to generate
the same end product. And so there is in very
many experimental systems, a kind of whack-a-mole,
where inhibiting one process in metabolism
can be bypassed by an alternative pathway. And so this is really a
plea for more basic science understanding. We have lots of good
hypotheses, and we’re starting to understand
the unique metabolism of different cancer types. But we need to have a better
understanding of that circuitry so that we are getting past
this whack-a-mole strategy but really being able to
durably intervene in metabolism. So with that, I’d like
to thank the audience. It’s really great to
be here and thank you. [APPLAUSE] OK. So thank you all
for your attention and for these really
terrific questions. So there were a
number of questions in different categories. So I’m going to try
to read them according to the theme of topic. And then Brendan, Nabeel, and
I will do our best to answer. And you can feel free to
contact us afterwards, too, with additional questions. Our information
is on the website. And you can also look up
what our individual labs do and learn more about
how to contact us this way. And just to start
with, I will not have time to read all of
these excellent questions. So I apologize in advance if
I don’t get to your question. So the first set
of questions has to do with on-target
versus off-target. How do you ensure
that drugs target only the mTOR of
cancer cells and do not inhibit normal cell growth? And that goes along with another
question directed to Brendan. What are the limitations of
targeting metabolic pathways? So I think this is really
the most important aspect of any approach to
targeting cancer is what the therapeutic window
is, because we’re specifically targeting proliferating
cells and we’re targeting the pathways
that drive proliferation. So the most common off-target
effects, of course, are those that are also affected
by traditional chemotherapies. These are proliferating
cells, hair follicles, the lining of the guts, and
immune cells in particular, which is the most
troubling of the on-target, off-target effects. These are cells that, when
induced to proliferate, take on a metabolic
program that is somewhat similar to the metabolic
program I was talking about, that they are driving an
anabolic program to promote biomass and expand immune
cells, for instance. When they are revving up
to attack a foreign entity in our body, they will
do a similar metabolism to what the metabolism
a cancer cell does. So targeting these
metabolic pathways, those are the cells that
we worry the most about. But other proliferating cells
certainly can be affected. Now we think that
there– history tells us, work from
people like Dr. Farber, tells us that there is
a therapeutic window to be had for some therapies
depending on the cell setting and depending on the underlying
metabolic vulnerabilities of that cell setting. So we think that the fact
that this metabolic program is occurring in an uncontrolled
manner in cancer cells is where that therapeutic
window comes from. Our normal cells have tight
control over these systems and can shut that system down
if things if things go awry. But, again, this
continues to be an issue. And I think will continue to
be an issue that we are always tackling and coming up with
new cancer therapies is what is the therapeutic window. And, Nabeel, would you
like to add anything to the topic of on-target
versus off-target of cancer metabolism? Well, I think there is a
conundrum, because metabolism is operating. We’re targeting something that’s
completely normal or required in all normal cells. And so where does that
therapeutic window exist? And so I think this concept
of metabolic imbalance is very important, where a
normal cell would normally be coupled to
nutrient availability. Whereas this constant growth
signal in a cancer cell will often drive it to die
despite a nutrient lack. So it might be
possible to harness this paradoxical situation
in the cancer cell, which is insistent on growing
despite nutrient limitations. I also want to
add that we’re not targeting things in the dark. And like Brendan mentioned,
cancer metabolism and cancer biology now has to
be multidisciplinary, which means that we have a
tremendous amount of resources and information. And so one of the most powerful
tools that we can go to is to mine genomic data. And so we can look at the
gene expression differences between normal cells
and tumor cells and really try to avoid
targeting pathways that seem to be commonly
important in normal cells and tumor cells, and really
try to uniquely target pathways that seem to be
specifically different in tumor cells or specific
stages of cancer. So along those lines I’m going
to read another question. And this is addressed
to me, but both of you can answer this as well. So are there certain
types of cancers that are more likely to use
glutamate in metabolism? And on the contrary,
which cancers are least likely to use
glutamates or glutamines in metabolism as a fuel? And so again, yes, the
answer is absolutely. Different types of cancer
prefer different types of fuels. So certain types of
cancer really like sugars, and those can be imaged
by FDG PET imaging. Certain kinds of
cancers seem to prefer amino acids and other fuels. And certain types of
leukemia, for instance, seem to prefer to burn
fatty acids versus sugars. So part of unraveling
fuel choice is a major goal of the field. And one way that we
can get some clues is to look at one,
what are the changes in the oncogenic
signaling drivers. And often that’s
a good first clue, because the signaling
pathways often ultimately lead to changes in gene expression. And then you can also
make predictions. So, for instance,
mixed signaling drives a lot of tumors. And mixed signaling, it’s
a transcriptional pathway that upregulates
the enzymes that are involved in glutamine
uptake and amino acid uptake from a cell,
as well as a lot of the enzymes I
showed that metabolize glutamine and glutamate. And so if you see upregulated
glutamine or a mixed signaling signatures,
that’s a good predictor that that tumor cell type
might use amino acids. All right. And here is another
question to anybody. So how do you dictate
which metabolic pathways to target to turn off? Yeah, so this is
a great question. And I think it’s
one that we don’t know completely the answer to. I think as researchers,
we’ve identified lots of metabolic vulnerabilities. The challenge, I think,
comes from identifying which patients to treat. This is really something
that Nabeel alluded to. But that decision of
which patient to treat is really a
multifaceted decision. And it comes with many
different data points that we must consider,
because it’s really which types of cancer in which
patients will respond best to specific metabolic
pathway inhibitors will really be dictated by
the genetics of the tumor. So what are the
driving mutations that give rise to the tumor? There are anatomical
considerations. What is the nutrient
niche of the tumor? Say, comparing a pancreatic
cancer to a lung cancer, for instance. They’re in very
different settings, and their metabolic
demands will be quite different from one another. And then, finally,
there is something that we have a very hard time
modeling in the laboratory, which is differences in
dietary intake and physiology of the individual patient. And all of these,
I think, are going to contribute to the effects
of targeting metabolism in individual patients. And so I think what we
find in the few drugs that have entered the clinic is
that there are responders and nonresponders. And it’s very
difficult at this stage to predict which
ones will respond and which ones won’t respond. So the question was about which
metabolic pathway to target. And I kind of
pivoted it to which patients to target with which
metabolic pathway inhibitors. I think that that’s the puzzle
we’re trying to piece together. Just one comment
is that the toolbox to be able to ask that
question experimentally is expanding very dramatically. So many companies
and also in academia, there’s been a lot of
attempts to make inhibitors for these many, many metabolic
enzymes that don’t currently have a drug that
can inhibit them. So we can use our
experimental systems to be able to,
perhaps, uncover new what we call vulnerabilities. And so this is an expanding
toolkit that will have, that hopefully will give us new
hypotheses along those lines. The next question is somebody
watching from Facebook from Illinois. So what do we know about
metabolic reprogramming of the tumor microenvironment? Nabeel, do you want
to take this first? Yeah, sure. That’s a great question. So the general view for
certain cancer types like pancreatic cancer is that
the microenvironment ends up being very low in
nutrient availability. But there’s also a
kind of crosstalk between different cells, so
that within pancreatic cancer specifically we know that some
of the connective tissue cells’ nutrients are actually being
effectively used by the tumor cell, so that there’s a kind
of complicity between these two cell types. That would be one example. Also, there’s some
experimental data that suggests that
the local nutrients that are available in the liver
that can be used by cells that metastasized for other organs. And so to give a new fuel
source for cancers and perhaps enables the very
effective residence of some cancers in the liver. So those are the two examples
that I can think of right away. All right. This is a different topic. If you remove the target of
one of the metabolic pathways so that there is a
metabolic imbalance, do you think that mTOR or
another signaling pathway would have some sort of
compensation mechanism to bypass it and still function? Sure, I can take that. In the example that
I showed in my talk, we tried lots of different–
and this kind of gets to the last question
I had as well, which is which
pathway to target. What we found is
that if we inhibited a specific metabolic pathway,
that shut off the TOR pathway. So mTOR– I didn’t
get into it today– is also very sensitive
to perturbations in intracellular nutrients. And so manipulating
a metabolic pathway can affect the intercellular
pool of nutrients. And so what we found
was that inhibiting specific metabolic pathways,
some metabolic pathways mTOR could sense that that
pathway was being inhibited and therefore it shut down. And the vulnerability was lost. So, again, it’s the equivalent
of us firing the carpenter, but the carpenter sent telling
the general contractor, hey, I’ve been fired. And that then the
general contractor says, all right, stop building. We have no carpenter. So the vulnerability
is therefore lost because you can’t
create this imbalance. And so there are settings
where this occurs. And I think the TOR signaling
turning off in this case is beneficial to the tumor
because it will survive. And it won’t starve
itself to death basically by continuing to
drive this anabolic program when it can’t build a whole cell. So I think that
there are scenarios where the inhibiting a
specific metabolic pathway will cause some kind
of adaptation that prevents the target from
killing the cancer cell. From hitting the target,
killing the cancer cell. OK. So the next question hits on a
new and really important topic. Do you think targeting cancer
cell metabolism will be as effective as immunotherapy? Nabeel. So I think Brendan actually gave
an example of the curative form of targeting metabolism, which
is nucleotide metabolism, so some of the most
classic chemotherapies. So we do have an old type of
metabolic targeted therapy that is curing people today. In terms of these
new findings where we’re targeting various
aspects of glutamine metabolism and other things that
we’re talking about, these are entering the
clinic, and they’re looking quite interesting. So I think ultimately
all of us are feeling that complementary
approaches are needed, and it’s going to be
a case-by-case basis. But certainly there
is enough promise here that I think we’re all
very invested in this area. So for those of
you who might not be as familiar
with immunotherapy, it’s basically a set of
new and very exciting therapeutic strategies
that activate our body’s own immune system
to kill the tumor cells. And so in that sense having
this immunological memory and seeing the tumor as a
foreign agent for some patients gives a really dramatic
and long-lasting response that’s an anticancer response. And so it’s very
dramatic because it’s such a durable response. And some patients have been
followed for years and years, and you don’t see recurrence
of the tumor in very severe metastatic tumors even. Now the challenge is
that immunotherapy doesn’t work for everybody. And it actually works for a
surprisingly small fraction of the population. So still 10% to 20% of some
patients of some tumors are very responsive
to immunotherapy. But for some reason
we don’t understand, many patients do not
respond to immunotherapy. And some are some tumor
types are just not good candidates
for immunotherapy. And so I think another
opportunity on the horizon is thinking about how these
basic fundamental principles of cancer metabolism could
synergize in combination with immunotherapy
to kind of widen the spectrum of
responsive patients. I think that there’s definitely
maybe not a new movement but certainly a recognition
that there are really no magic bullets. And certainly, hopefully,
you don’t leave here thinking that specific
metabolic pathway inhibitors are magic bullets. We think that they are a
previously underappreciated aspect of the arsenal
to kill cancer cells. But we think that really
combination therapies are going to be key in targeting
many different aspects of tumor biology, metabolism
being one of these. And so we’re trying to find
as cell metabolism or cancer metabolism researchers
what the most promising therapeutic targets
are to add to that arsenal. Certainly we hope
that some of these will have single agent
therapy activity. But it seems like to get a
durable response in cancer therapy, it’s more
likely we’re going to combine these therapies
with existing therapies OK. So in the last few
minutes, I’m going to read a set of questions
that have to do with a topic we have a lot of
questions on, and then we can all address that. So from Facebook in California,
somebody watching asks are there any
diets or foods that are helpful in stopping cancer. Another question was do
cancer researchers themselves avoid eating sugar. [LAUGHTER] Another question asked
if different fuel types cause different byproducts
and turn on/off certain genes within cells, why not
focus on what kind of fuels we put into ourselves. So there is a whole theme there. And I think those
are very relevant and important
questions to address. So I think– Do you want to answer that? I think there’s probably
two layers to this. Certainly there are many
studies in animal models that suggest that we can
manipulate the growth of tumors by changing the
diet of the animals, either by restricting
their calorie intake, changing specific aspects
of their diet, low protein, high protein, a
high fat, low fat. And also we can, there
are dietary changes that can advance the tumor and
make the tumor grow faster. So certainly you can manipulate
the growth of a tumor by changing the diet. Now whether this is achievable
in us is less understood. Most of the nutrients that
are circulating in our blood are homeostatically maintained
in a very tightly monitored over a very narrow range. So it’s hard to get
your body to all of a sudden have no
glucose in your blood, because your brain
would shut off. So it’s a difficult
thing to think about in patient populations. I think where the
biggest promise comes is whether certain dietary
interventions might improve the activity of existing
therapies or therapies that are being developed
to target metabolism. So dietary interventions
in combination with targeted therapeutics that
target metabolism or signaling pathways or other aspects
of cancer biology, that might be a promising avenue. And I think along
those lines, it’s equally important to know what
kind of dietary interventions are really dangerous
in combination with cancer treatment
and therapy. And this is something
that’s highly understudied that deserves a lot more focus. And then going back
to the diet and cancer incidence or therapy, we
do know that statistically obesity and high
fat diets are linked to the increased incidence of
13 different types of cancer. OK. So that relationship
is quite clear. And I think what we also know
is that if you experimentally test the effects of
laboratory models of cancer in diets that are lacking
a certain amino acid or a metabolite, you
can see that reflected in the metabolite profile of
the bloodstream of that animal and in some cases of the tumor. But it’s not always clear
that matching what you eat will be reflected exactly
in the cancer cell. I’ll just say that, despite
these clear associations, really the massive increase in
incidence of cancer associated with, for example,
smoking or sunlight in certain individuals,
for diet the impact is generally much, much smaller. I think it’s the
reassuring thing. So I think there’s a positive
benefit that’s clearly in diet. But the epidemiology
for many cancer types, this enormous number of studies
looking at individual contents of a diet and looking for
increased cancer risk, and they’re certainly there. But the magnitude,
I have to say, is less than for a lot of the
very established risk factors. OK. So I want to thank
you all for coming, and I hope that you guys have
all learned something today. [APPLAUSE] One second, sir. I hope you all have
learned something new today about cancer metabolism. And I think you could see from
the massive number of questions that we got as well
as the hands that were raised that there are
many further experiments to do and many questions. And please do reach out
to us or Gina beyond this. So thank you again. Thank you Gina in the office and
Barbara and Brendan and Nabeel. [APPLAUSE]

0 Replies to “Cancer Metabolism: From molecules to medicine”

  • Research has discovered, research has discovered, blablablabla…. so many years….. can we still cure cancer? Not, really…really not.

Leave a Reply

Your email address will not be published. Required fields are marked *