Michelle Monje: New therapies for brain cancer

Michelle Monje: New therapies for brain cancer


(gentle music) – [Narrator] From the campus
of Stanford University. – [Russ] People are worried about data, they’re worried about their
privacy and their security. They should be. We need secure systems. – [Narrator] This is The
Future of Everything. – [Russ] But we can’t have a system that closes that data off. It is too rich of a source of inspiration, innovation, and discovery
for new things in medicine. – [Narrator] With you host, Russ Altman. – Today on The Future of Everything, the future of brain cancer
therapy and response. Few things create more fear and anxiety than the idea of brain cancer. I’m a physician, and I know that, when a patient comes into my office complaining of a headache, what they are really
number one worried about is do I have brain cancer, and so it’s very important to
reassure them appropriately after appropriate tests that
they don’t have brain cancer, ’cause this is one of the
things people fear the most. The brain is a special organ. It has 100 billion
cells, they’re connected, they communicate with one another to create all of the amazing capabilities of human thought, emotion, and action, and it develops, you know,
right from the very start, during gestation and early childhood, through a complex series
of growth, interactions, even pruning of cells
that are not necessary, and refinement of the system. This allows cells to make
decisions about where to go and how to make their connections, and the whole physical layout of the brain takes all of this time during gestation, childhood, all the way
into young adulthood, and hopefully some things
useful happen, even in aging. It’s carefully and it’s
beautifully orchestrated, but it can go wrong. And when it goes wrong, it
can lead to brain cancer, and of course, one of the more
tragic parts of brain cancer is when it affects children. Now, we have a variety of treatments, and we might learn a little
bit about those today, but these almost always have
toxicities and side effects that limit their utility
and their effectiveness, and also have implications in
the long term for the patient. Some of theses side effects may affect the core functions of the brain, including even cognitive
impairment after treatment, and brain cells cannot
typically grow back. People are working on that, but currently, if cells are lost, they don’t come back, and so it’s important to
prevent and understand any kind of neurological
damage during treatments. Fortunately, the modern tools of research are shedding light on these issues and giving us causes for hope. Dr. Michelle Monje is a
professor of neurology, neurosurgery, pediatrics, pathology, and psychiatry at Stanford University, and studies brain cancer,
particularly in children. She searches for new therapies, and she also studies the
effects of those therapies, and uses all of that to
understand the fundamentals of how the brain develops. Michelle, brain tumors in children are particularly tragic and challenging. You know that better than I. What progress has been made and what are the most
promising developments? – So, that was an excellent
introduction, Russ. – Thank you. – Brain cancer in children is one of the worst diseases
that we can imagine. When I saw this disease
first in medical school, I just couldn’t turn away from it, and so I dedicated my
career to trying to take better care of children with brain tumors. And I can say that, over the last decade, we’ve made, as a field,
just enormous progress. You know, when I started
studying these tumors 10 to 15 years ago, we
knew very little about, you know, the mutational
profile that is driving the initiation of the cancers, about what these tumors need to grow, about why they exhibit such a remarkable but poorly understood spatial, meaning different parts of the brain and central nervous system, and temporal, meaning at certain ages, kind of pattern. So, certain cancers happen in certain places in the nervous system at certain times of childhood
and adolescent development, but what has been governing those patterns has been really poorly understood. – Is the growth of the cancer related to the development of the brain? Are those going part in parcel, and is something going wrong, basically? – So, that’s really the hypothesis that I started my research program with, that if we better understood
neural development and neuroplasticity during childhood, adolescence, young adulthood, and on into, you know, old age, that
we would understand more about how these tumors emerge and what we could do to
effectively treat them, because what has been
so frustrating is that, you know, for the worst
acting brain cancers, we have very limited
therapeutic options at present. That is rapidly changing,
which is so exciting and so wonderful to see, and for the tumors that
we can effectively treat, we use such big guns, if you will, that there is often, if
not usually lasting damage to the nervous system that
really affects the individual for the rest of their lives. – They often say that you’re
trying to kill the cancer before you kill the
patient, and it must be especially worrisome when the
toxins that you’re delivering, and when I say toxins, I mean the very powerful chemotherapies, when those are going into the brain, which is such a tender and critical organ, it just makes you worry. – It makes you worried,
and for good reason. You know, our therapies are presently, you know, they’re the best
we have, we need them, they’re life-saving, I’m
not at all advocating not using the therapies that we have, but they are devastating, and they induce long-lasting damage that is also, or has been, you know,
really poorly understood. And so, you know, the
overarching goal in the field is to develop more effective therapies for all kinds of brain
and spinal chord cancers, and for those therapies to be safer, more specifically effective,
and/or to develop ways to regenerate the nervous system and repair the damage that
these therapies are doing. – Yeah, so how have you,
so, with all your knowledge, and you’re both a
clinician and a researcher, how do you decide where
do you focus your efforts, and what do you find to be
the most promising directions? ‘Cause obviously that’s what you spend all your time thinking about so you can use your efforts productively. – Right, right, so some of
the most exciting developments in oncology in general, and in childhood brain cancer specifically, have come from, number one,
a deeper understanding of, you know, what is really
driving these cancers, and that comes back to
fundamental neural development, and understanding how
we can perhaps interrupt some of the factors that are enabling and encouraging the growth of the cancers, and again, that comes
back to understanding neural development and plasticity. And the other really
enormously promising area is in immunotherapy and leveraging the power of the immune system to try to specifically
eradicate the tumor cells. And so– – So, the immune system is in the brain, it’s not walled off in some way? – Yes, that’s absolutely
right, and actually, you know, discoveries
in basic neuroscience and basic immunology have elucidated that, in fact, that not only the resident immune cells of the brain,
which are called microglia, they’re a resident tissue macrophage cell, we’ve known about their
present for some time, but in addition, there
are lymphocytes that are, you know, we used to think about the brain as kind of an immuno-protected site, but in fact, lymphocytes
are traveling to the brain, they’re regularly surveying the brain, they might be contributing
to normal processes of neurophysiology, and
those lymphocytes are, in fact, being drained from the brain through a lymphatic system
that was only developed, oh, sorry, was only discovered
in the last few years, so we didn’t even know that there were lymphatics in the brain, but it turns out there is a neuro-lymphatic system. – Yeah, so we’ve heard in
the popular press about these amazing immunotherapies where you can get your own immune system, the
patient’s immune system, to realize that the cancer is bad, and to specifically target it to kill preferentially these cells. And it’s not easy, because these cells also have hallmarks of
being part of the patient, and your immune system is trained, don’t attack yourself. So, this has now started to
play out for childhood cancers. – So, this has,
immunotherapy for some other non-central nervous system– – Melanoma is a big one. – Yeah, melanoma’s a great example, leukemias, lymphomas, there have been enormous strides forward in terms of effectively leveraging the
person’s own immune system to recognize the cancer. That has not yet played
out for brain tumors, adult or pediatric, although
there are some strides forward, and what we’re beginning to understand is that some brain cancers allow the immune system to see it, and others really hide
from the immune system. You know, I think of
pediatric brain cancers as being somewhat ninja-like. They are hiding from the immune system, they’re diffusely, quietly infiltrating much of the central nervous system, and so part of our challenge is to alert the immune system to this invader, if you will, or to deliver an
immuno-therapeutic product, like an adoptive cell, immune
cell that we’ve taken out, altered, and put back so
that it can see the cancer and specifically eradicate it. – Trying to give the immune system a little bit of help in saying, hey guys, these cancer cells may look like they’re normal neural
cells, but they’re not, they’re the bad guys, go after them. – Right, so the trick
is to find the signal that allows the immune system to see the cancer cells as different from the rest of the brain,
because as you said, they’re very, very similar. And so, understanding
what these cancer cells are expressing on their surface that can be seen by the immune system, whether it’s the person’s
own immune system or an immune cell that
you’ve given some help to is a challenge, and there’s been, at least in the laboratory,
some huge strides forward in that for childhood brain cancer, and I hope to see some of those things come to the clinic very, very soon. – This is The Future of Everything, I’m Russ Altman, I’m speaking
with Dr. Michelle Monje about brain cancer, especially
in kids, and the outlook. So, until these immune
therapies really develop, we’re kinda stuck with these, what I call toxic therapies, where you’re basically trying to kill the rapidly-dividing cancer cells. But you’ve taken an interest, not just in getting
those therapies to work, but also to understand
their long-lasting effects. These are children, and they’re gonna have hopefully 50, 60, 70
years of life afterwards, and you’ve begun to ask the question, what is it doing to the brain over the long haul, so
what do we know about that? – Right, right. So, you know, what we have, I think, intuitively understood by
taking care of children who’ve gotten these therapies is that some process of
neuroplasticity or neurodevelopment is fundamentally altered
after these therapies, but why that happens
has been very unclear, and so, my laboratory’s been studying this for a number of years, and a central theme that is emerging is that
many of our cancer therapies change the activation state, if you will, of the resident immune
system in the brain, the microglia, these tissue macrophages. Now, in a healthy brain,
microglia contribute to a number of really important processes, like you mentioned,
connections in brain cells are forming during childhood, and then they get pruned back. Microglia prune those connections, which are called synapses, microglia contribute to development of the myelinated
infrastructure of the brain, to the white matter, they
likely do additional, you know, trophic, growth-promoting things that we haven’t understood
and are working to understand. – I’m struck that, I
shouldn’t think of the brain as just sitting there. It’s a very active organ
with lots of things going on, even though it looks like
it’s just a blob of jelly. – Right, it’s constantly changing, even, especially during childhood, but well into adulthood. And if I could just take a side, you know, make a side point about that, the brain is not only actively developing, but how we use it changes
the way it develops, and we kinda know that, because
when we practice something, when we study, we change
our nervous system’s ability to perform a task, or to remember a fact, or to, you know, develop a skill, and so– – So something must be changing, because I couldn’t do it last year and now I can do it this year. – That’s right, and so,
part of what’s changing are the details of those
connections between brain cells, and other things are changing too, and so part of our research program has been focused on understanding how activity in the nervous system, you know, which is induced by
experience and by practice, is influencing not just those
connections between cells, but also other fundamental things about the structure of the brain, and specifically the
insulation around the axons that contributes to white matter. – So, the axons are the
appendages of the cell that help the cells communicate. – That’s right, so the sort
of electrically active, you know, cells in the
brain, which are neurons, connect to each other through these long processes called axons, and then they connect at the synapse. And in order for a signal
to travel effectively between one neuron and another, or one part of the brain and another, that signal has to go along an axon, and that process is greatly facilitated by the establishment of these, the myelinating
infrastructure of the brain. So, myelin is formed by cells– – It’s almost like an insulator on a wire. – It’s very much like that.
– Keep the signal moving. – It’s exactly like that, actually. It decreases transverse,
you know, capacitance, and increases the speed
of the signal transduction along the wire, or axon, if you will. And that covering, that
myelin covering on the axon, is formed by a cell
called a oligodendrocyte that’s broadly in the class
of cells we call glial cells. – And glial, we all recognize that, we all hear about
glioblastoma, and glioma. – Yes, that’s right. – So I’m thinking that this is a cell that can cause us trouble. – That’s right, so this is a cell that can, on the one hand, contribute in really important ways to
development and plasticity, and that’s one thing that
we have focused a lot on, and understanding how activity regulates the changes in those cells, both during childhood development, and well into adulthood. On the one hand, that’s a cell type that can give rise to these
glial cancers, like glioma, and on the other hand, it’s a type of cell that is very susceptible to damage by chemotherapeutic agents
and other cancer therapies. – This is The Future of
Everything, I’m Russ Altman, I’m speaking with Dr. Michelle Monje, who’s telling us about these glial cells, which are both our best friends, and also can be our enemies. So, what have you learned about how these cells respond to chemotherapy, and I guess they’re very sensitive? – They’re very sensitive, but they’re sensitive
in a very interesting and perhaps therapeutically
targetable way, and so– – Oh, so this is good news. – So, this si good news, and so, I mentioned microglia,
which are, you know, one major class of glia. I mentioned oligodendrocytes,
and their precursor cells, that’s another major class of glia. There’s also a third class
of glia called astrocytes, and it turns out that some commonly-used chemotherapy medicines,
as well as radiation, induce activation of microglia so that they are no longer trophic. Instead, they are inflammatory. – [Russ] So, what does trophic mean? – Growth-promoting. Growth and plasticity. They’re not doing the good stuff. Now they’re in a defense mode, and when they’re in that state, there’s some unintended consequences. And so, work from Ben
Barris’s lab here at Stanford a few years ago demonstrated that when microglia are
activated, they can activate this third class of
glia, called astrocytes, to become toxic, rather than supportive. – [Russ] Okay, sounds bad. – It’s bad. And, as well– – [Russ] So the chemotherapy
is activating the glial cells that are then turning
on these toxic cells? – Right, so they’re changing the microglia and the astrocytes after, at least, the kinds of chemotherapy
medicines that we studied, perhaps not all chemotherapies, but we studied one in
particular called methotrexate, they become activated,
they stop being helpful, they start to be somewhat harmful, and they disrupt very dramatically the function of these
myelin forming cells. What is exciting is that, if
we can normalize the microglia, and the way that we’ve
done this experimentally is to actually remove
them for a period of time, which we can do with
medicines that target them. That helps the astrocytes
return to their normal state and become supportive and not toxic, and it normalizes the function of these myelin forming cells in a way that rescues cognition. – Now, I see that you’re
painting a picture now of therapies that are treating the cancer, but have these unfortunate side effects, but there may be this secondary therapy that can try to mitigate the side effects. So, you’re still getting the good effects of the toxic medication, but
then you’re adding other, either medications or
maneuvers of some kind, to try to minimize their long-term impact on the brain’s processes. – That’s exactly right, so,
as we start to understand what’s going wrong after cancer therapies, we can start to intervene therapeutically, and right now, we’re working in the lab to understand what our timeframe is, is this something we
have to do right away, or can we come and try to help people who’ve been suffering from the cognitive effects of
cancer therapy 10 years later, and try to improve their cognition through rescuing some of these
processes of development. – And I’m struck that,
by studying the cancer, the cancer treatments,
and then the mitigations of the cancer toxicities, you’re probably learning
very fundamental things about how the brain develops that may have implications
for things far beyond cancer. – That’s right, which is one of the wonderful things about basic science is you study one problem
and you start to see connections to other problems, and so, you know, this dysfunction of glial cells is something that is now being recognized in a number of different
neurological diseases. And so, microglial activation, which we found after radiation, after methotrexate chemotherapy, also happens in most, if not all, neurogenerative diseases,
like Alzheimer’s disease. And so, as we study one problem, you know, we’re really learning things that are applicable to many. – Well, we’ll definitely
have to get more into that. This is The Future of
Everything, I’m Russ Altman. More with Dr. Michelle
Monje about brain cancer, brain cells, brain toxicity,
and what we can learn about diseases that may have
nothing to do with cancer, next on Sirius XM, Insight 121. (upbeat music) – [Narrator] From the campus
of Stanford University. – [Russ] People are worried about date, they’re worried about their
privacy and their security. They should be, we need secure systems. – [Narrator] This is The
Future of Everything. – [Russ] But we can’t have a system that closes that data off. It is too rich of a source of inspiration, innovation, and discovery
for new things in medicine. – [Narrator] With your host, Russ Altman. – Welcome back to The
Future of Everything. I’m Russ Altman, I’m speaking with Dr. Michelle Monje about neurology and what we can learn from neurology about brain cancer, and from
brain cancer about neurology. So, one of the things that your lab does is study the very basics
of how neurons function, even in the normal brain. How do those studies inform your understanding of how cancers grow? Because, obviously, the things
that’s worst about the cancer is that they grow, and
they grow out of control, and they start taking up
space, they crush other parts. So, the growth of the
cancer really is critical, and I guess it’s related
to the basic processes of how normal cancers or
normal brain tissues grow. – Absolutely, absolutely. And so, that’s actually, that idea is really one of the guiding
principles in what we do, and so, because my laboratory
and my clinical practice focus on glial malial malignancies,, gliomas like glioblastoma,
which also happens in children, although there are some differences between the adult and
the pediatric disease. We wanted to understand, at
a very fundamental level, what promotes the replication and growth of normal glial cells? And thinking about, you know, the origins, developmentally, of
these gliomalignancies, what promotes the
proliferation and growth of, specifically the glial
cells, that are perhaps giving rise to these cancers. And so, one of the, I think,
really exciting things about the way that the brain, you know, functions, and changes, and
is plastic and adaptable, is the discovery that experience through neuronal activity influences the proliferation of these
glial precursor cells, and this actually is
fundamentally important to the way that experience and activity changes brain structure
and therefore function. And we call these changes
in the glial infrastructure myeline plasticity. Well, it turns out that the cancers hijack those very mechanisms that are normally playing out to promote adaptability and
plasticity of the brain. And so, this is– – That seems quite diabolical. – It is quite diabolical. – Cells that now respond to my learning and my interaction with the environment, the cancer cells have figured out how to imitate some of
that to get the glial cells to do things that they shouldn’t be doing. – That’s right, that’s right. And so, you know, when you
think about these cancers, we often think about cancer as a ball, as a nodule, right, growing? But most of these glial malignancies, particularly in childhood,
but also in adulthood, really diffusely invade the brain, and they are intimately interacting with all of the other cells that
are present in the brain that are normally contributing to these processes of growth and plasticity. And so, as we have dug, you know, dug in and drilled down to understand the mechanisms by which brain activity can promote brain cancer growth, we’ve uncovered some really
exciting therapeutic targets, things that we can target to disrupt this ability of the cancer to hijack these growth signals that are produced as a result of activity,
and one of these targets is resulting in a clinical trial that we’re hoping to open in late 2019, so I’m really excited about this new direction of targeting these micro-environmental
dependencies, if you will, the dependency of the cancer on the brain environment
in which it’s grown. – And it sounds like these won’t be the kind of blunt instrument, toxic, kill the cancer before
you kill the patient. I don’t know if the word precision, but it seems like this is a much more targeted kind of way to treat. So, can you give us a
little feel for what you’re, like, how do you trick these cells into not being bad? – Yeah, so, one of the signals is a molecule, a protein,
that gets released from normal brain cells as a
result of brain activity. So, whenever the brain is active, whenever neurons fire, this
molecule gets released, and it gets released into the environment where the tumor can use it to grow through the activity of an enzyme that actually clips it
off of the cell surface and lets it, you know, be free to bind to the cancer cells. So, we can prevent that,
the molecular scissors, if you will, the enzyme
that clips that molecule, so that we can prevent it being available for the cancer cell. – And so, the cancer cells never get the signal to grow? – Right, that signal to grow, and there are many signals
to grow in the brain, but this one seems to be
particularly important. Now, that’s not to say that
this particular therapy will be without any
neurological side effects because we know that the
clipping off of this molecule is part of normal brain physiology, but we think that it’ll
be a much more limited and specific side effect profile. – This is The Future of Everything, I’m Russ Altman, I’m speaking with Dr. Michelle Monje about new approaches to take advantage of our understanding of neurology and neuroscience
to more precisely confound the ability of cancer to grow. In the end of our discussion, I just wanted to go to the clinical side. So, you’re doing this very detailed, very profound work in neuroscience, but you’re doing it for kids, and you see these kids. So, what is the experience of a child like with these terrible diseases? What have you seen in terms of with the experience that they have acutely with the disease, and then the sequelae afterwards, and how are kids responding
to these cancers? – So, I have to say that my patients are enormously inspiring, and everything that we’re doing is really to try to help them. Kids are remarkably resilient. You know, they’re brave,
they fight these cancers, they come to terms with their outcome when the outcome is not going to be good in a remarkably brave and mature way, typically towards the end. They start to think about
how their experience can help other children. And they think a lot about their family, and you know, there’s
a very well-known case that I think really
illustrates this principle of a little girl who lived in the Midwest, she was not a patient of mine, but I know her parents very, very well, as they’ve really engaged in trying to support the research
community for this disease, and she had one of the universally lethal forms of brain cancer, and knowing that she was going to die,
she left Post-It notes throughout her house, hidden
for her parents to find. – Oh my god. – And it’s been about 12– – How old was she? – She was six. – Oh.
– Yeah. – And they’re not still finding them, or? – They are still finding them. And this is actually a wonderful book that this amazing couple wrote
called Notes Left Behind. – How do you explain to a child what’s going on in their brain when you have to break the news to them and to their parents, and what are the kinds of questions they have? – So, number one, it’s
really important that kids have a sense of what is happening. They have to know that they have cancer, they have to know that it’s serious. We often wanna protect children
from scary things, right? Tell them there are no monsters. But, you know, it’s really important that children understand, at least at the level that is appropriate for them, what is happening. And so, it depends on the age, but we talk about spots,
we talk about bumps, we talk about trying to fight the bumps, and we talk about the fact that we don’t always have the right medicine to effectively fight
that spot or that bump, but that we’re gonna take care of them throughout the whole journey. And they understand that, I think, as time goes on, and with
conversations with their family, they understand it more and more. They often have really
insightful questions, and particularly older children, you know, really focus on making sure that everyone around them is okay, making sure that their
parents will be okay. – Altruism is a normal phase
of this terrible disease. How do you, now I’m gonna
turn to the parents, how do you start to explain
the incredibly complex underlying biology, not to the children, but to parents who are dealing
with something terrible? This is tough stuff to understand. Your work is the result
of many years of study. How can you simplify, I don’t even wanna use that word almost, but how can you give them the rough idea of what’s going on, especially when you’re introducing them to new medications that are working in entirely new ways, and you have to get consent from them to participate? – Yeah, yeah. So, you know, I think
really doing our best to explain in English
and not in med speak, you know, how these cells
interact with each other and what we’re trying to do to, you know, make them behave better, if you will, is critically important. I recently created kind of, in an effort to effectively, I’m sorry about that, I lost my headphones. (laughing) To effectively communicate
the science behind, you know, chemotherapy-induced
cognitive impairment, a short video, a cartoon,
describing, you know, how cells that normally
need to work together to effectively do their job, you know, might become dysfunctional
when one member of that group starts to overreact to something. – This is what we’ve been talking about for the last 20 minutes. So, if somebody wants to Google that? – Yeah, so it’s on YouTube. It was part of what’s
called a video abstract on the cell website. It’s actually also on
my laboratory website, so if you go there. – Right, so if they
Google Michelle M-O-N-J-E, that should get them– – Yeah, that should get them there, yeah. – Well, thank you for listening
to The Future of Everything. I’m Russ Altman. If you missed any of this episode, listen any time on demand
with the Sirius XM app.

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