>> Sandra Charles: Good morning,
and welcome to today's
cancer symposium.
Each time we try to
expand a little bit,
bringing in more
employees and, of course,
with that this technology and
some of the attendant issues.
So, thank you for your
forbearance, and I look forward
to us having a very
informative and very,
what should I say,
well-rounded panel.
We have people from our Culpeper
[assumed spelling] campus
in Virginia joining us, and
I welcome those as well.
I'm Dr. Sandra Charles, the
library's physician and chief
of the Health Services
Division, and over the years,
it's been my pleasure to
work with Dr. Tomoko Steen
of Science, Technology,
and Business
and [inaudible] Lyle
[assumed spelling],
one of our stalwart
employee advocates
to bring you these
cancer symposia.
This is just a brief
PowerPoint showing what,
over the past four years,
what we have done in terms
of addressing the
issue of cancer,
as we try to keep our employees
informed, as well as hopeful
and knowing all that's
coming down the pike.
So initially, we started
out like doing sort of like
in September, we
do prostate cancer,
in October we do breast cancer.
And then we picked up on the --
in 2016, the Moonshot
Initiative,
where the whole idea was to
start to get some of the,
I call them, low-hanging
fruit in terms of what kind
of progress being made in cancer
to get the word out to people.
And we had on that date, 2016,
members of the Blue Ribbon Panel
that Moonshot Initiative,
and serendipitously,
the Cures Act was also signed
right about that time as well.
So, then we went on in
2017 to talk about genomics
and unlocking the secrets
of cancer through genomics
and had a very stellar
lineup, followed in 2018,
by our program, talking
about translational medicine,
basically bench to bedside,
where we had our panelists
talking about bringing the fruit
of the research to the bedside
to the treatment modalities.
And so, here it is we are today
with four also stellar
panelists,
talking about those
treatments and some
of the progress that's
been made technologically,
and I won't delay
much, because we --
there's a lot for them
to do, and I don't want
to be the one to hold you back.
So, I would like to welcome
them here and, Tomoko,
would you like to
introduce our panelists,
so that we can get going?
But I hope everyone
has a program,
and we want to leave time
for you to ask questions
of these guest speakers.
So, I take my leave.
>> Tomoko Steen: Thank
you so much for coming.
I'm Tomoko Steen from
Science and Technology
and Business Division.
Instead of spending
each biography --
speaker's biography, we
have in this program --
so let me quickly
introduce our panel.
First speaker is
Professor Robert Clarke.
He is a breast cancer expert
from Georgetown Medical School,
and the second speaker
is Michael Dean.
Dr. Michael Dean is a
senior investigator,
and he's a geneticist,
looking at the genetic side
of the cancer and at the
National Institutes of Health.
He's now expanded the two --
he's going to talk about
lung cancer but expanded
to different types of cancer.
So, if you have any
questions, you can ask.
Next speaker is Dr.
Jonathan Lischalk,
I'm sorry, my pronunciation.
He is [inaudible] proton
therapy, one of the few
in the country, and we have
a proton therapy facility
at the Georgetown, and if you
have any questions, you know,
further questions, you can ask
him, and the last speaker is
from National Cancer
Institute, Dr. Soumen Roy,
and he is working
on the side effect
and [inaudible] microbiome
for how the impact
of the different type of cancer
treatment affect the patient's
toxicity and so on.
So, first speaker,
Dr. Clarke, please.
It should be on the
desktop [inaudible].
>> Robert Clarke: Good morning.
It's a great pleasure
to be here.
It's nice to have folks
in the room and to those
that are listening or
watching online, also, welcome.
This is October, it is Breast
Cancer Awareness Month.
So, I'm going to talk
about breast cancer.
This will be a fairly
straightforward presentation,
not too much research.
I'm going to tell you a little
bit about what cancer is,
what breast cancer is, and
how we treat most patients.
So, you'll get a sense of the
disease from soup to nuts,
and you'll get research
pieces, I think,
from some of the
other presenters.
So, I'm going to keep mine
as straightforward as I can.
So hopefully, it will set
the scene for many of you,
whether the talks are
on breast cancer or not.
So, cancer has been around
for a very long time.
The cancers that
we know have been
around for a long time are those
of the tissues that managed
to make it into fossils.
Those in soft tissues have
long since disappeared,
but there's clear evidence
of cancer in species
as early as dinosaurs.
In fact, probably older, it's
very likely that what we think
of as breast cancer
arose, as mammals evolved.
It's the same basic tissue
performing the same function.
So, the earliest mammal
like creatures came
around 200 million years ago.
So, there's nothing new in
the sense about breast cancer.
It's been around
200 million years.
We haven't cured it yet,
but we're working on it,
and you'll get a sense of
some of the new advances
that have led to changes
in clinical practice,
as I go through my presentation.
So, what is cancer?
Fundamentally, it's a loss of
control of growth in cells.
Most cells in the body
don't keep making copies
of themselves.
There are some that do,
because that's their job,
but most don't, and some of
the ones that get changed,
where the DNA gets mutated,
gets altered, and that control
of growth is lost,
leads to proliferation
that shouldn't occur, and
that causes a tumor to appear.
Though not all tumors are spread
or are particularly
dangerous, some, of course, are.
Benign tumors are those that
stay locally, they stay put
where they arise
in the first place.
For many of those, they're
not life threatening.
Some of them clearly are.
Those that occur in the brain,
for example, may not spread
to the rest of the body,
but if they keep growing
where they're growing and
they can't be eliminated,
they become very problematic.
But there are many benign
lesions, and many of the lesions
that arise in the breast
naturally are benign.
They are not going
to kill anybody.
It's the ones that spread,
and it's when they spread
that we have difficulty
managing the disease.
And those are the ones that
are referred to as malignant,
where the tumor starts in
one place, maybe the breast,
for example, but it can spread
to the liver or the lungs
or the skin or the brain.
And then we have
to use treatments
that can go throughout the body,
because we don't always know
where those little deposits are.
We just know that they're --
it's gone beyond the breast.
So, benign, you can usually
remove them, if you have to,
with surgery and radiation,
but if they have spread,
we have to use different
treatments.
Now, what causes the damage to
DNA that can lead to cancer?
Well, every time a cell
replicates its DNA,
occasionally, it
will make mistakes,
and while the cell's usually
pretty good at finding
and repairing those,
some are not.
Some damages that
curse simply naturally,
a mistake in the reading
and replication can persist,
but there are exposures
in the way
that we live our lives normally
that can increase the risk
that there will be additional
changes in the DNA sequence
that are not fixed, and
that will transform the cell
from a normal cell
to a cancer cell.
And that loss of growth control
will occur, and in some cases,
the ability to spread locally
and then disseminate throughout
the body will eventually arise
[inaudible] that
tumor progresses
and becomes more aggressive.
The sorts of things
that we think
of as causing cancer
include chemicals,
which are probably
amongst the most common,
although we don't fully
understand why most cancers
arise, what the chemicals
might be.
There are some that, of course,
we understand quite well.
There are carcinogens.
That's the type of
chemical that causes cancer,
this damage to DNA and tobacco.
So, smoking, in fact, is
the leading avoidable cause
of cancer and cancer
mortality in the United States.
Alcohol can increase the
risk heredity, and we'll talk
about the BRC mutations
in a moment.
There's a lot of [inaudible]
for associative data
that implicates changes,
features in the diet,
hormones we know are involved
in breast and probably prostate
and one or two other cancers.
Exposure to radiation,
and you'll hear a lot more
about radiation today
as a treatment.
There are viruses, HPV, the HPV
vaccine was developed in part
of Georgetown and at NCI,
and that now can prevent
an infectious disease piece
that can lead to cancer.
We treat, as I described
earlier, local treatment,
cut it out, burn it basically.
With the systemic treatments,
the treatments that we put
into the bloodstream, which can
get our -- the drugs anywhere,
almost anywhere in the body,
there what we're really looking
for mostly are ways
of poisoning,
specifically, cancer cells.
And I'll describe some of
those for you in a moment
in the context of breast cancer,
and there are hormone therapies.
If hormones increase the risk,
then blocking the effects
of hormones are effective
treatments and, in some cases,
effective preventive approaches.
That's also true
in breast cancer.
So, what is breast cancer?
Simplistically, it's a tumor
that arises in the ducts
or the lobules of the breast,
and that's sort of
captured here.
It's a relatively simplistic
view, but what happens is,
as the cells lose their
growth control, they can begin
to acquire the ability to spread
into the local tissues
in the breast.
In some cases, they can
get into the bloodstream
or the lymph stream and begin to
spread, and so they can spread
or metastasize throughout
the body.
And not all breast
cancers are diagnosed
from a lump in the breast.
Sometimes it's the
metastasis that's found,
and when the metastasis is
found, it still has features
of the breast cancer
that it came from,
which can allow a
pathologist who looks at it
to say this isn't in the breast,
but it's from a breast cancer,
let's go look and see if we
can find where the primary is.
Quite a few cancers
are diagnosed
that way, not just in breast.
So, what affects the risk
of getting breast cancer?
I wish we really knew.
We have lots of data that show
that some exposures can
increase the likelihood
that breast cancer will arise,
but very few of them tell us
in whom they will arrive,
that a particular woman
won't get breast cancer
because of an exposure, and
the effects of the exposure
on increasing risk are
really quite small overall
with the exception,
particularly,
of one or two genes that
we know are inherited.
And you may or may not be
able to read it on this slide,
but most women who are diagnosed
with breast cancer have none
of the established risk factors.
So, anyone who gets a diagnosis
of breast cancer, it
is not your fault.
So, the one or two
genes that we know
that significantly increase
the risk of breast cancer,
that are inherited, are
called the BRCA genes,
and there's BRCA1 and BRCA2.
And the reason that they
increase the risk of breast and,
as it happens, of ovarian
cancer and one or two others is,
because what those proteins
normally do is they help correct
mistakes in DNA or
damage to DNA.
And when there's an inherited
mutation in those genes,
the protein that's produced
doesn't effectively find
or correct those mistakes
or that damage to DNA.
And that's what increases the
risk, and the lifetime risk
for BRCA1 or BRCA2
for getting breast
or ovarian cancer is very high,
which is why once their --
a family is found and
all of those who have
that mutation are found, it is
not unusual for women to opt
for having their breasts
completely removed
and reconstructed and
their ovaries removed.
Now, there are lots and
lots of other things
that we think affect the risk
of getting breast cancer.
Very few of these have an
effect that would double
or triple the risk
to an individual,
and that's been a challenge.
We can look at large,
large numbers of women
with breast cancer and look at
exposures and find correlations,
but correlation is not
causation, as we say.
And so, we struggle, we struggle
to understand fully what it is
that causes many women
to get breast cancer.
That being said, don't smoke,
don't drink lots of alcohol,
try and keep your weight
normal, have a healthy diet
and exercise, and you'll
probably eliminate the increase
in risk for many
of the exposures
that could affect your
risk of breast cancer.
And at the same time, you'll
probably reduce your risk
of cardiovascular disease
of many other cancers,
perhaps some neurodegenerative
diseases.
So, it's kind of just concepts.
It's almost all we have
to offer at the moment.
The one preventive drug
we have is tamoxifen,
but it's usually given only
to women who have a high risk
of developing breast
cancer because of a mix
of other features that
they're exposed to,
which I won't have
time to go into.
Now, if cancer fundamentally
is a disease of damage to DNA,
the longer your DNA is around,
the more likelihood
it will get damaged.
And so, it's not surprising that
cancer tends to be a disease
of older age, that you
can get a sense of that
from those pink bars, which
show you the age of diagnosis
for breast cancer in women.
And that peak comes around 50
years of age, which just happens
to be about when most
women go through menopause.
So, that tells you something
about lifetime exposure
to estrogens, that probably
is one of the risk factors
that you can do absolutely
nothing about.
Men can get breast cancer
too, about 1% largely,
because there's a
small residual amount
of breast epithelial
tissue in the male breast.
And that can get changed
just like it can in women.
It's just there's
so much less of it
that so many fewer
men get breast cancer,
but for women, it's
one in eight.
It is the most commonly
diagnosed form
of cancer in women.
It is the second most prevalent
form of cancer mortality
in women, and the only one that
comes higher is lung cancer.
Don't smoke, avoid
tobacco products.
The risk of breast cancer
death, specific death,
is higher in African American
women than it is in Caucasian
or non-Hispanic white women,
and we don't really know
why that is the case.
The outcomes are also worse.
So, we have a lot, and you'll
see, as I go through quickly,
that we have a lot to learn.
Now, not all breast
cancers are the same.
They fall into different
subtypes that we tend to define
by whether or not they
have receptors for hormones
or a specific growth factor.
The hormones are
estrogen and progesterone,
and the growth factor
is a member
of the epidermal growth factor
receptor family called HER2.
And they look different,
they behave differently,
and they are treated
differently.
And the risk of death is
different for each type.
Now, the frightening statistics
here, 268,000 new cases
of invasive breast cancer in
the United States each year,
42,000 women will
lose their lives
to this disease every year.
That's one death from breast
cancer about every 30 minutes,
if you average it
out, in the US alone.
Over half a million
women will die
from this disease
worldwide every year.
We have made significant
progress.
You will see some of
that, but you can tell
from these statistics,
we have a long way to go.
Now, 70% of those breast cancers
express either the estrogen
receptor or the progesterone
receptor, and if you look
at the graph below, it gives
you a sense of how the presence
or absence of the estrogen
receptor is very important
in determining the
risk of death.
Those that don't have
the estrogen receptor
or that big bump at the
beginning, where the risk
of dying within the first
three years is very high,
but it drops thereafter.
For estrogen receptor positive
breast cancer, the risk of dying
in the first three to five
years is relatively low,
but it increases every year.
And by the time it gets to
about three or four years,
that risk stays at that level
for the rest of a woman's life.
And this is one of the
challenges that we struggle
with in breast cancer, is we
don't know when those tumors
with estrogen receptors
will recur, if they're going
to occur, because they can come
back 10 or 15 or 20 years later,
when a woman has
lived for 20 years
with no evidence of disease.
And when it comes back,
it usually comes back
as having spread elsewhere,
it has metastasized,
and it is then very
difficult to cure.
So, that's a challenge.
The good news about that piece
of it is that women can live
for 10 or 15 or 20 years
completely cancer free,
apparently cancer free.
And if you're diagnosed in
your 60s and you were able
to live 20 more years without
your breast cancer coming back,
you would get to see your kids
go up and graduate from college
and get married and have kids.
So, even when we cannot
cure all breast cancers,
we can give women lives to
live, and we hope to be able
to continue to do much better.
How do we do that?
We do it either by cutting
it out, burning what's left,
and poisoning what we can't see.
Surgeries, in the old days, we
used to do radical mastectomies.
That's very rare now.
In fact, we know that even the
smallest of those surgeries,
in most cases, have exactly
the same clinical outcome
as removing the entire
breast for most women.
And the reconstructions that
we can do now, after surgery,
are absolutely fabulous.
So, even if you have to
get a breast tumor removed,
that doesn't mean that you
have to be, in some way,
permanently disfigured.
We can rebuild.
Plastic surgeons are fabulous
at this, and that gives --
the bottom picture there
gives you some idea
of the different
approaches that can be taken
to rebuild the breast.
Now, the other local
therapy is radiation.
You're going to get more of that
in a moment, but this is one
of those things where
it's just too much
of a bad thing can actually
kill you and kill the tumor,
because radiation exposure
can increase the risk
of getting cancer.
But if you use a focused, high
intensity radioactive beam,
you can kill cancer, and
that's what you see here.
And so, surgery and radiation
probably cure quite a lot
of breast cancers of the
early stage breast cancers,
particularly if they haven't
spread at the time of diagnosis.
And what's been changing,
and you're going to hear more
about this, is a new way
of delivering radiotherapy
that greatly reduces the
toxicity and the damage
to normal tissue,
surrounding the tumor.
Now, for breast cancer,
that's important.
For example, if the tumor
is in the left breast,
if you can spare
damage to the heart,
which just lies just behind it,
then you can kill that tumor
and eradicate what was
left by the surgeon
that they couldn't get out
and not damage the heart.
And you'll hear a lot more
about that proton therapy.
Chemotherapy is the
one most people think
of when they think
of cancer treatment.
It's the one most people
probably hope they never have
to get, largely because,
again, we use drugs
to kill the cancer cells,
and many of them kill
normal cells too.
Normal cells that are
proliferating get targeted just
the same way as the
cancer cells,
which have lost that
growth control.
And it's those killing those
normal cells that causes much
of the side effects
that's associated with some
of these chemotherapy drugs,
but they cure some patients.
There is absolutely an
overall survival benefit
for chemotherapy, surgery,
and radiation therapy
for women with breast cancer.
And the other group
of treatments
that we have are those that
target the estrogen receptor,
because we know that the
estrogen receptor is a driver
of many of those 70%
of breast cancers
that are diagnosed
new every year,
and there are two
ways we do that.
We can give drugs called
aromatase inhibitors
that stop the button
making estrogen,
and we can give drugs called
antiestrogens that compete
with estrogen and stop it
from binding to the receptor
and turning that receptor on,
and those drugs have been around
and very effective
for a long time.
Tamoxifen was first
published upon 1972,
and we continue to
make progress.
So, one of the newest treatments
that was published literally
a few months ago shows
that if you add this drug called
ribociclib, which is a drug
that stops cells from going
making copies of themselves.
It's -- blocks their growth.
If you combine that
with an antiestrogen,
more women will live longer,
and there is an actual
overall survival benefit
with this particular drug.
There's a whole class of them
that target this, the CDK46.
They're called CDK46 inhibitors.
A phase three study published
literally a few months ago shows
that there's an overall survival
benefit when you combine it
with an endocrine therapy
in the metastatic site.
So, while since we've
seen something
in estrogen receptor positive
breast cancer actually improved
overall survival, we have lots
that improved clinical benefit
that keep the disease back
for a longer period of time.
But this actually
improves overall survival.
That's one subgroup,
that's the 70%.
Let's look at the
next one, HER2,
the growth factor
receptor positive one.
Here we made dramatic changes
also in the last 20 or so years,
with antibody therapy and
small molecules that target
that particular protein.
The one that's probably most
familiar to people is Herceptin
or trastuzumab, which is
an antibody-based therapy
that targets the receptor,
and there's a significant
overall survival benefit
for women with HER2.
Until we had a way of targeting
this, the outcome for women
who had HER2 positive breast
cancer was pretty poor.
Now, we have drugs
that significantly
improve overall survival,
and quite recently, we've shown
that if you combine these drugs,
along with the standard
chemotherapy, you can even push
that overall survival
benefit further up.
So again, in the last few years,
we've had a dramatic change
in overall survival
benefit for women
with HER2 positive
breast cancer.
The last group we
call triple negative,
because they don't have
the estrogen receptor,
they don't have the
progesterone receptor,
and they don't have
that HER2 protein.
This is about 10 to 15%
of all breast cancers,
and it's the most difficult to
manage clinically, and it tends
to be more common amongst
African American women
than amongst other ethnic
groups, although it arises --
it can arise in any woman.
We don't have a targeted therapy
like the estrogen receptor
or like HER2 yet for these
breast cancers, and they,
if you remember that graph
that showed that big bump
at the beginning,
that's where most
of those triple negatives are.
So, the risk of dying within the
first five years of a diagnosis,
when you have triple
negative breast cancer,
is amongst the highest
risk of any
of the breast cancer subgroups.
So, we treat with surgery and
radiation and chemotherapy,
and there is a survival
benefit for those approaches.
What has recently come to
the fore is immunotherapy.
Now, one of the reasons that
the outcomes are so difficult
to manage for triple
negative breast cancer is,
because they tend to grow
more quickly, and they tend
to have more mutations
in their DNA.
That's a bad thing, but what the
immune system often looks for
and detects when
something goes wrong is
when there is proliferation
that shouldn't be occurring,
when something is growing
where it shouldn't,
or when it's got a
lot of mutated DNA
and those proteins are
expressed on the cell surface
and not recognized by the immune
system called the neoantigens,
the problem that we face is
that the cancer cells turn
off the immune system.
So, although there's all
these signals present,
telling the immune system
[inaudible] and get us,
because we shouldn't be here,
when the immune system gets
there, it gets shut down.
There are lots of lots of ways
that cancer cells can do this,
and we've only really begun
to target a few of these
in the last few years.
But some of those have
had dramatic effects
in some patients in other
cancers, and we're beginning
to see that there may be
a way to make these work
in this triple negative
breast cancer.
We probably haven't quite got
the right switch turned off
to turn the immune system that
the cancer cells are turning off
to get the immune system
back to work for everybody.
But it does seem to
be doing quite well.
So, I probably talked
longer than I should have,
and I'm going to
finish with this slide,
because the positive things,
the survival rates for breast
for invasive breast cancer,
which is the most common type
of breast cancer
that's diagnosed,
the average survival rate
at five years is 90%.
And at 10 years it's over 80%.
Those are significant
improvements for women overall.
The new and -- the local
and systemic therapies
that we have clearly
are improving outcomes
and clearly are letting
some women live today,
who wouldn't be alive if it
wasn't for these new treatments.
We have lots and lots
of new things coming
up in clinical trials.
We've only scratched the
surface of immunotherapy.
So, there's a lot we can
discover, and we have tools
to make these discoveries today
that we didn't have 10 years ago
that are absolutely amazing.
We probably just don't have
quite enough [inaudible].
That being said, I think we
have made tremendous progress.
We're on a couple of
paths of discovery
that have tremendous potential
to lead to new treatments
and quite possibly
fairly quickly.
So, despite the statistics
that are quite sobering,
there's a very great possibility
that we will transform treatment
and outcomes for women
in the next few years.
I'm going to stop
there, and I don't know
when we're taking
questions but--
>> Tomoko Steen: To the end.
>> Robert Clarke: To the end.
So, thank you for
your attention.
[ Applause ]
>> Tomoko Steen:
Thank you so much.
It's very informative.
So, next speaker is --
is this [inaudible]?
That's the one, okay.
Next speaker is Dr.
Michael Dean.
He's a senior investigator
from [inaudible]
Translational Genomics
at the National Institute
of Health,
and he has been covering
a wide variety of cancers,
and I think today he's going to
talk about [inaudible] cancer.
>> Michael Dean: Okay,
thank you very much.
It's a great honor to be part of
this panel, and it's incredible
to be in the institution
that hosts Thomas
Jefferson's library.
Rather daunting, I was just
over there before I came here,
and it's totally humbling.
So, I want to take off from
where Dr. Clarke started,
tell you about some
of the new things,
new ways we're using genetics
and genomics to diagnose cancer.
And this is helping us more
effectively treat cancer
as individual patient
individual tumor,
and some of the focus
will be on lung cancer,
but much of this will
work across cancer.
So, the recent focus on lung
cancer is the number one cancer
killer, as Dr. Clarke said,
more women are diagnosed
with breast cancer
than any other cancer,
more men are diagnosed
with prostate cancer
from any other cancer.
But what kills more men and
women is lung cancer, and,
like in breast cancer, we're
making steady progress.
We wish this curve
was going up faster.
This is the increase
in five-year survival,
but we're still at only 20 to
30% of people diagnosed today
with lung cancer will be
alive five years from now.
Obviously, we have a long
way to go to improve that.
So, one of the big problems with
cancer, I'll talk about a minute
about the cancers that
we actively screened for,
but most cancer diagnosis
are opportunistic.
The patient comes
in finding a lump
or there's some other
symptoms that leave the patient
or the doctor to
look for cancer.
This is a problem,
because by the time
that cancer is big enough
that you can feel it
or that you have symptoms from
a liver cancer or lung cancer,
you probably already
have advanced disease,
which is hard to treat.
For leukemia, it's blood
testing, staining of blood cells
that gives us the diagnosis.
For solid tumors, one of
the big advances are many,
many different types of imaging,
where we have many different
tools that find cancer
in different parts of the body.
And then the ultimate
diagnosis is a biopsy,
going in taking a piece of
that tumor, putting cells
on a microscope slide
and looking
to see what we have
and categorizing it.
And a huge advance is the whole
area of molecular pathology,
like in breast cancer
where we look for HER2
and progesterone receptor
estrogen receptor,
pathologists have multiple
different antibodies
that can stay in tumors
there to classify them.
And now, increasingly,
we're taking the DNA
from the two tumor,
sequencing them and finding
out exactly what is going on
with each individual tumor.
And as you'll see, this
totally changes our treatment.
So, there are cancers that
we actively screen for,
cervical cancer with HPV
testing and pap smears,
skin cancer mostly
by the individual finding
something abnormal and going
to their doctor or
from a dermatologist.
Colon cancer is highly effective
to screen by colonoscopy,
by finding a blood in the stool,
and we can largely
prevent those cancers
by these screening programs.
Then there's a class that
includes breast cancer,
obviously, we're using image
to find cancers earlier,
but that is not, obviously,
eliminating all cancer.
We're beginning to in
very high risk patients
that are heavy smokers
screen to find cancers early.
In certain parts of the
world, where there's a lot
of stomach cancer, they actively
screen people in the population
by endoscopy to find
those tumors.
Last is the lowly
prostate cancer
where we've been doing PSA test,
digital rectal exams on millions
of men, but the US public health
service, when they really look
at that data, does that
really improve mortality?
The answer is not so much,
and so we're left, you know,
with a very important
cancer without a lot of --
without a really good screen
to find the cancers early.
All the rest of the cancers
we don't have an active
surveillance problem,
so a program.
So, we don't have an effective
method to screen everybody
out there to find cancers
early, when we might be able
to treat them better,
and so this is obviously
an area of need.
It's an area of lots of
research, both by companies
and scientists and
an area where we need
to make a lot of improvements.
As you already know,
the three main areas
of cancer treatment are surgery,
chemotherapy, and radiation.
When we give that chemotherapy
or radiotherapy before surgery,
that's called neoadjuvant
or after surgery
that's called adjuvant.
And for every cancer,
there's a different program,
there's a different
system and schedule
for what is most effective.
And what's important to
know, that's all been worked
out mostly by trial and
error, by clinical trials,
and this is where there are
two heroes, the clinicians
and scientists who carry out
those very difficult studies
and the patients who volunteer
their time, so we can figure
out really what is the best way
to treat all different
types of cancer.
Now, to get into more
targeted therapy,
we need to have a little
bit more background.
So, one of the things
that's been puzzling,
we have all these different
agents that in the environment
that can cause cancer.
What's in common?
One thing that's in common is
almost all these agents cause
chronic inflammation or
damage to the tissue.
And what happens when that
occurs over decades is
that the normal tissue needs
to grow and repair that damage.
And exactly as Dr. Clarke
says, simply the act
of those cells dividing
when they didn't need
to means mistakes get made.
Those errors can
accumulate as genetic damage,
causing a premalignant lesion
which, if that continues,
can go on to a malignant lesion.
And exactly as Dr. Clarke says,
some of these agents actually
damaged the DNA on their own.
So, from studying these
genetic events in cancer cells,
we've identified
different classes of genes
that are mutated
in the cancer cell.
One group we call oncogenes.
An oncogene is essentially
an accelerator of the cancer.
These are mutations that cause
or create an activated
gene driving cell growth
and survival.
So, one example, our
growth factor receptors
that are normally there on
the surface of ourselves
that normally are only active
when the growth factor binds
to the receptor, then
they send a signal,
and then they're
supposed to shut off.
What can happen in
the tumor cell is
that receptor gets mutated,
and now it's stuck on.
So, this is like the
accelerator of a new car.
You know, you push it
down when you want to go,
you let it up when
you want to slow down.
If it gets stuck,
you know, down,
then you have a big problem.
The good thing about this is
that we've come up with ways
to begin to try to reverse this
or block this from happening.
So, many of these oncogenes
include growth factor receptors.
There are a class of
enzymes called kinases.
What they do is bind
a molecule called ATP
and transfer a portion of
that to another molecule,
typically, another protein.
Now, often that's a tyrosine
amino acid of another protein.
So, these get called
tyrosine kinases,
and there's a whole
class of drugs
of tyrosine kinase inhibitors,
which you may have heard about.
So, researchers begin
screening for molecules
that would bind the net
little pocket where ATP binds
and block the molecule off,
kind of like sticking a key
in the lock and breaking
it off, and then, you know,
nobody can open the door.
So, a cancer where this has
worked spectacularly well is a
type of leukemia called
Chronic Myelogenous Leukemia.
This disease is caused
by an activated kinase
called ABL, A-B-L.
It's actually activated through
a chromosomal rearrangement,
and Dr. Brian Druker
[assumed spelling]
at Oregon Health & Science
developed a molecule now known
commercially as Gleevec
or imatinib,
which is a kinase inhibitor.
It binds here in the pocket
where normally ATP would bind
in the ABL protein and
sticks there and prevents ATP
from binding and prevents
the thing from signaling.
Now, back when the first
clinical trials were started,
chemotherapy was the standard of
care for this type of leukemia,
and about 50% of patients
were alive two years
after getting chemotherapy.
Interferon came along, that
improved things a little,
but Gleevec was really
a miracle.
These patients, almost
all of them survived.
A few of them couldn't
tolerate the drug,
a few of them had their
tumor develop resistance,
but by and large, this
stabilized the drug
in nearly all of these patients.
Now, the treatment doesn't
kill the leukemic cells.
So, the patient has to keep
taking this drug, essentially,
throughout their life.
I think there are
now some patients
that have been weaned
off the drug,
and then the leukemic
cells were gone,
but the drug has no really
terrible side effects.
So, you take a pill
once or twice a day,
and your leukemia
is under control.
I wish every single kinase
we had an inhibitor like this
that would have this
kind of effect.
But one of the things
that was truly amazing,
and this is where science is
really exciting is this same
treatment had a big advance
for a rare intestinal tumor,
gastrointestinal stromal tumor.
This is caused by
different activating kinase
that are called KIT,
and it was shown
that the same drug
Gleevec can inhibit KIT.
Now, GI stromal tumors
about, you know,
three to to 6,000 Americans
get this disease every year,
equally amongst men and women,
about average age of 50.
And we don't know any of
the risk factors for them,
so we have no way to
prevent this disease.
It just occurs.
Now, before Gleevec came along,
this was not a very
good disease to get.
Fifty percent, only 50% of
patients were alive nine months
after the standard
of care at the time,
a type of chemotherapy.
When those patients
were put on Gleevec,
getting either one pill
a day or two pills a day,
you can see they
did way, way better.
So, 70% of patients were
alive 30 months out.
Not as good a response as we saw
with the leukemia, but still,
obviously, way, way better
than the standard
of care at the time.
There are now a whole host --
there's a whole library of
these tyrosine kinase inhibitors
that are being used on a variety
of cancers, and this has been,
you know, one of
the major advances
in therapy over the last decade.
One of those areas
is in lung cancer.
So, one of the growth
factor receptors
that is often activated in
lung cancer is called the EGF
receptor, and there are a
number of inhibitors specific
for that specific receptor.
There are other inhibitors
that are more broad
that affect EGF receptor and
a family of related proteins.
Once we identify a target
that's effective, you know,
research biotech pharmaceutical
companies are great
at coming along with
other ideas.
And so, there are
monoclonal antibodies
against the [inaudible]
receptor,
and those can block the
receptor and also be affected.
Now, others -- other --
one of the major types of
lung cancer is non-small cell
lung cancer.
Some of those cancers have
other kinases activated like ALK
or ROS1, and they're targeted
drug specific for those.
Now, typically, a given lung
cancer will typically only have
one of these receptors
activated, and there's no way
to know from looking at the scan
or even the pathology slides
saying there's malignant cells
which one it is.
We have to have a molecular
test, either to sequence of DNA
from the tumor or some other
antibody test to figure
out whose tumor has EGF
receptor, whose tumor has ALK
and give them the proper drug.
But one of my professors
in university is a woman
who never smoked,
who had lung cancer.
Her tumor has one of
these receptors activated.
She has gone into
complete remission,
takes a pill twice a day, and I
just saw her a few months ago,
and she is perfectly
healthy so far.
Now again, as Dr. Clarke said,
if cancer only stopped here
at the local malignant,
you know, the local growth
where it started, we
wouldn't have a big problem.
The big problem we have
with cancer is a lot
of most cancers become
resistant to therapy
and or become metastatic.
And so, this is an area where
a lot of focus needs to be put
on how do we understand
these processes,
and then how do we use that
understanding to try to come
up with better treatments?
One of the things that
we have learned is
that although there's genetic
damage that we can recognize
to get us to this stage, it
seems to be mostly nongenetic,
but aberrations of gene
regulation that get us
to these later stages.
This is called epigenetic,
because it doesn't involve
changing the DNA it causes --
it's involved changes
in the regulation.
Now, you have about this
much DNA in every single one
of your cells, and how
that gets packed in is
that DNA gets wrapped around
proteins called histones,
and those get packed up together
in a structure called chromatin,
and this is highly regulated.
So, in your pancreas cell, your
insulin gene may be, you know,
unpacked and available, when
you need to make insulin.
None of the other cells in
your body need to make insulin,
so that gene is sort of
packed away and inactive.
What we found is that many
tumors actually mutate the genes
involved in this
kind of regulation,
and so we have a whole new
class of genes that are altered
in cancer that are involved
in remodeling that chromatin
that are involved in
regulating entire programs
of gene expression.
We're only at the very beginning
of understanding what the
implications of this are,
but we are starting
to see therapies
that are in this class.
But let me back up and
sort of explain sort
of why this makes sense.
So, all animals start
off as a fertilized egg,
grow into an embryo and a
fetus, and then the adult,
we have hundreds of
different cell types.
We have blood cells,
neurons, muscle cells,
kidney cells, et cetera.
All of those cells, with
a few minor exceptions,
have exactly the same DNA, as
did the original fertilized egg.
The reason all these cells
have different properties is
that they're regulating
their genes differently.
They turn on different
sets of genes
and turn off other
sets of [inaudible].
If we lay that concept
onto the cancer cell, yes,
we have these genetic
events that get us
to the original malignant cell,
but then what we think
may be happening is
that the cancer cell
can then turn on,
if it needs blood supply,
because it's got too big
and it needs its own blood
vessels, it turns on the gene
to generate blood vessels.
It turns on the gene to migrate
to other parts of the body.
It can turn on the genes
to become resistant
to the immune system
resistant to therapy,
and because a large tumor has
millions of cells, if every one
of those cells has the
possibility to turn
on in programs of gene
expression and turn
on different properties,
then you can begin to imagine
of why it is such a challenge
to completely eliminate cancer,
especially once it grows big.
I like to think of this as the
tumor developing the ability
to unlock the genome to make
all of the tools that are
in the tool chest of our
genome available for its use.
Now, this may overwhelm you.
It overwhelms me.
There are days I think this
is so incredibly complicated,
we'll never be able to figure
this out, but then I think
of how innovative
human beings are,
that once they understand
exactly how a problem works,
they can figure out
ways to fix this.
So, I'm excited.
I think we're finally
at the part
that we understand
how cancer works,
and now it's the next
phase which is, you know,
I won't kid you, it's going
to be difficult to figuring
out how do we attack
this, but we are starting.
Here two FDA approved drugs,
they're called HDAC inhibitors,
histone deacetylase
inhibitors, and they work
by altering gene expression
patterns in tumor cells.
So, here's two that have been
used on a rare form of lymphoma
that affects your skin.
Here's a patient before and
after treatment with one
of these drugs, and you can see
things have gotten a lot better.
Now, these are early
days and, you know,
the response rates are,
you know, are measured
in months or a year or so.
But this is the beginning,
I think, of developing drugs
that we're going to use
to change how cancer
cells express genes
and hopefully be
another tool that we have
to fight this disease.
Dr. Clarke introduced the
idea of the immune system.
The other tool that we have is
the immune system can regulate
abnormal cells throughout
this entire process,
and if we can harness
that, we may be able
to eliminate cancer cells.
So, the proof of concept that
this really would work has come
from Stephen Rosenberg, right
here [inaudible] at the NCI.
He has been, for decades,
taking, for instance,
melanoma tumors from patients,
isolating from the patient
their very own T cells,
identifying those T
cells that will react
against that patient's tumor
growing up in big labs,
and I've been to this
lab, and I've seen it,
it's totally phenomenal,
and then infusing those back
into the same patient.
When it works, it's spectacular.
Metastatic tumors all up
and down the patient's body
disappear and don't come back.
Now, he, you know, he announced
that [inaudible], you know,
I think to do this on 10
or 20 patients a month,
it's not something that we can
do across millions of patients
across the country, but it shows
the power of what the power
of the immune system if we
can properly harness this,
we can get rid of cancer.
Here's one of those
patients, you know,
of they were completely filled
with tumor before treatment.
Here's a few weeks
after treatment,
those tumors are mostly gone.
Here's a few years
after treatment,
and the tumors still have
not come back, but I mean,
what we obviously want
is some way to do this
across many patients,
and we know that our
cells have mechanisms
to suppress T lymphocytes
from killing our cells.
We have to very carefully --
the body has that very
carefully control the system not
to develop autoimmune disease.
You don't want your lymphocytes
killing your own cells,
and tumors have been able
to use those same pathways
to activate what are called
immune checkpoints to survive.
So, tumor cells are turning
on many of the same inhibitors
of the immune system, but
once we've recognized that,
we've come up with
ways to fight this.
So, here's a T lymphocyte that's
recognizing a tumor as foreign.
It's all primed to kill it,
but the tumor cell has turned
on this other protein, PD-L1,
which binds to PD-1 of a T cell
and keeps it from
being activated,
keeps it from killing
the tumor cell.
Well, we can come in with
antibodies or therapeutics
to either bind up that
PD-L1, so it can't bind
to the T cell's PD-1 or
bind a PD-1 and a T cell,
so it can't bind to
PD-L1 of the tumor cell.
And when that works and
the T cell is now activated
and can go back to
what it wanted to do
and kill the tumor cell.
Here's one of these early trials
with an inhibitor,
PD-1 and lung cancer.
All these patients in blue
have had their tumor shrink.
These patients in gray have had
their tumor stay the same size,
and these patients in red,
their tumor progressed.
And you can see their
survival, all the patients
in blue were alive 12 months
later, most of the patients
in this gray area were
also alive 12 months later.
These therapies,
these checkpoint inhibitors have
had many very impressive effects
on cancers.
They typically tend to be in
cancer with lots of mutations,
and there are lots of
immune cells out there
that can recognize that as for.
So, lung cancer, melanoma, but
also bladder, stomach cancer,
there's about 10
or 12 cancers now
where there's an FDA
approved drug from one
of these classes
that is working.
And now every pharmaceutical
company
in the world has a drug
part of this class,
and they're all trying to figure
out where's the best
place to use this.
We first started
using this on patients
with very advanced
disease, who, you know,
who were not responding
to any available therapy.
Now, we're going to start
using this more and more
in earlier stage disease
and figuring out, again,
the schedule, when is the best
time to give the immune therapy.
Maybe it's best to
give that first,
activate the immune system,
and then use the other
therapies we have.
That all has to be
worked out one by one,
through the different
cancer types.
So, moving forward,
we have a number
of really tremendous challenges.
We're starting to come to the
idea of thinking of the tumor
as a multicellular 3-dimensional
entity, more like an organ
than just a group of cells
that are all the same.
And so, that changed our
perspective on how --
what we need to understand and
what we need to go forward.
We need to understand how
tumors are changing their gene
expression, how this occurs over
the evolution of the cancer,
and how might we be able
to intervene with that
to shut off the tumor cell or
get it to differentiate and die
like it is programmed
to do that.
We need to understand much
better the immune response
of the host, how the tumors --
how the patients
that didn't respond
to checkpoint inhibitors, what
have, you know, what's different
about those patients and
the ones that responded,
and can we use this
to develop more tools,
using the immune
system to [inaudible]?
And all this knowledge,
obviously, we want to use
to better diagnose
and treat the cancers
that we failed to prevent.
Now, because we're in a library,
I have to give you
some resources
and also some homework.
Cancer.gov is the National
Cancer Institute's website.
Cancer.org is the American
Cancer Society's website.
Both are completely
outstanding resources,
if you want any information
about cancer
in general, any specific tumor.
Clinicaltrials.gov is a
website where you can search
for any clinical trial in
the country or actually
in the world, if you
want information.
Patients treated in Bethesda at
the National Cancer Institute,
if they're accepted in a
clinical trial, all the care
and travel costs are free.
So, if you have friends
or relatives anywhere
in the country that might
qualify for a trial,
you can make this available.
There are a number of
popular books out there.
"The Emperor of All Maladies", I
think, you know, has been super,
super popular, and
it's very, very good,
and Dr. Clarke spoke
of Herceptin.
This is an outstanding book.
It really gives you the entire
story of how hard it was
to develop Herceptin of
the heroics of the doctors
who developed this, who
set up the first trial
of the first patients who'd
volunteered, people at Genentech
who fought to keep that program
alive, even AIDS patients
who told breast cancer
patients you've got to go out
and protest, you've got to go
out and fight for this drug,
so that it gets in there.
This is an excellent book on
immune therapy that that came
out fairly recently, that tells
the story of how it happens.
This is not a cancer book.
This is Richard Preston's
latest book about Ebola,
but it's a phenomenal story
of how public health science
medicine came together
to prevent what was
a terrible outbreak
but which could have been a
disaster for the entire world.
And thank you very much, and
if you don't know what --
if something funny -- mole
looks funny on your body,
if you don't know what
you should be looking for,
here are those pictures.
Thank you.
[ Applause ]
>> Tomoko Steen: This
was a great example
of translational medicine
[inaudible] genetics
to [inaudible].
So, next speaker is
Jonathan Lischalk.
Dr. Lischalk is a clinical
instructor at the Department
of Radiation Medicine at the
Georgetown University Hospital,
and you are going to hear
about proton therapy now.
>> Jonathan Lischalk: So,
thank you for the introduction.
My name's Jonathan Lischalk.
I'm a radiation oncologist
at Georgetown,
and we just had two really great
lectures to give us a background
of what we're dealing
with here in oncology.
I'm going to be focusing
on a specific type
of cancer treatment, and it's
radiation, and within radiation,
we basically primarily
utilize X-rays to treat cancer.
That's usually what we're
talking about, but an exciting,
not necessarily new,
but type of treatment
that we have available
now [inaudible] is called
proton therapy.
And that's something
that I use a lot
of Georgetown now
to treat patients.
So, this is a outline
of the talk.
I'm going to start by
discussing some of the history.
I think it would surprise a
lot of people that this type
of treatment goes
back many, many years,
almost all the way back
to the discovery of X-ray.
We'll talk about the
physics of proton therapy.
I'm going to try not to
bore you, but this is really
where the bread and butter kind
of differentiates X-ray-based
treatment from proton therapy.
We'll see a little bit
of the modern evolution
towards proton systems
and centers that we see today.
We'll talk a bit about why
this is an important type
of treatment relative to X-rays,
when we would it use it
[inaudible] why it may be
beneficial, and then finally,
our experience haven't been open
for over a year now
at Georgetown [inaudible]
treat patients.
So, starting with the
history of proton therapy.
To give you a bit of context,
the X-ray was discovered
in the 1890s in Germany.
So, only two or three
decades later,
Ernest Lawrence was a
scientist out on the West Coast,
invented the cyclotron.
And the cyclotron is
essentially a machine
that accelerates a particle,
and shortly thereafter,
Lawrence Berkeley Labs
built one of these machines.
Now, the first clinical
kind of idea for using this
for cancer treatment came
out of this paper here
by Robert Wilson in 1946.
And about three years
later, at Harvard,
which is where Dr.
Wilson was at,
commissioned the
first cyclotron.
Now, the first patients were
treated in 1954 and then in 1961
at Harvard, and for
decades and decades,
there were only two
facilities in the United States,
one on the West Coast, one on
the East Coast, that were able
to treat these patients.
In 1988, FDA approved proton
therapy as a form of radiation
to treat different
types of cancers,
and about a year later
[inaudible] California
[inaudible] open the first
hospital-based system.
Prior to that, these systems
had been more closely aligned
with the Physics
Department of Harvard
and [inaudible] out
of Berkeley Labs.
But this is the first
hospital-based center.
So, you can see, for many
decades, this was a type
of technology that was
just not available widely.
These are some interesting
photos.
This is the first cyclotron that
was built by Ernest Lawrence
out there in California
Lawrence Berkeley Labs.
And about a decade later,
the Harvard cyclotron was
commissioned and then taken
over to the campus at Cambridge.
So, what about the
physics of proton therapy?
In radiation oncology, we
primarily treat patients
with X-rays, and if we
remember high school physics,
the proton is part
of the nucleus.
It's in there with the -- it's
in there with the neutron,
and then electrons are
running around, but a hydrogen
with an electron removed
is what we're using
when we're using proton therapy.
And there's a lot of
different machines
that accelerate this particle,
and the reason why you need
to accelerate it is
compared to an X-ray,
which is essentially massless,
a proton does have a mass.
And so, you need really big
heavy equipment to be able
to accelerate that proton,
and this on the right side
here is an example of one
of those types of machines.
It's a cyclotron where you
basically have two magnets
that are alternating
and charged and kind
of accelerating an
electron that's placed right
at the center of
those two magnets.
And then as they speed up and
speed up, you get to a point
where this proton is now of
an energy that's high enough
to be useful clinically.
This is another form
of an accelerated --
this is a synchrocyclotron.
It's one of the more modern
ways to accelerate a proton,
but essentially, these are
accomplishing the same thing,
where they're accelerating this
proton, this particle to be able
to penetrate into a patient
in through the skin and enter
into where the tumor is
and then deliver the dose
to kill those tumor cells.
Now, the energy of a
proton is very important,
because it dictates the depth
to which that it can reach.
So, if you have a tumor that's
very deep in the pelvis or deep
in the lungs, you need to
have very high energy proton
to penetrate through
that patient's tissue
and ultimately reach that tumor.
So, you can see here
on the X axis,
the energy of a given proton
dictates how deep it can
penetrate relative to water,
which is oftentimes will be used
to measure a tissue equivalency.
So, to get up that
to that energy,
you did need these huge machines
to accelerate that particle
and use this technology to
treat patients with ligands.
Now, this is probably one
of the most important slides
in my talk, and it shows the
comparative dose distribution
for the most common type
of radiation treatment
that we have, which is the X-ray
here in the blue line relative
to the proton here,
the green line.
And what we're seeing here
on the X axis is depth.
So again, depth and tissue,
you can think about this
as particle traversing
through somebody's body
and getting into the tumor.
And then on the Y axis, you
can see the dose distribution.
Now, if you looked at an
X-ray, the X-ray comes in,
and its dose maximum is
relatively superficial,
and then it continues
through a patient's body
and exits out the other side.
It's like why we use chest
X-rays to evaluate patients
that have [inaudible]
problems, we have CT stands,
but when we use these
therapeutically,
the X-rays do get to the tumor,
but then they continue past
that target and outside.
The difference with the
proton is that it can come in,
oftentimes with a lower energy,
and because this is almost
like throwing a bowling ball
through a room, it doesn't slow
down until it gets to
the range of the proton.
And once it gets to its range,
again, dictated by the energy
of that proton, it starts to
very rapidly deposit its dose.
You can kind of think about
this area as the location
of the tumor in a
patient's body,
and it rapidly deposits its
dose, and then it stops,
and it goes no further.
So, you have this area
of no radiation exposure.
So, you're effectively able to
decrease the amount of radiation
that you're using
to kill the tumor,
while still killing the
tumor, by 50 to 60%.
It's almost like if you were
giving somebody chemotherapy
for leukemia, and then all the
sudden you could drop that dose
by 50%, and then you could
achieve the same outcome.
And so, this is why it's
a really exciting form
of technology in our field.
So, what were we using this
for the first several
decades in treating patients?
Well, you can imagine
that 50, 60 years ago,
the technology was
really not there.
We didn't have CT scans or MRIs,
computers, or planning software.
So, we were very much
limited in the types
of cancers that we could treat.
One of the most common things
that was being treated in --
at Harvard and Berkeley Labs
were tumors within the brain,
so central nervous
system tumors.
And by 1975, they'd
actually treated a very --
one of these rarer tumors
called a pituitary adenoma
at Harvard almost up
to 1,000 patients.
And so, these were tumors
that were easier to treat,
because it was simpler to set
a patient up and make sure
that they're not moving,
because it's easy to see
on an X-ray, the skull anatomy.
The tissues were not changing,
there was no motion
like breathing.
If you're trying to treat a
lung tumor, that tumor can move,
as a patient's breathing and
try to manage a proton beam
with a moving target
is very challenging.
So, in the early era of proton
therapy, these were limited
to only a few sites of
cancer that we could treat.
So, what about modern
proton systems?
We've come a long
way since the era
of just having two facilities,
one on the West Coast
and one of the East Coast.
And really, if you look at
the evolution of centers,
after Loma Linda opened in 1990,
you didn't really
have another one open
up until MGH opened
theirs at Boston in 2001.
A couple more centers
coming online
of the subsequent 10 years, but
really just a handful of centers
across the country compared to
today, where we're seeing almost
over 30 operational
proton centers.
So, this is a form of technology
that has become more ubiquitous,
and that's an improved
patient access,
which is very, very important.
When you're getting treated with
radiation, oftentimes you have
to come in for a week,
two weeks, six weeks,
nine weeks of treatment, Monday
through Friday and to try
to have a facility
that's very, very far away
from somebody's home is
extremely challenging.
So, this has changed our ability
to offer this type of treatment
to patients across the country.
One of the other
important aspects
to all early proton centers was
that they were very,
very, very big.
This is actually an
interesting example
of the Heidelberg Ion
Therapy Center where I worked
that has a facility, and this
is a man to give you kind
of context of the
size of this facility.
Now, these things were three,
four, five stories big.
This blue thing here
is called the gantry.
What the gantry is, it's
basically a rotating machine
that aligns that proton
beam up, so that it can come
in from different angles
to enter a patient
for a given tumor.
The geometry [inaudible]
into the tissue
and how the patient is lined
up is very, very important.
Now, this facility actually
treats patients with carbon
as well, and that's why
this gantry is so large,
but these are huge facilities,
100,000 square feet facilities
that you need oftentimes over
$250 million dollars to invest
in these types of facilities.
And this is kind of
thet raditional model
of a proton therapy center.
To give you an idea of what
this looks like, schematically,
that accelerator that I
mentioned at the beginning
of the talk, you'd have
one of those kind of --
like maybe two, three rooms away
from where a patient was
actually getting treated.
This accelerator would
then accelerate a proton
into what's called a beamline.
So, it gets to that useful
speed, it's pulled out
and extracted, and then there's
potentially one, two, three,
four, five other rooms or
gantries similar to the photo
that I just showed here.
This is a gantry, where
you could treat patients.
Now, these aren't
autonomously functioning rooms.
They actually are feeding
off of the same accelerator.
So, you can't treat all these
patients at the same time,
but these facility's really big,
and it was really challenging a
medical center to want to invest
in what is -- would easily
be the most expensive piece
of medical equipment, over $200
and $250 million
dollars oftentimes.
You could imagine the amount of
energy that would be required
to maintain a facility
like that.
So, these -- this conventional
model of proton therapy center,
I think, was really challenging
to became ubiquitous
throughout the US.
They were so expensive
to invest,
and now this technology
has improved,
and costs have come down.
We've been able to
invest in these from a lot
of NCI designated cancer centers
can now [inaudible] open these
centers up.
So, we're in Washington DC right
now, obviously, we're limited
in space both up and
down, we have limits
in where we can build.
And out where we
work in Georgetown,
there's even less space.
So, one of the things that we
wanted to do when we invested
in proton therapy was have
that center on our campus,
so that we could [inaudible]
treat a lot of patients
that get chemotherapy
at the same time.
So, working with our
medical oncology colleagues,
who are directly on site or
surgical oncology colleagues,
who are on site, rather
than have a facility 10,
15 miles away, where patients
are being seen at the same time.
This is something that
we wanted to focus on,
so that could be a kind
of all-inclusive care
and not require that massive
upfront investment cost
and also be a more of a patient
centered form of treatment.
So, our facility is
actually right on the campus,
right within the Lombardi
Cancer Center itself.
So, patients come in, they
get the radiation treatment
and they're getting
chemotherapy at the same time.
They go up one floor,
and they're already
in that [inaudible] in
the infusion center.
So, I showed you a photo of
the accelerator that the kind
of the graphic of
an accelerator,
but this was a picture of one
of the early accelerators.
It was 250 tons, a really
large piece of equipment,
and as time has gone on, those
accelerators have become more
and more advanced,
smaller and smaller.
And it's allowed us to minimize
the size of those facilities
as well to the point where
we're now with a facility
over at Georgetown it's
only three stories high.
You can see that a patient
brought into this room here,
and I'll have another
couple of photos
to show you what it
looks like in this room.
And that's the three-story
facility above and below,
because the gantry is
actually rotating right here,
and the accelerator is
placed onto the gantry.
So, that's why we're able
to kind of fit this piece
of equipment right into
the Lombardi Cancer Center
and treat patients right
there in our own department.
So, if you were to walk into the
treatment room and take a look
at the equipment, this is
basically what you would
be seeing.
This photo is basically this
portion of the room right here.
So, if your patient is getting
treated with proton therapy,
you would walk in, you would
lie down on this table.
And this is what we
call a treatment couch.
We have various types
of equipment to kind
of immobilize the patient, so
that they're not moving around.
You can imagine we want to
be on the order of a couple
of millimeters of accuracy here.
So, if we're treating a
head, neck, or brain tumor,
we'll have to create a patient
specific mask, and we'll put
that onto this table,
so the patient is kind
of fixed in place.
Now, this is what we
call a robotic couch top.
It's kind of cool.
It basically has six degrees
of motion adjustments,
so that we can get that
patient lined up once they're
on the table into the position
and adjust on the order
of a couple of degrees or
a couple of millimeters
with this robotic couch top.
Now, the location where the
proton is actually coming
out is right here.
This is what we call the
treatment head, and what's cool
about our facility is we, right
here, there you can't see it,
but there's little leaves
that come in and out and shape
that proton beam, as it's
entering the patient,
so that the lateral aspect
of the radiation field can
be very sharply, I mean,
kind of personalized to the
patient's anatomy and the tumor.
Now, depending on the
location, whether you need
to treat a patient from the
front or treat the patient
from the back, this
gantry is going
to be rotating about
190 degrees.
When that happens, this thing
right here basically goes above
or below the treatment level.
Now, once the patient's set up,
we'll oftentimes get a CT scan,
and this looks at
3-dimensional anatomy.
So, if we're treating a lung
tumor, we get the CT scan,
we line it up, we make
sure that the breathing is
within a certain degree
that we've already kind
of compensated for, that there's
no other surprises before we
treat the patient, so a lot
of image guidance in terms
of setting the patient
up and making sure
that we're hitting
the right spot.
This is a different
view, kind of this is
from the treatment head.
You can see the gantry here,
again, the patient couch top.
Back here is where we have
the radiation therapists
and physicians.
This is where they're getting
images to set the patient up,
and this gives you
an idea of what goes
on in the background here.
These are X-rays
that are obtained
for patients being treated.
We line these X-rays up
with the radiation plan
that we've developed prior to
the patient getting treated
to make sure that we're
in the right spot.
This is, for example,
a CNS tumor here,
and they're getting their --
the bones and their head lined
up to the X-rays that
are being [inaudible]
with this X-ray panel
that kind of comes
out before the patient's
treated, and this is one
of those masks that
I mentioned before.
So, that's kind of the
evolution of the systems
and the facilities
that we've treated.
How does this type of
treatment relate to our bread
and butter X-ray
type of therapy?
Well, the basic idea goes back
to that first physics slide,
which is the proton comes
in, it gets to the target,
and then it stops
and goes no further,
and that's basically
called the lack
of an exit dose for a proton.
I think this is best
illustrated here.
This is a type of tumor
that pediatric patients get,
a medulloblastoma,
where you have
to treat the whole brain spine.
Now, with X-ray type of
therapy, which is shown here
in the middle, you can see
that to be able to do this,
because you don't have a Bragg
peak or that lack of exit dose,
you're radiating in all of this
tissue, lungs, heart, GI tract,
all of this tissue is
receiving radiation.
You can see the excess radiation
here when you compare it
to a proton plan that is
achieving the same type
of cancer control or cancer
outcomes, but sparing all
of these anterior structures,
and what that means is
that you're reducing the risks
of side effect profile risks
down the line for
patients that are young.
Young patients with
these types of cancers,
they're at much higher risk
of developing maybe a
tumor from radiation.
Radiation can cure
cancer, but there's a risk
that you can cause cancer.
So, to reduce that risk, you
want to get radiation dose
down to zero for all
of these structures.
You really just want to target
where the malignancy is.
So, we have a lot
of publications
over the last several decades
that have demonstrated
improvements in the dose,
improvements looking at how
when we create these plans,
we're using software to kind
of create a radiation
plan that's specific
to a given patient's tumor.
And when we compare the
proton plans to photon plans
or X-ray plans head to
head, we have a lot of data
that supports improvements
in the dose.
The challenging part is trying
to improve the clinical
outcomes also will improve
with reductions in dose
to these normal tissues.
What's interesting is
that there's certain areas
in oncology where we've already
decided that protons are better,
and we don't need to use a
randomized trial to prove that,
and one of those sites
is pediatric patients.
I think if you had a child
and you saw these two dose
distributions, you wouldn't need
to put them on a
randomized control trial.
You would say there's
no equipoise for that.
We don't want to radiate these
normal organs, and we've done
that in radiation oncology
for pediatric patients.
Now, in adult tumors, it's a
little bit more challenging,
especially depending on
the site of the tumor
and the age of the patient.
So, what we're trying to figure
out now is what is
the clinical --
the real clinical
benefit in what we see
from a dose symmetric
improvement here.
I'll give you some
other pictures.
This is a pituitary adenoma,
and what I'm showing you here
as proton therapy is
advanced, we've seen the dose
in the surrounding
normal structures.
And let me kind of give
you some landmarks here.
This is the tumor here in
the red, and all this dose
out here is stuff that really
doesn't need to be there, okay?
But depending on the radiation
technique that you're using,
you have to get the
dose in somehow.
Now, this is an X-ray-based
plan, and you can see
that there's different
beams that are coming in
and converging on this area.
But there are all these
normal structures here,
including brain temporal
lobes, the optic nerves,
that are receiving radiation
and if we can do a better job
of reducing that
dose of radiation
in those normal structures,
maybe we can reduce the
side effects as well.
And I think as you compare the
evolution of proton therapy,
this is an older form of proton
therapy, and then a newer form
of proton therapy and
really the newest form here,
and I'm not going to
get into the details
of the physics on
how this works.
But you can see this -- the
surrounding halo of radiation,
reducing down as you
kind of advance even
within proton technology.
Now, depending on the site that
you're treating with radiation,
you can see various
clinical benefits
and using another brain
tumor as an example, say,
this is a low grade
glioma or a tumor
of the primary nervous
system in an adult.
You can see that, as you
compare an X-ray-based plan
to a proton-based plan,
there's a lot of reduction
in normal dose, and we know that
brain tissue is very sensitive
to doses of radiation,
all the way
down to very low [inaudible]
doses of radiation.
Patients can have neurocognitive
effects, you know,
it can almost cause
a type of dementia
to occur earlier in patients.
You can have endocrinopathies
when you radiate somebody's
pituitary access, hearing loss,
optic problems, cataracts,
secondary malignancy.
So, the results of having this
excess dose can lead to this.
Now, moving on to other
sites for lung cancer,
which we heard of, number
one killer in the US,
locally advanced lung
cancer in particular.
We know that radiation
dose for patients
that have lung cancer is
very important to consider
when you're thinking about
the dose to the lungs
and the dose to the heart.
These are patients that might
have been smoking for many,
many years, and they don't
have the same tolerance
of side effects as
younger patients do.
So, this is an -- kind of a cool
plan that I wanted to show here
for a patient that had a large,
a locally advanced lung cancer,
because these two beams are
coming in here from the back
and then one slightly from
the front, this is a side view
of the heart, and
the tumors over here.
And what's kind of amazing in
a patient that has lung cancer
and a lot of cardiac disease
and lung disease, this is able
to come and stop and go no
further and reduce the risk
of any cardiac side effects
for this type of patient.
Similarly seen in a different
type of thoracic tumor,
thymic cancer, which is a rare
tumor at the front of the chest,
you can see the same idea
here, except kind of flipped,
two beams coming in from the
front stopping, going no further
and then blocking all this heart
out here, reducing the risk
of a patient's risk of
cardiac toxicity down the line.
Same thing can be seen for
other sites like lymphoma.
This is a younger patient with
lymphoma that I treated, and,
in this case, any
tissue exposure
for a young patient is
going to reduce the risk
of a secondary cancer
from radiation 10, 20, 30,
40 years down the line.
And then more complicated
cases where, say, this --
this is an instance where a
patient had a lung cancer before
they got radiation and
chemotherapy to cure it,
but then it came back.
A lot of the times, they
wouldn't have any options
for curative treatment,
but we have the ability
to get radiation dose and treat
a tumor that's recurred already
in an irradiated field, which
is a very dangerous situation
and do this while staring
all these normal structures
including the spinal cord.
So, this is a form of technology
that is really exciting to have
as a complimentary form of
treatment in our department.
So, the -- I think the question,
which is a very complicated
question to answer,
and I have trouble answering
this on a day to day basis,
and sometimes I actually
just have to create plans,
both X-ray-based plans and
proton plans for a given case
to figure out which is
better in which situation.
Now, this was published in
the JCO about 10 years ago,
and these are just kind of
generalized bullet points
when you would consider protons
being better than X-rays.
There are some cases where
X-rays caused a lot of problems,
that cause a lot
of side effects,
and we want to reduce
those side effects,
and this is one way to do it.
When the normal tissues
are so sensitive to X-rays
that you want to reduce any
radiation dose, this is --
a good example's
radiating somebody's brain
or treating a pediatric patient,
protons might be a better idea.
When you need to increase
the radiation dose,
because a tumor is
just so aggressive
that it doesn't respond to
standard doses of radiation,
sometimes you can achieve this
with this type of technology,
[inaudible] radiation cases
which I already mentioned
and then also pediatrics,
which I think is the
most commonly used site.
So, just briefly, in
the last few minutes,
this has been our experience at
the Proton Center at Georgetown
over the last year and a half.
We've been using this technology
to treat almost every site
in the body, and so it's been
a very heterogeneous group
of patients.
I think if you look back in
the 1950s and 60s and 70s,
when this technology was only
available in a couple places
in the US, where they were
really just treating a couple
of sites, this is where
we're going with this type
of technology to be able to
have advanced treatment planning
and delivery techniques
that we can treat,
really any cancer anywhere
in the body, brain cancers,
gastrointestinal
tumors, thoracic tumors,
genital urinary really
across [inaudible]
including breast cancer here,
really across the board.
And this is what we're hoping to
offer to our cancer population.
So, I'll conclude by saying
this is a exciting type
of radiation treatment
that's actually been
around for a very long time, but
is now becoming more available
for patients, both in the
United States and abroad.
Our advancements in technology
and the cost and our ability
to integrate this into an
existing cancer center have
allowed a lot more centers to
adopt this type of technology.
I think this is a great
complimentary form of radiation
to have at a radiation
oncology center.
I don't think this is going
to completely replace X-rays.
And, in fact, there's a
lot of cases where I prefer
to use X-rays, but this is
an excellent option for a lot
of clinical situations,
pediatrics, of course,
taking the highest priority.
And then we have a
lot of ongoing trials,
looking at proton therapy versus
X-ray therapy head to head
which is better and a lot
of future challenges as well
in terms of treatment
planning, managing motion,
as I'd mentioned earlier
is a big challenge.
And, of course, we always have
challenges with insurances,
as physicians in oncology.
Insurance coverage, I
think will be an issue
in the future as well.
So, thank you for your time.
[ Applause ]
>> Tomoko Steen:
Very interesting.
Next speaker is going to
talk about gut microbiome.
We have two lectures already we
sponsored for the microbiome,
especially gut microbiome,
from the supervisor actually,
who was Dr. Roy [inaudible].
>> Soumen Roy: Yeah.
Cancer, yes.
>> Tomoko Steen: Is going
to talk about side effect
of cancer therapy
using gut microbiome.
>> Soumen Roy: Thank
you so much.
So, good afternoon, and I would
like to really thank Dr. Steen
for inviting me, Library of
Congress to sharing my research.
And before me, the other three
panelists, Dr. Clarke, Dr. Dean,
and Dr. Lischalk [inaudible]
giving a wonderful foundation
and information,
different kinds of cancer
and the therapy options.
So, that made my
[inaudible] much easier
to give you the other aspect
of the cancer therapy that how,
you know, you can
impact the quality
of life of cancer patients.
So, one of the thing in the
cancer survivors and the quality
of life by the development
of different cutting edge
therapy options, the percentage
of cancer survivors
has increased really,
really high in the
last couple of years.
And especially, you know, the
statistics number like yesterday
like based on January 2019,
it is estimated that there's
like 16.9 million cancer
survivors in the United States
from the different cancer
therapy [inaudible].
And also, it is estimated
that by 2019,
29% increasing [inaudible]
should become
like 21.7 million
cancer survivors.
So, there are different
therapy options,
as the previous speakers
mentioned that chemotherapy,
radiation therapy, and
also immunotherapy,
and all of this therapy
has severe side effects,
not all, but most of them.
And those side effects cause,
like, nausea, vomiting,
and gut toxicity, and also
it causes nerve toxicity
and anorexia, which
is like [inaudible]
which they lose the
interest of eating food,
they lose weight
[inaudible] a lot
of toxicity during the therapy.
Once the patients are
cured, they can get
on to other kind of toxicity.
So, today I'll focus
one of them,
so in terms of side effects,
and that is communication.
So, communication is the
key component of life,
and we all communicate by
talking, by writing letters,
and discussing and
sharing our stories.
And one of the interesting thing
I came across recently from one
of the articles in
[inaudible] of society
that before the fire
was, you know,
invented the primitive
people, like,
they didn't know what
to do in the evening.
And once the fire was there,
they just started
[inaudible] sharing a story,
and communication was --
became one of the biggest thing
and born and forming
the social structure.
And if you look someone who's
communications and the mode
of communication that
impacts the quality of life,
and one of the communication --
the mode of communication is
hearing, and then hearing loss
in nearly 750 million
adults worldwide,
and those are experiencing
hearing loss.
And one of the biggest inducer
of this hearing loss is one
of the drug called cisplatin.
So, cisplatin was discovered
by Barnett Rosenberg in 1965,
and it was approved
by FDA in 1978.
It is in the market and
the clinic, lasting more
than four decades,
still like the efficacy,
and the side effects are,
like, really [inaudible].
So, cisplatin is to treat like
lung cancer, testicular cancer,
bladder cancer, solid tumors,
and many other head
and neck cancers.
And you can see, like, it goes,
and it leads to many
side effects.
One of the biggest side
effects is that hearing loss.
So, I started working at NIH
and the National Institute
on Deafness and other
communication disorders before
joining [inaudible] I studied
how chemotherapy can cause
hearing loss and what could
be the protective mechanism,
and others are like
nerve toxicity,
and patients experiencing, like,
heavy toxicity in the kidney
and a lot of time due to
kidney failure the therapy has
to be stopped, although
the efficacy is great.
And others are like [inaudible]
neuropathy, so the --
although there are some
patients, those who are treated
with cisplatin, even
if the cancer is cured,
after many years they feel
the pain in the nerve.
So, there are, like, a
lot of research is going
on to understand what is the
cause of these side effects
and how to treat that.
So, I asked questions, like,
in my previous institute
like how -- what
is the mechanism
of [inaudible] causing
the hearing loss?
So, you can see the sound
travels through the outer ear,
and it vibrates this bonds,
and then this physical --
the sound energy goes
through this tunnel,
and this is the inner ear.
And this then converted
to electromechanical --
electromagnetic energy
and goes to the brain
and then [inaudible] here.
So, if you do a cross
section in this --
the inner ear called
cochlea, and you see this kind
of structure, and when
-- once you give --
and this is the structure,
when you see the inner ear,
is it technologic -- the
architectural [inaudible],
and it has three rows
of outer hair cells,
and one of those [inaudible]
hair cells will [inaudible] I'm
talking with you this
[inaudible] membrane is
vibrating, and this, an
electromagnetical energy goes
in -- go -- is going to your
brain, and you can hear it.
So, if you give cisplatin --
so after cisplatin
administration [inaudible] given
systemic -- thorugh
systemic infusion,
and it goes to the ear,
and there's a portion
of the cochlea called stria
vascularis [inaudible] enters
in this tunnel, and it
kills those hair cells.
Just to show you one of the
figure how it looks like.
So, this is the cochlear
in mice,
and these are the three rows of
outer hair cells [inaudible],
and you see how the
hair cells are missing.
And nearly 50 to 80%
of the cancer patients,
those who are treated
with cisplatin become
death permanently.
And although you might
think that, you know,
there are so many other options
now, why cisplatin, you know,
cisplatin is one of the
cheapest drug in the market,
and it's so effective.
New -- recent therapies
are coming up --
they're also taking to
combine cisplatin along
with the immunotherapy, so
that they have less toxicity,
while still long
[inaudible] long way to go.
Okay, so what could be
the protective strategies?
So, what happens is, in
case of hearing loss,
once the [inaudible]
is in the system,
so either you could do repair
those outer hair cells,
those are missing by
[inaudible] by targeted therapy,
and those are like -- none
of [inaudible] therapy
can do [inaudible].
I will give the cisplatin inside
another [inaudible] specifically
to the tumor, so that you can
relieve the system [inaudible].
But so far there is
no drug in the clinic
which can cure [inaudible].
And another possibility
for would be intervention.
So, how that would
be, you know, reduced.
So, I was thinking
like, you know,
once you persist
[inaudible] in the patients,
there's like a window,
the hearing loss doesn't
happen immediately.
It takes some time, like, you
know, sometimes it's one week
to a month to start losing
high-frequency hearing loss.
So, I was thinking, is
there any human [inaudible]
that could be responsible for
causing this hearing loss?
So, in case of [inaudible],
you see, [inaudible] deficient
and it should kill the
tumor and goes to the tumor
and then tumor killing.
And in some cases, it can
cause resistance, and --
but what happens is, you know,
earlier Doctor Clarke mentioned
that it not only does
kill the cancer cells,
it also kill the healthy tissue.
And it can cause
[inaudible], in some cases --
also in the ideal cases should
clear of the unnecessary drug
and reduce the toxicity.
Then after giving
[inaudible] in the system,
it cause [inaudible] toxicity,
and it impairs the barrier
of the gut lining, and there's
a lot of toxicity happens.
And then patient
experience diarrhea,
and I'm losing off electrolytes.
And another toxicity is
[inaudible] as I mentioned,
and then cachexia, which is
like really the muscle wasting.
Patient become really thin
and [inaudible] toxicity.
So, why [inaudible]?
So, one of the first
site of injection
of [inaudible] compared to
like a lot of microbiota
around like 2.5 pound and
this is recently considered
as another [inaudible], because
they regulate pretty much
everything now.
And so, the first
question that I ask,
does [inaudible] regulate
[inaudible] in the cochlea?
So, to understand that then I
move from the Hearing Institute
to the NCI [phonetic].
And in 2013, a very [inaudible]
from my current supervisor
[inaudible] promised that came
out that commercial
bacteria is gut [inaudible].
They control cancer
response therapy
by modular [inaudible]
or microelement.
And at that time, I was
working with [inaudible]
and then I thought
to talk to him
and then continue
this research to see
if we can modulate
gut microbiology
to reduce the toxicity
of this [inaudible] drug.
So, what are the microbiota?
So, [inaudible] with microbiota
partners, and, you know,
we are composed of specific
bacterial [inaudible], cortisol,
fungi, [inaudible], and
[inaudible], and it actually --
microbiota not only is in
the gut, but it also --
it's kind of covered
in the entire external
surface of our body.
And it regulates the different
barrier surfaces in the gut,
and there is numerous --
more than the human cells
and the DNAs called microbiome.
And they come to nearly 100 time
more genes than the human genes.
So, what are the microbiota?
So, they're the key
orchestrator.
So, in a recent bit of news,
a paper [inaudible] microbiota
nearly regulates everything,
every disease.
And so, one thing is
like in the hearing,
it's nothing has done yet, so
I'm kind of investigating now.
So, one of the thing that
regulates microbiota,
the age, and mode of delivery.
Like how the babies are
delivered or that they're
from the C-section or
from the normal delivery.
And there's some studies
showing that the babies --
those who are delivered
through C-section could be --
more tend to [inaudible]
chances of there.
But there's no like
[inaudible] data applicable,
but a lot of studies are
going on on that direction
and then also, of
course, genetics.
Also, recollect the composition
of gut microbiota,
and what else?
So, the geographical
location and the lifestyle,
mutation has a huge
impact on the composition
of gut microbiota kind of food
that we eat, like high fat
or the vegetarian or the
Mediterranean food, the hygiene,
and also like the probiotics.
There are a lot of -- the
counter in the pharmacies,
you can buy probiotics,
and really,
we do not have much information
how these probiotics can
interact with our immune system
or with the other microbiota.
So, the caution has to be taken,
but it will take
[inaudible] probiotics.
And also, antibiotics; it
impacts heavily the composition
of gut microbiota, especially
in the developing countries.
So, the antibiotics you
can buy in the clinic
without a prescription
of the doctor,
and then there's no regulation
on that [inaudible] infections
and disperses and different
disease also change the
composition of gut microbiota.
And that can imbalance the
composition of microbiota,
and it can, you know,
promote [inaudible] cancer
and other diseases.
So, in that paper what
the [inaudible] soon,
before I joined the lab,
that they introduced,
you know, the tumor into mice.
And then the treatment -- the
mice with the platinum compound.
There are two kinds of drug,
oxaliplatin and cisplatin,
and in another set of
experiment, they treat the mice
with three different
antibiotics, which is neomycin,
vancomycin, and [inaudible].
So, and the composition
of three antibiotics,
they remove ground positive
bacteria, ground negative,
and anaerobic bacteria
from our gut.
And also, they use jumper mice.
So, what has happened is --
and [inaudible] can
explain shortly this graph,
so the green line here --
so this is the tumor volume.
So, higher the graph goes
up, the bigger the tumor.
So, when the mice are not
treated with any therapy
and when the mice are
drinking normal water,
and only the antibiotics,
these two group, they are --
the tumors are growing
really high.
And then once the -- and this
is the normal tumor treated
with oxaliplatin, the
tumors are cleared.
But when these mice are
treated with antibiotics,
you see the tumors are growing,
so it's really bad [inaudible]
the impact of the therapy.
And it also -- the
similar case in case
of cisplatin is you want the
mice treated with antibiotics,
the tumor is growing, and the
therapeutic efficacy is gone.
So, that really -- it issued
a new line in the cancer
and gut microbiota research.
So, then I started
asking question
that whether gut microbiota
can regulate the toxicity.
And it can seem recently
[inaudible],
so recently like
[inaudible] radiation therapy
and the cisplatin,
oxaliplatin, and [inaudible]
and different [inaudible]
for [inaudible] PDL1,
they all is regulated
by microbiota.
And [inaudible] discussing the
[inaudible], so what I told you
so far that chemotherapy
kills the tumor,
and also at the same time it
causes system and toxicity.
And we know now that gut
microbiota also regulate cancer
initiation and progression, and
it also regulates chemotherapy.
However, very little is known
how gut microbiota can regulate
system and toxicity.
And that's what my question was,
so then we asked the question
whether the alteration
of gut microbiota can regulate
[inaudible] side effect.
So, we proposed this
experimental plan,
so we had four experimental
group,
control where the
mice are not treated
and cisplatin we'll
give the mice the drug.
And you treat the
mice with antibiotics,
so the antibiotics is not here
given as a therapy or something.
We are just creating
experimental model
where you can remove the
bacteria and see the impact
of the drug and either
germ-free mice.
And in the fourth group we used
the drug and the antibiotics.
So, this is the experimental
setup,
so we gave the mice three
weeks of antibiotics.
And then after three weeks
of antibiotics we
have done sequencing.
We know that this different
class of microbiota is gone,
and then we introduce
[inaudible]
to a really heavy
dose of platinum.
We used that dose to
create toxicity and see
if that can anything in terms
of reduction of toxicity.
And then we did a readout and
every day, like what the weight
and collection of different
tissue for other experiments.
And for germ-free mice, I
just put this picture just
to give you the background
that this is really
intricate experiments.
[Inaudible] an animal has
not a single bacteria,
and this really tricky
kind of facility
that took a lot of time.
I took this picture from
the [inaudible] we have two
[inaudible] facility where
our dedicated staff members,
they maintain those mice,
and then [inaudible] this
experiment inside this isolator
and then see what happens.
So, the first question with this
cisplatin hinders [inaudible]
loss regulated by microbiota?
So, here you can see that normal
cisplatin in the blue line
when you give this high dose
of platinum from day zero,
on day four, these mice lost
nearly 20% of their bodyweight.
Once you remove or modulate the
microbiota with antibiotics,
the mice are protected.
And this is across male,
female of both [inaudible]
at resonating male and
female, some differences.
We did this experiment
more than seven-eight time;
we always see the same thing.
And then we did that
experiment also in [inaudible]
and see also germ-free
mice is protected compared
to the conventional mice.
So, take this point so we know
that if you deplete
gut microbiota,
it has [inaudible]
the mouse bodyweight.
But one can ask, how do
you know this is really
microbiota affect?
This could be that
these mice ate less food
or have different
kind of metabolism.
So, we -- this [inaudible]
activate those, but anyway,
so we did microbiota
reconstitution experiment.
So, far I've shown
you [inaudible]
that you have conventional
mice, normal mice.
You give platinum;
this causes toxicity.
You have germ-free mice.
You give platinum;
it is protected.
So, now what happened?
You take the normal mice, and
you collect the sickle content,
which is the, let's
say the fecal sample.
And then you give
the sickle sample
through fecal microbiota
transfer
in these germ-free mice, and
then you wait for three weeks
and this process
called reconstitution.
And then you give cisplatin
and see what happens,
and these mice become
not like weighted mice.
So, you see that normal
mice, this purple, one,
this is the conventional
mice, and that --
we made it conventional mice,
they all lost bodyweight,
like same as conventional means.
Which means once you
convert the germ-free mice
with the normal --
the microbiota, those
germ-free mice lose protection.
But here in this line, you
can see the germ-free mice
did protect.
So, this really shots that
gut microbiota modulate the
toxicity [inaudible].
And we have done many
other different experiments
to understand what is the
mechanism of this toxicity
and what the -- and the reason
that the data indicates
the gut microbiota,
it regulates the
transporters in the kidney,
and it clears the drug from
the system circulation.
And this is one of the
pictures showing that the
in the kidney cross section,
you can see the cisplatin
causes a lot
of [inaudible] more
[inaudible] signal is causing --
showing that [inaudible]
diversion.
Here you can see that
once the mice are treated
with antibiotics, it is -- the
damage is really, really less
or more like negligible.
And this is the graph; you
can see that the treatment
with antibiotics in the
mice reduces the toxicity
by platinum, and this
could be really helpful
if we understand the
mechanism could be used
in the clinic as well.
Where after giving the treatment
to the patients, after like --
the cisplatin has
very short half-life,
and after that the unnecessary
platinum, which is bound
with different protein in
the system, you can clear
and reduce the toxicity.
So, what is the impact of
cisplatin on gut microbiota?
So, you can see,
another test we have done
to see what the drug are
doing in the composition
of microbiota, you can see the
[inaudible] we have done this
experiment with fifty mice.
And after four days, they
lose 20% of bodyweight,
and within this group,
within these 45 mice,
you can see this is only
creating two clusters.
And one of the cluster, this
one, we focused on this,
and this lost significant amount
of bodyweight compared
to this cluster.
So, we focused on this,
and we saw they have specific
microbiota presence in this.
And another striking thing is,
this is one of the [inaudible]
sequencing of gut microbiota.
And these grey lines are
the lactose, and this --
these top bars, these are
the mice from this group.
They are losing lactose
[inaudible], so this is one
of the examples that
I'm showing.
So, seems like the toxicity's
associated with losing
of [inaudible] species
from the gut composition.
So, then we wanted --
we asked a question,
can specific microbiota
modulate and also
like promote protection.
So, if you can bring back those
lactose [inaudible] would it
protect against platinum?
So, then we took three different
lactose [inaudible] species,
and then we created a
synthetic consortium.
The reasoning I'm doing that is
if you take the total
[inaudible] content
because like millions
of bacteria,
you don't know what these are,
and then it's really difficult
to understand the mechanism.
So, we took -- defined --
and these microbiota
came from human,
and then we -- it
is well defined.
And then we added this
lactose [inaudible] species
with this one, because if
you give a single [inaudible]
to the mice, these
bacteria not survive
in the [inaudible] conditions.
We have to give [inaudible]
ecosystem.
And then we looked
for the toxicity.
So, in this graph I'll
explain, so this one,
and this is the conventional
mice,
this is the grey color one
here, lost 20% of bodyweight.
And this is microbiota
consortium plus cisplatin,
and this experiment was
done in germ-free mice.
So, we gave the microbiota
consortium
to the germ-free mice, and
then we gave cisplatin.
The protection is again
lost, and you see here,
once the microbiota
consortium was mixed
with the [inaudible]
species, the defined one,
and this is a single isolate,
and that is protected
significantly conflict
with the conventional one.
And this is the germ-free
mice again showing protection
against cisplatin.
So, this [inaudible] case
that if -- you can give --
treat the mice with
a specific bacteria,
and that can protect the mice
against the cisplatin
[inaudible] toxicity.
So, the -- going back to
the question, you know,
does microbiota regulate
platinum clearance
from the cochlea?
So, we have done from
many different organ,
and this is the cochlea data.
You can see on day four
cisplatin has really cleared
from the cochlea.
And there's a paper [inaudible]
from my previous lab showing
that once platinum
enters the cochlea,
they retain their
whole life permanently,
and they don't leave
from the cochlea.
And that might be
one of the reason
that it's causing the produce
of hearing lost over the years.
And this data shows that
if you modulate microbiota,
that can really clear platinum
from the system and circulation.
And we have also done experiment
in germ-free mice
[inaudible] data
and also a different
specific microbiota.
So, ongoing study, what
I'm doing now is, you know,
I don't give much
background here,
but this cochlea is thought
to be [inaudible] organ,
and this is very, you
know [inaudible] one
of the most difficult
organ to reach.
Any organ you can
think of in the body
that you can have
biopsies, but the cochlea is
so inside the bone
and this is one
of the hardest bone in the body.
You cannot get any biopsy;
you cannot reach
there without surgery.
So, this is one of the difficult
-- the problem that we have,
and another thing, we do not
know which kind of cell entered
into this [inaudible] space and
whether they have any specific,
you know, immune cells.
There is a lot of studies
showing this [inaudible]
by [inaudible] that immune cells
are present in the cochlea.
So, what I have done
in this project,
I have done single-cell
[inaudible]
and high dimensional
[inaudible] technology
to characterize the immune
cells within the cochlea
and quantify the amount of
cisplatin in the single cell.
Then I can now know from
the single-cell data
that which cell is
modulating this inflammation
in the cochlea.
And the idea is to understand
better mechanism into that,
and from that, [inaudible]
to understand
and characterize the
immunity of the cochlea.
So, in summary and conclusion,
but I've shown you that,
you know, once cisplatin is
in the system and circulation,
if you can deplete
microbiota by antibiotics,
it can reduce cachexia.
It can reduce DNA damage, and
also it is [inaudible] toxicity
and it meant [inaudible]
integrity.
So, you can think that, okay, in
the beginning how can you give,
you know, an antibiotics
to the patients?
And that's a very critical
question, and so we are trying
to find out a balance.
And I think we understand better
now that there's a balance.
Some of the microbiota is
responsible for causing toxicity
and some are for efficacy.
So, if you can maintain that
balance, then we can, one hand,
kill the tumor; at
the same time,
we can maintain the toxicity.
And another is happening
is, you know,
after the [inaudible] toxicity,
we have disperses
in the microbiota.
And that recruits many
different kind of immune cells
that maintain the --
at the [inaudible] site
and leads to toxicity.
So, this one, if we can
regulate disperses of microbiota
by giving probiotics or
like removing specific class
of bacteria, then we can clear
the platinum from human tissue
and also reduction of
long-term toxicity.
And ultimately, which
will enhance the quality
of cancer patients.
And there's a similar kind of
study also [inaudible] as well
and where we show
that microbiota also
regulates [inaudible] toxicity.
So, with that, I would like
to thank all my lab members
[inaudible] and [inaudible]
team and the funding
from [inaudible] agency I had
from the [inaudible] foundation.
Thank you so much.
[ Applause ]
>> Tomoko Steen:
Thank you very much.
So, we have a few minutes to
ask questions to the speakers.
Anybody? Yeah?
[ Inaudible ]
Could you repeat the question?
>> Michael Dean: So,
the question was what are
immunomodulatory agents
in antiangiogenic [inaudible]?
I'll answer the antiangiogenics,
so as a tumor gets bigger,
it needs to develop
its own blood supply.
And so, some tumors
actually secrete factors
to essentially recruit blood
vessels into the tumors,
so the tumor can get nutrients.
And so, the that antiangiogenic
factor's the idea, well,
if we can suppress that, starve
the tumor for blood supply,
then the tumor would die.
And it's one of those things
that worked fabulously in mice.
When we went to apply
it in humans, you know,
we are starting to
see some applications,
so that is a new
line of therapy.
>> Robert Clarke: I can try
and take the immune one,
though it's not my field.
Basically, the idea is to
try and stop the cancer cells
from turning off
the immune system.
So, when you have an
infection, for example,
the immune system
gets turned on.
The t-cells, they come in.
They get activated.
They remove the infectious
disease,
and then they get turned off,
because you don't want them
attacking the normal cells.
What happens when they come
into a tumor cell is
they just turn off.
And they do this by signaling
between the cancer cells
and the immune cells, and
there are receptors and ligand
that turn off the activation
of the immune cells.
So, what the drugs that we
currently have do is they block
that signaling that turns
off the immune system
and then allows it to become
activated and stay activated
and then kill the cancer cells.
There are lots of different ways
that the immune system can
get regulated in that way.
I mean, we don't have
drugs that target all
of that communication
[inaudible] communication,
the question really.
But more drugs and more
classes of drugs are coming
through very, very quickly
now as we understand
in much greater detail
how that communication
between tumor cells
and immune cells
in the tumor microenvironment
occur.
[ Inaudible ]
>> The barrier around
it is cancer cell
that controls remote--
[ Inaudible ]
At least in the beginning, the
cancer cells are encapsulated
and before it ruptures and
spread the [inaudible].
So, the question is whether this
cancer cell can be controlled
by the growth and
[inaudible] by some--
[ Inaudible ]
>> Robert Clarke: So--
>> Tomoko Steen: Could you
repeat the question, sir?
>> Robert Clarke: I will try.
So, I think you're asking, in
part, how does the body respond
to the tumor, or
does it wall it off?
And is there a way to
improve communication
or alter the communication
amongst the cells in a way
that will cause the
cancer cells to die?
So, yes you do see an attempt to
wall off the tumor in some cases
where you see what we would
call a desmoplastic response.
And you see cells
coming in and they try
to change the tissue
dynamics between the cancer
and the normal cells, but
generally it is not successful.
I'm not sure how well
we've been able to manage
that piece as a target.
The other thing though is
that cells do communicate
with each other, and there
are cell-cell contacts,
there are gap junctional
communications, for example.
And there's pretty good evidence
that in some cases the normal
cells, if they conform those
with cancer cells, can slow
them down and stop them.
And cancer cells have fewer
of these gap junctional
communications
than normal cells do.
And there are drugs that
can, in experimental systems,
break that cell-cell
communication,
but I don't think any of them
made it into the clinic yet.
But it's certainly an
area of active research.
I don't know if anyone else
wants to take that one.
>> Tomoko Steen:
Any other questions?
>> Yeah, I got a question here
on this [inaudible] therapy.
[Inaudible] therapy's
good in terms of--
[ Inaudible ]
From the surrounding molecule,
and then it becomes reactive.
But--
[ Inaudible ]
>> Jonathan Lischalk: So,
the question was, how does --
how do antioxidants
play as a role
in decreasing the side
effects of radiation?
Well, the inherent radiobiology
of what we're trying
to accomplish with whether it's
X-rays or protons is DNA damage.
And the DNA damage, if you can
accumulate that in a tumor cell,
tumors are just not --
tumor cells are not
able to fix themselves.
They have a lot of mutations
that basically accumulate
over a time or are inherent
in the cell, for instance,
like the VRCA1 mutation
we talked about earlier.
And they're not able
to repair DNA damage,
and so much of the damage that
we cause with radiation results
in the -- us removing that
cancer cell's ability to divide,
which is an inherent
problem with cancer cells.
And we do that by damaging
the DNA, and when they try
to divide again, they
can't, and they die.
And so, part of the way that
oxygen plays a role in that is
that when a -- whether it's an
X-ray or a proton damages DNA,
if the oxygen is around,
that damage is then fixed.
We call it the fixed body
oxygen, so that it's still there
so that when that
cells try to go on
and divide again,
it's not able to.
And so, it's something
that historically we try
to avoid antioxidants
during radiation therapy
to allow radiation
to be more effective.
Now, as the proton's
traversing through its length,
it's not really -- you know,
it's getting to the point
where it's depositing
[inaudible], its range.
And so, earlier to that,
the dose is much smaller,
and the damage is a lot less.
But, you know, it really depends
on the location of the tumor
and the type of tumor.
>> Tomoko Steen:
Any other questions?
Can I ask a question, actually?
I was told that proton
therapy is not good
for the medicalized cancer.
Is that--
>> Jonathan Lischalk: So, you
know, radiation is radiation,
whether it's X-rays or protons,
it can kill cancer cells,
whether they're [inaudible]
or primary tumors.
Now, the question is, what
are you trying to accomplish?
And in certain situations,
when a patient has a
metastatic disease,
at that point it's stage four.
And really, theoretically, those
cancer cells could be anywhere
in the body, and so the type
of therapy that you would want
to choose is something that
can go throughout the body,
and unfortunately, we can't
just irradiate everything
in the body.
It would be just too toxic.
And so, you know, proton
therapy could be used
for certain situations where
drug therapy is so powerful
that maybe there's
one focus left
that isn't responding
to the drugs as well.
So, I wouldn't say that
it's a very common approach,
but it's certain feasible to do.
And it would -- you know,
that those cancer cells would
respond to the radiation.
>> Tomoko Steen:
Another question is--
[ Inaudible ]
>> Jonathan Lischalk: Well,
you know, the radiobiology
of proton therapy
is challenging,
because we've studied X-ray
radiobiology for many years.
And proton therapy's interaction
with matter is thought
to be maybe 10% more
efficacious relative to X-ray.
So, when I'm doing a radiation
plan with proton therapy,
we're kind of giving it a 10%
increase in its damage effect.
Now, whether that graph
that I showed you early
on where the proton comes in a
lower energy and then deposits
and then stops, the relative
biological effect may be
variable along that path.
And right now, it's an
active area in investigation
to understand if we're
on a different part
of that proton path, what -- how
is it interacting differently?
So, it's a -- it's something
that I think in the next 10
to twenty years we'll be
able to take advantage of.
>> Tomoko Steen: Thank you.
Another question to Doctor
Roy, the [inaudible] actually,
working [inaudible] question
about diet in the cancer
and microbiota relationship.
Do you have any comments
on that?
>> Soumen Roy: Yeah, like a lot
of new research has been showing
that microbiota, like diet
[inaudible] the microbiota.
And, you know, there are
recent studies that show
and that may [inaudible], and
also like in general, you know,
what we eat, it becomes
[inaudible] beside microbiota,
which is very important
to eat [inaudible] to see
like what the body needs.
And then -- you know, because --
and then go for it in
terms of regulating.
And one study show [inaudible]
that the diet also
regulates the hearing loss,
so one of the [inaudible] study.
>> Tomoko Steen: I see.
Very interesting.
Any other questions?
Yeah?
[ Inaudible ]
>> Soumen Roy: So, thank you so
much for asking this question.
This is wonderful question.
So, the question is whether
fasting can impact the efficacy
of toxicity of the therapy.
So, in general, like, you know,
there are a lot of recent terms.
It's called like fasting,
intermittent fasting,
so in the current era like
there's a tendency that we eat
in every four hours, five hours.
And before the body could clean
up or utilize the entire food,
[inaudible] we eat again.
So, the body never get rest.
So, if someone is fasting,
or like it's called
like intermittent fasting, if
there's a gap between one meal
to other meal, at
least eight hours,
that body gains enough
time to detoxify
and utilize all the food.
And there's a study shows
couple of years ago from MIT
that if the mice
they are fasting,
they have more intergenerational
stem cells,
and they are have better varied
integrity in the gut lining.
So, once the therapy's given,
they are like, you know,
causing less toxicity, and
they are more resistant
to the toxicity.
So, the fasting clearly helps
a lot in terms of therapy
and any other aspect
of lifestyles.
>> Tomoko Steen:
Very interesting.
>> Michael Dean: Another
thing you may have heard of,
some of the growth factors
that are important in cancer
or insulin or insulin-related
compounds.
And so, there's some new
therapies coming online
targeting that system, and maybe
they'll work better in patients
where we can lower their insulin
levels during cancer treatments.
And that's also something
we've looked at.
[ Inaudible ]
>> Soumen Roy: You know,
like there is to say--
>> Tomoko Steen: Could
you repeat the question.
>> Soumen Roy: The question
is like whether the --
after the treatment, in case
of best cancer patients,
whether it is becoming
more relevant compared
to like cardiotoxicity, right?
That's what you mentioned.
Yeah, they're like lot of --
not a lot of clinical data
available like, you know,
worldwide which you can
make a conclusion out of it,
but I'm sure like the
doctors can give you more --
better answer.
But in terms of like
hearing loss,
there's a huge heterogeneity
of different treatment and also
like the record of preexposure
of different antibiotics
and drugs that could also impact
the progressive hearing loss.
It's always better to, you know,
like check about the
hearing sensitivity testing,
but [inaudible].
>> Tomoko Steen:
One last question.
[ Inaudible ]
>> Michael Dean: I don't
know a lot of good data.
Typically, you know, marijuana
smokers don't smoke nearly the
quantity that tobacco
smokers do.
I think it's no question that
breathing any kind of smoke
into your lung is not
terrific for your health.
But I don't know of specific
studies showing a clear increase
between marijuana smoking
and lung cancer, no.
>> Tomoko Steen: Anybody?
No? Before I close, I like
to thank my colleague,
Ashley [inaudible] put
the books together.
So, if anybody's interested,
and also she put
together the reference.
This is the Library of
Congress, so please pick it up,
and then thank you so much
for the other speakers,
wonderful panel, and
very informative.
I hope--