Faculty Forum Online, Alumni Edition: Advances in Breast Cancer

Faculty Forum Online, Alumni Edition: Advances in Breast Cancer


Hi. I’m Whitney Espich, the CEO
of the MIT Alumni Association, and I hope you enjoy this
digital production created for alumni and friends like you. Welcome to the
MIT Faculty Forum. My name is Anne Gibbons, and
I will serve as your moderator today. I’m a contributing correspondent
for Science and an author. And as a reminder, we
welcome your questions during this chat. For MIT alumni
joining us via Zoom, please use the Q&A feature
found on your toolbar. For all others
listening on YouTube, you may add your questions
to the Comments field. We also encourage you to
tweet using #MITBetterWorld. We will get to as many
questions as we can. So today, we will
hear from a panel of experts who will share
some of their current projects and research on breast cancer. Let’s start with Dr. Debu
Tripathy, class of ’81, from the University of Texas
MD Anderson Cancer Center. He is on the cutting edge
of clinical research, looking at new therapeutics,
and can talk to us about that. Welcome, Debu. Thank you. It’s a pleasure to be here. There has been a
groundswell of interest in how we are applying
new knowledge in biology to actually treat patients. And this is very evident
in the area of cancer. And I just wanted to share
with you some examples as a launching point. Let me get a few slides
up to illustrate this. I’ll share my slides
here in just a second. One of the examples
of a genetic driver of cancer, the obvious question
is what actually drives cancer. It’s for the most part
alterations in the genetics and other aspects of how a cell
behaves that really gives it a growth advantage. It allows it to proliferate
in an uncontrolled fashion. In fact, you might think
cancer develops all the time because it’s selection
of the fittest, which is a process that is
continually ongoing. And in fact, it does. Our body has ways of
suppressing cancer when it develops,
either immunologically or through other cell circuitry. The HER2 oncogene
was identified over 20 years ago as a gene
that is amplified, that encodes a growth
factor receptor that makes cells grow
much more rapidly, and not in a controlled fashion. And that’s how one defines
an oncogene, essentially. And this HER2 oncogene
is amplified in about 20% of breast cancers. And like other growth
factor receptors, it binds other molecules
called ligands, which then induces a growth signal. And this is a normal
part of physiology, but in the cancer
process this protein is present in abnormal amounts,
and inappropriately drives growth. There are other cases where the
growth factor may be mutated and can do the same thing. Interestingly,
this growth factor and antibodies
against it can also activate the immune system. So the drugs that
have been developed are shown schematically here. And I won’t go into the details
of how these drugs work, but they essentially
interfere with the function of that growth factor
receptor in a way that it actually
inhibits growth. And all of these drugs now
have been actually approved by the FDA. They have been tested
in clinical trials where they’ve actually shown
an improvement in survival. In patients that have
advanced breast cancers that are HER2 positive, we’re
still unable to cure patients permanently, even
with these drugs. But they can get into
remissions and live longer. And when we use it for
early-stage breast cancer, it actually lowers the risk
of developing a recurrence and dying of breast cancer. So it actually saves
lives in that context. However, resistance
almost always develops. And as you will hear from
some of the other panelists today, unraveling
mechanisms of resistance or inappropriate growth
and understanding the details really
is going to be the key for us to make
headway in many diseases, including cancer. The ability to see multiple RNA
species, as shown on the left, and also to sequence genes
using next-gen sequencing has really accelerated
our ability to understand what are
these drivers of cancers. How do they cooperate? How do they work together? And how can we disrupt
it using a variety of different
pharmacologic drugs? And interestingly, what
happens to a tumor cell is, again, ongoing evolution,
selection of the fittest. And any genomic
variation that may exist in the
cancer– and we have to think of a cancer really
more as a micro ecosystem, where natural evolution can occur. We do see it. In fact, this diagram shows
expansion of certain clones that can be measured over time. And interestingly, it’s
very similar to the figures that Darwin used
nearly 200 years ago to describe transmutations
and evolution of the species. So we’re actually going back
to this evolution paradigm and looking at
sequential tumor tissues, as shown in this diagram,
from a patient that’s actually being treated with
anti-HER2 therapy, and trying to understand
why do patients eventually become resistant
to these therapies by looking at serial
sections over time and using some of the newer
high-throughput technology to discern what actually
evolves over time at the proteomic level
and at the genetic level. And we feel that, by doing
these types of analyzes, that we will actually be able
to identify key mediators of– let me stop the screen here– key mediators of what actually
drives resistance, and make these drugs work much better. And then the last
thing I want to say is that some of the
other phenotypes that are important other than
abnormal growth factors, there’s many aspects
of cell biology that can be disrupted that
lead to malignant growth, inappropriate growth. And I’ve only touched
on one example. But because there has been
such an interest in immunology, I just wanted to touch
on that a little bit. It turns out that one of the
drugs we use against HER2 is an antibody that
was actually designed to just block the growth
factor itself, the function of the growth factor. But it turns out that
that antibody has what’s called an FC portion. It’s a standard part
of many antibodies that is able to activate other
parts of the immune system– in this case, T-cells that
then react against the tumor. So unexpectedly and
unintentionally, this drug actually induces
an immune reaction. And we’ve known about cancer
immunity for a long time. Patients do develop immune
reactions against our cancers. For the most part,
they tend to be too weak to make a difference,
and the cancer cells find ways to evade these
immune mechanisms that we have. But in the last
decade or so, we’ve identified how the
immune system naturally dampens itself to avoid an
over-exuberant immune reaction. And by tweaking these levers, so
to speak, on the immune system, we’ve actually been
able to reactivate them against cancers. And it’s starting to make a
difference in certain cancers. In melanoma, in
renal cell cancer, and in certain other
cancers we are actually improving survival. It’s not always
curative, but we expect that, as we learn more
about the inner controls of the immune system, that
we will be able to get more and more specific. And there’s other very
interesting areas going on, such as engineering T-cells
to recognize certain antigens. And obviously, there isn’t
time to discuss these all, but I just wanted to point
out how that has been really a revolution that all
has been driven, really, by our understanding of basic
science and basic immunology. And I think this is going
to be a recurring theme, and you’re going to hear
this from my colleagues who are going to present some
of the work they’re doing, how it’s so critical for us to
understand these systems to be able to apply it. And as a medical oncologist
that sees and treats patients and sees
resistance develop, it is certainly going to be
an area of rapid advancement, I predict, in the
next decade or more. So I’ll stop there. And thanks for your attention. That’s great. That’s a great setup
for our next speaker, who is Natalie Hendrick. She’s class of ’12 MIT and a
graduate student researcher at the Harvard Medical School. She’s a cell biologist who is
looking at the new role of cell signaling in biology
with potential of using that pathway,
those pathways, for possibly treating cancer. So she’ll talk to us
about basic research and why that’s an interesting
area for breast cancer. Yes. Thank you. I’m going to share my slides. So I’m a PhD student in Dr. Joan
Brugge’s lab at Harvard Medical School. And I’m going to talk briefly
about some of what I’ve been doing in my thesis work. I’ve [INAUDIBLE] focused
on the protein YAP, which is the downstream effector
of the Hippo signaling pathway. Sorry. So YAP is classically
considered as an oncogene, or a protein that promotes
tumor growth and progression. This is a study from our
lab several years ago, where, using the normal
breast epithelial line MCF10A and over-expressing YAP,
increasing levels of YAP in these normal cells,
we were able to see an array of phenotypes that are
consistent with actually breast cancer cells, such as growth
in oncogene independent conditions, invasion,
growth factor independent
proliferation, as well as a complete morphological
phenotype change and EMT. However, recent data suggests
that the story with YAP is more complex than
we initially thought. If you look at actual patient
data using the Cancer Genome Atlas, which is a database
that has all sorts of tumor data from patients, we can
see that, in many cancers, YAP is both increased
as well as decreased. And specifically
in breast cancer, the number of cases
where YAP is high is actually equivalent to
the cases where YAP is low, which suggests that the story is
more complex than we initially thought. Actually, a paper done by
a former graduate student in our lab found that YAP has
a role in cytokinesis, or cell division. She found that, when YAP was
decreased in the MCF10A cells that I mentioned earlier, there
was hyperdynamic mitoses that led to irregular cell
division and increased chromosomal abnormality, which
is also a hallmark of cancer. This is where I wanted
to pick up the project. And I wanted to look
at non-dividing cells. So I’m going to show a few
live cell microscopy movies. These are the MCF10A cells
starved of growth factor and then stimulated. We can see dynamic response. And when we knock down YAP
using RNA interference, we see hyperdynamic response,
increased protrusions, and increased migration. And going to– oops. This is another hairpin that
gives us a similar response. So my lab is known
for 3D culture, which is a method of growing
cells in conditions that are more physiological. So these are MCF10As
grown in Matrigel. Normally, these form these
nice spherical mammospheres, but when we knock down
YAP we see invasion into the surrounding matrix. Just to have a quantitative
readout of this, I quantified the circularity
as the normal cells form the spheroids, and we have
a significant decrease in circularity in the
YAP knockdown cells. And finally, I wanted to mention
migration, which I alluded to on my first movies. So normally, these cells
migrate as a sheet. So this is a wound
healing assay, where cells move into the gap. And when we knock
down YAP, we see that there is a loss
of this cell migration, and cells actually
come off individually, which suggests that the
cell-cell junctions are actually impaired. This is the other
hairpin that I have. [INAUDIBLE] this leads to
an interesting hypothesis, that there is maybe
spatiotemporal control of YAP levels in a tumor. So most of the
literature suggests that YAP is an oncogene,
and studies from our own lab support this. So perhaps when a
tumor is starting out it’s beneficial for
high levels of YAP, which would lead to high cell
division and tumor growth. But as a tumor progresses
and eventually metastasizes, it could be beneficial for
YAP levels within the cell to decrease, which would
result in decreased cell-cell adhesion,
which could allow individual cells to break
off and invade and eventually metastasize. So further studies need
to be done on this, but it’s an
interesting hypothesis that our work raises. And I want to say
that this highlights the importance of really
understanding basic cell signaling and cell biology
because, up until recently, it was just widely perceived
that YAP was an oncogene. But our work and the
work of several other suggests that actually there
might be a tumor suppressive role of YAP, as well, and
targeting YAP could actually enhance tumor progression
in certain cases. That’s great. Thank you. And then for our next speaker
is also doing basic research. That is Richard
Possemato, class of ’01. He got his PhD in ’08, so
a double dipper at MIT. He is a biologist who’s at
NYU, New York University, who’s looking at alterations in
tumor metabolism, the potential for the importance of
that in cancer pathways. So I’ll leave it
to you, Richard. Thanks, Anne. Yeah, so as Anne
mentioned, we try to understand how tumors acquire
and utilize the nutrients that they need to grow. And this is important in
a variety of tumor types. And we use breast
cancer frequently as one of our
systems because of– and I’ll explain
to you a little bit why we’re doing some
of our work in breast cancer in a little bit. So when normal cells
in our body are going about their
daily tasks, they perform all this through a
fairly orderly and efficient use of nutrients. But in cancer, there’s
this transformation in the priorities
that the cell has. They’re not doing things in an
orderly fashion, where they’re trying to simply efficiently
use ATP and glucose from the environment, but
they’re putting together all the building
blocks that they need to grow in a
fairly haphazard fashion because their drive is to
engineer more cancer cells. And this creates some
problems for growing tumors so they can outgrow
their ability to take in nutrients
from the environment. And also, they can activate
pathways, mechanisms by which they need to make a
new cell in a different way than what happens
in normal tissues. And I’ll show you
some examples of this. And if I can share
my screen here. So I like to make this
introductory slide here to describe overall what’s
going on in tumor metabolism. So this idea that the cells
need to make building blocks to make more cells,
essentially, is generally referred to as biosynthesis. So they need to make
these nucleotides that are composing DNA and
RNA inside the cell, these lipid species that make
up the membranes of the cell, and then these amino acids
that are building blocks for all the proteins and
enzymes, all of these machines that are working
inside of our cells. And because cancer
cells are driven to do this more
than normal cells, they need to put together
additional tumor cells to grow, they need to engage in a
variety of cellular processes. And those are shown in this
green ring on the outside. They need to make energy
in the mitochondria. And this is chemical
energy in the form of ATP. They also need to
manage the byproducts of this altered
metabolism, for example by altering their
ability to recycle things or to excrete things that
they no longer need, such as– toxic byproducts for tumor cells
might be things like ammonia, for example. And then there could be
reactive oxygen species, sort of supercharged
oxygen molecules that are produced a
lot by cancer cells. They also need to engage
in efficient nutrient uptake from the environment
to get all the raw materials that they need for making
these building blocks. And then they need to
manage, essentially, redox balance to make sure that
they have sufficient oxidizing and reducing power to power
all these chemical reactions. And so all these things
happen inside the cancer cell. The cancer cell is
sitting inside a tumor, and so it’s taking cues
from both other cells in the environment– and you
heard about how interactions with immune system might
be important for cancer– but also there
are molecules that are in the environment, such as
oxygen and glucose, amino acids that the cancer cells need
to make efficient use of. And then the organism that
the tumor is growing in is also going to impact the
ability of the tumor to grow. So is this tumor
growing in an organism that may be diabetic or obese? And this can all impact the
metabolism of the tumor. Recently, we’ve been focusing
on one particular pathway. So one particular
route of biosynthesis. And that’s the
ability of the cells to produce the
amino acid serine. And one of the reasons why we
focused on this was because we noticed that, in
different breast tumors– and we have different
stained sections here– there were varying levels
of a particular enzyme that’s required to make
this building block, serine. And that enzyme is called PHGDH. That doesn’t really matter
too much with the name is. But we found that this
difference in expression was explained almost entirely
by the subtype of breast tumor that we were analyzing. So for example, in ER-negative
tumors or basal-like tumors, we saw very high
expression of this enzyme, whereas ER-positive
tumors we didn’t see very high expression. And in subsequent work
by us and by others, it was found that the expression
of this particular enzyme correlated with a
subtype of breast cancer that’s particularly
difficult to treat. And that’s called triple
negative breast cancer because it doesn’t express
these hormone receptors and because it doesn’t express
HER2 and that other growth factor receptor that was
referred to recently. And because there’s
no expression of these genes in this
subtype of breast cancer, there’s no handle by
which clinicians can go after this cancer subtype. And so finding a
pathway that’s activated in basal-like or triple
negative breast cancer is something fairly important. So expression of this
gene and activity of this biosynthetic pathway
is emblematic of this type of breast cancer. And so we’ve been
trying to understand why this might be
the case, and then to use animals such as a mouse
to generate a model where we can induce a basal-like
tumor in that mouse, and then ask what happens
when we avoid this gene. And those experiments
are ongoing. But to sort of give
you a flavor of what intracellular metabolism,
metabolism that’s occurring inside the
cell, might look like, this is an example, a schematic
of a biosynthetic pathway that makes serine. And what happens here
is that cancer cells will take up this molecule
glucose from the circulation. Glucose is one of the
most abundant molecules in the circulation, and
it’s used fairly robustly for all kinds of
biosynthetic reactions. So glucose is taken up
very abundantly by tumors. And this can be metabolized
through something that you probably learned
about in high school called glycolysis. And one particular intermediate
between breaking down glucose, shown here, 3PG,
is shunted off of glycolysis and used in these three steps
to make the amino acid serine. And serine is an
interesting molecule. It’s not only made by the
cell through this route that I showed you
here, but it can also be taken up by the cell. And both of these processes
are activated in cancer. And serine is also
not just produced, but it’s consumed a
lot by cancer cells. And it can be used
to make proteins. It could also be used to
make other amino acids, to make membrane lipids. And it can also be used to make
nucleotides, so building blocks for DNA and RNA. And for all of these
reasons, serine is one of the most highly
consumed metabolites in cancer. And so being able to
modulate its availability is something that cancer
cells, and particularly these basal-like breast cancer
cells, care a lot about. And so this is one
vignette into how we study the
metabolism of what’s going on inside the tumor. And the ultimate goal is to
be able to identify processes or pathways like this that
cancer cells specifically rely on so that we can target
them for anti-cancer therapy. That’s great. Very interesting. Are you finished? I didn’t mean to– Yeah. Thank you. –that’s great. Maybe we can follow
on that immediately. I’m curious if the
serine pathway, this sort of enhancement and
overproduction of it in cancer cells, is that
important to multiple kinds of cancer, not
just breast cancer? Is this an important pathway
in only breast cancer, or in others as well? Right. So there have been
several studies that have suppressed
this biosynthetic pathway in a variety of contexts. And so there are various
other cancer types– lung cancer, a particular
subtype of lung cancer has been shown to be
dependent on this pathway, and melanoma also has very high
activation of this pathway. So there’s examples that may
be present in other tumor types where we can be looking
at this, as well. So you’re looking in mouse
models at this point, at what happens when you
interfere with that pathway basically. That’s what we’re
doing right now, right. So we can activate breast
tumor formation in a mouse by deleting BRCA1, which is
something– a molecule that’s familiar to a lot of people
in the breast cancer field. This is a gene that’s mutated
in familial breast cancers. So we can delete that
gene, and then we can delete an important
tumor suppressor called P53, which is mutated probably
80% or higher of all cancers. And so by deleting
those two genes, we can induce a mammary tumor
information in mouse models. And then we can ask what happens
if we additionally ablate the ability of those cancer
cells to make this amino acid. And then down the
road, ideally, I suppose, you would then
try different therapeutics, potential therapeutics,
things that could interfere with that pathway. But you’re at the
basic understanding level at this point, right? Absolutely. And so there’s reason
to believe, for example, that if you starve cells of this
pathway that they may have– they may become more
sensitive to other commonly used
chemotherapeutic agents. So I mentioned that serine
can be used to make DNA. So if you block the
ability of cancer cells to officially make
DNA, are they now more sensitive to
other agents that target DNA metabolism,
which are fairly abundant in
anti-cancer treatment. That’s really interesting. It leads me into a
question for Debu, which is, in your discussions
about potential new therapeutics, they’re often
combinations of therapeutics that people are
putting together. You talked about
some new drugs that are exciting that have
just been approved, but it seems like some of
the clinical research you’re involved with is looking
at how you can combine some of those drugs to be most
effective with different stages of cancer and different types. Maybe you can sort of
discuss some of those most promising therapies? What do you sort of
see coming online or that’s just newly online
that is making a difference? Well, there are several
different characteristics that we can target. Growth factors and growth
signals is one of the areas that we can study the most
because the growth phenotype is very easy to detect. As you heard from
Natalie, she’s working on a pathway that
affects not only growth but morphology so you
can screen for it. But generally speaking,
most cancer cells have enough fluidity–
in other words, there’s enough
genetic differences or genomic variation
that escape mechanisms can develop very easily. If you think about clonal
diversity, which basically means that all the
cancer cells are not carbon copies of each
other, but rather they have subtle differences that, just
by random chance, one of them might be resistant
to a given therapy that would otherwise
be very successful. So you’re right, a
lot of the successes we’ve seen in cancer
therapy are based on not just combinations,
but rational combinations, combinations that are designed
to subvert a common mechanism of resistance. And in some cases, those
combinations are synergistic. In other words, 1
plus 1 equals 5, because you’re taking two
pathways that are complementary and depend on each other. So what we’re– much of the
research when we talk about a particular cancer pathway
is to understand mechanisms of resistance. And the best way
to understand these is to look at the
actual human model because some of these
mechanisms of resistance may not be reproducible
in a cell model, or even in an animal
model, because they depend on interactions with other
cells of the micro environment– immune cells, vascular cells. And so when we try to understand
these escape pathways, we really want to be as– set our experiments
up so that they were most likely to succeed
in elucidating what there are. And there’s a lot of
interesting technologies out there that you’d heard
about, small hairpin RNAs, ways to turn off the
expression of genes. You can actually screen
libraries of these interfering RNAs to discern which gene
or which pathway may actually be leading to resistance
to a given pathway. So you’re going to
see much more of that. I spoke about
immunotherapy earlier, but we’re finding
out that inhibiting DNA repair at the same
time as using immunotherapy may actually be synergistic
because one of the ways that cells escape immune therapy
is because they develop more mutations, and at some
point one of those mutations may lead to resistance. So if you could
subvert that, you may actually get more response. That’s just one example
of a synergistic pathway that we’re looking at. But most of us
believe that we’re going to really make headway
in cancer by understanding how to use combinations,
very similar to the way we really finally
got a handle on HIV is through using combination
drugs that subverted mechanisms of resistance to the
protease inhibitors and the dinucleotide
inhibitors that interfere with the growth of
the RNA virus, the HIV virus. You also talked about
evolution of resistance. That was very interesting. Are there any things that
you can report on now in that research? Are there exciting targets or
candidates there, or is it– give us a little update or a
little more insight into that? Yes, there actually are. In the area of
resistance to HER2, it turns out that just isoforms
of the receptor that now do not bind the antibody are seen. And this is a very
common escape mechanism is, if you’re targeting
a particular protein, the cell is going to manufacture
alternative spliced versions of that protein that
still do the bad thing you want it to do, but don’t
respond to the drug. And it’s a very clever
thing that cells do. It’s not that the
cells are being clever, it’s just that, you know,
one in a million cells may have a splice site
in RNA that changes, so now the protein changes. And of course, that one now
is going to continue to grow. It’s a clonal evolution,
clonal selection under selected pressure. So we see a lot of
the concepts that go on in evolution, but in
a really fast timeframe. So we have to continually
outsmart the cancer cell, and to look at the natural
mechanisms that develop. And normally, what we find
is a mechanism of resistance might be commonly seen– what we call a
recurrent mechanism. If we study many
different patients, you might see that
2/3 of the patients use this one mechanism
of resistance. So it makes sense
to co-target it. Other mechanisms are
going to be very rare, so you don’t want to develop
a drug for something that may only be seen in one
out of 1,000 patients. Of course, yeah. Getting the funds then
to develop that drug is an ultimate challenge. Exactly. So it has to have application
not just maybe even to breast cancer,
but is that pathway common in other cancers, and
making it a good drug target, I guess, is important, too. So Natalie, in your really
interesting research for this [INAUDIBLE] can be a
tumor suppressor gene. It seems like it has
these varied roles. What is next in your research? What do you sort of
see coming along next? You know, where
are you with this, and what are your challenges
as you go into it? So I’m sort of heading
in two directions to follow up the
observations that we have, looking at detailed
molecular mechanism. So we have these really
robust phenotypes, but we’re looking to see
how YAP is regulating the morphology of the cells. And also, I’m very interested
in taking the observations that I’ve found in
the cell culture and seeing if they hold
up in a mouse, as well. So definitely moving
in in-vivo, we call it, and seeing if this has
strong applications to potentially breast
cancer progression, as well. And what would you
do in the mouse? What would your ideal
experiment look like? Would you play around
with regulating it so it’s expressed
and not expressed, or are you looking at
knock-out and knock-in, or? So I’m a fan of using inducible
hairpins for mouse experiments. So the way that this works
is that you can control when you have YAP interfered
with, and you can decrease the expression of
the gene at your own timescale. And so I would put cancer
cells into the mouse and then let the tumor
establish and see if what I was mentioning
in my final slide is potentially true, if we
can have an established tumor and we decrease YAP, if then
we see increased metastasis. And so this is something
very interesting, I think, to track in the mouse. Really interesting. Could you stand back for
a minute for me, too, and talk about this is one
really exciting oncogene, right? Yes. One area of important research. Are there others that are
really interesting targets for breast cancer that
are under study that you could tell us about? Are there some other
candidates that are promising to play–
to interfere with? You know, to see if they can
be regulated as a therapeutic? So actually, YAP is not
generally thought of as one of the most promising
candidates for drug treatment because transcription factors
are notoriously hard to target. I think ideally kinases,
or the proteins that can alter other proteins,
are generally more targets that the pharmaceutical
companies go after. So one that is very
interesting is PI 3-kinase. And I’m sure this is something
Richard could tell you more about. PI 3-kinase is really
critical to cell metabolism, and is very commonly
altered in breast cancer. And yeah, I think
there’s definitely a long list of candidates. That’s interesting. And then I had a
question for Richard. And that is, when you talk
about cell metabolism, I know some of
your research looks at the role of the
mitochondrial DNA, right? Are there– can you talk
about that a little bit? When most of us
think of cancer, we think of mutations in, like, the
BRCA gene in the nuclear DNA. Can you talk to us about
the emerging research on mitochondrial DNA
pathology, or whatever you want to call it? Yeah, sure. This regulation,
how that’s emerging is an interesting
area for this kind of research for breast cancer. So the mitochondrion
is a small organelle that contains its own genome. It’s very tiny compared
to the nuclear genome. It’s about 16,000 base pairs,
whereas the nuclear genome is several billion. And this mitochondrial
genome encodes 13 proteins that are involved
in oxidative phosphorylation. So very specific to
mitochondrial function. And this genome is mutated
at a much higher frequency than the nuclear genome. So mutations hamper the
mitochondrial genome in tumor cells because there’s
so much damage just in general that they can occur
as cells divide. But when cells divide in
the context of a tumor, you now have lots of mutations
in the mitochondrial genome. And so you’ll get tumors
that are heterogeneous, some of which have frank loss
of mitochondrial function, or at least repression in
mitochondrial function, due to mutations in
the mitochondrial DNA. And so some people
have been trying to think about ways
to target this. And it seems like, if you
are able to find a tumor that has these mitochondrial DNA
mutations, that they may be more sensitive to drugs
that further suppress the mitochondrial genome. The problem with targeting
the mitochondrial DNA is that the tumor is going to
be so heterogeneous that you’ll quickly find escapers, as
we’ve just described, that are able to circumvent this. So there’ll be a portion
of the tumor that hasn’t mutated in the
mitochondrial genome, and they’ll very
quickly take over. But it’s interesting
to think about from a bioenergetic perspective. You know, if you have
a mitochondrion that’s partially dysfunctional,
is there something that you can do with a drug to
induce that state potentially in a tumor, and create some
kind of metabolic catastrophe without needing these
mitochondrial DNA mutations? And so people are thinking
about that, as well. Another I think pretty
exciting area of targeting genes and maybe even to be
able to target things like YAP, which is a
transcription factor, is the pharmaceutical
companies are now making drugs that don’t need
to target enzymatic functions, but just need a surface
that they can bind to, and that can then
interfere with the function of a whole variety of genes. And that has the potential
within the next three to five years to make
things that weren’t good targets into good targets. And so we can think
more creatively about the types of genes
that we can hit with drugs. That’s interesting. And it sounds like also
the mitochondrial work might be important
in the diagnostics when you’re evaluating best
therapeutics for a patient. If we ever get to that
personalized genome level, would you look at each one? Or are you thinking
more just for treatment, not necessarily for– I mean, I’m wondering
if it’s part of the screening of
diagnostics you might look for that activity or? I’m not sure. It might tell you
if there was more I guess oxidative damage during
the course of tumor agenesis. It’s hard to pin down. People had been
arguing for a while that these mitochondria
mutations might be selected for
during tumor agenesis because they’re so prevalent. But it seems like they’re
more just passenger mutations. And so the longer the cell
divides, the more likely they are to just sort
of pick these things up, and that that may
interfere in mitochondrial function eventually. But it’s hard for me
to get a hook into how we might use it in the clinic. That’s great. Debu– We are doing some
work with energetics to look at early responses
to therapy, the idea being that if you actually
have a successful therapy and you’re interfering
with growth, maybe the first thing you’ll
see is a diminution in that. And there is actually a clinical
test that we use for that. PET scanning
basically is looking at fluorodeoxyglucose
utilization. And there are several
cancers in which, if you are treating someone and
they get an immediate reduction in their PET scan
uptake within a few days of therapy, that actually means
that you’re on the right track. And so we actually make
clinical decisions on that. Not so much in breast
cancer, but they use it a lot in
Hodgkin’s disease right now, as a
quick response to PET means you’re on the
right track and you can continue with that therapy. And if not, it means
you need to change to one of the other options. Debu, I was going to ask
you to sum up for us. Are there– you know, you’re
looking at this basic research, lots of pathways being explored
with remarkable sensitivity. It’s really, really
interesting to getting to this basic cell biology,
and especially in tumor cells. But how about on
the treatment front? You just basically
gave an overview recently at a genetics
meeting, a cancer meeting on really exciting therapies. Are there any that you think
are transformative right now, or are particularly important? Just coming online that– One of the ones that I reported
at the last San Antonio Breast Cancer Symposium was
cyclin-dependent kinase inhibitors. And these now– three of
them now have been approved. So they’re relatively recent
additions to our armamentarium. And they definitely do
extend remission times in patients with hormone
receptor positive breast cancers. And the cell cycle has always
been sort of the holy grail because it really
drives cell division. And now we finally have
drugs that work against it. It’s not the magic
bullet, though. Patients do eventually develop
resistance to even these drugs. So, you know, going
back to your issue about trying to understand all
these pathways in totality, you know, clearly
there are going to be different cancers that are
driven by different pathways. Now that we’re doing
next-generation sequencing across a lot of tumors– and I think Natalie had
alluded to some work from the TCGA, the
Cancer Genome Atlas, that informed some of her work– we’re finding that there are
many, many mutations that drive cancers. In fact, in breast cancer,
many of the mutations are seen in only a small
percentage of patients. PIC3CA, as Natalie mentioned,
is one of the most common. It’s 30% to 40% of
hormone receptor positive cancers will have that. But many of these mutations
are very rare indeed. So what that’s telling
us is that there are many roads to Rome. There are many, many ways a
cancer cell can hijack growth pathways to become malignant. And it may very
well be that we have to develop customized
diagnostics that then tell us, OK, we’re going to take this
off-the-shelf combinatorial for this subclassification
of tumors. So pharmacology and
cancer treatments are going to be,
and already are, becoming very, very
complicated, where it’s based on the genotype
and phenotype of the tumor. Maybe not so much the tumor– what organ it arose from, but
what biological classification it is. And there’s going
to be thousands of biological classifications. So it’s going to
get complicated, but at least there are
some opportunities there. That’s a great
note to end it on. Many roads to cancer, but also
many opportunities, perhaps, to block them. So I want to thank you on
behalf of the Alumni Association for tuning into this
Faculty Forum online. Thanks again to our alumni
panelists, each of you, from the University of Texas,
Harvard Medical School, and New York University. We didn’t get to
all the questions, but we’ll forward any to– you can forward more to
the panel if you have more. Tweet today about– excuse
me– tweet about today’s chat using the hashtag
MITBetterWorld, and send follow-up
questions or feedback to [email protected] Thanks again for watching. Thanks for joining us. And for more information on how
to connect with the MIT Alumni Association, please
visit our website.

Leave a Reply

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