Professor Mark Saltzman:
So, what I’m going to talk about today and Thursday is two
topics, which what I hope to do is sort
of bring together some of the information that we’ve been
talking about over the course of the term.
To do that, I want to focus on two areas, today talk about
cancer–a big subject, and so we’ll just scratch the
surface. The main point that I want to
make is how some of the technologies that we’ve been
talking about over the course of the term are having an impact on
cancer diagnosis and care, and to sort of point to some
areas where they’ll likely be more progress and opportunities
for progress in the future. Then, on Thursday,
we’ll do the same thing but talking about the subject of
artificial organs. One that we’ve brushed on a
couple of times through the semester, but just try to spend
some focus time on it on Thursday.
Section meeting on Thursday afternoon, we’ll do a course
review. I’ll be there for each of the
sections. I’ll just be leading a
discussion about what we’ve covered in the course and what
kinds of things will be on the final.
Any questions? You know what’s described
here on this slide, that cancer is a deadly and,
unfortunately, not uncommon disease.
These are some statistics from 2006 collected by The American
Cancer Society. One of the things that we do
fairly well as a nation, now, is keep track of cancer
cases and progress. This has been an important part
of our learning about where cancers occur,
what are the causes and what treatments work and what don’t.
The American Cancer Society has been a big part of that effort
to collect information on where cancers occur in the country,
in what people, in what age groups,
and to provide that information for people that are working on
research for cancer. This just summarizes some
of that information. For 2006, new cases of cancer
you can see over a million new cases, deaths from cancer about
half a million and roughly equal between males and females.
Here’s some common types of cancer occurring in females,
breast cancer in both males and females, lung cancer,
and in males only prostate cancer.
The statistics are alarming. You look at the number of
deaths that are caused by cancer and if you want to learn more
about sort of that, I urge you to go to The
American Cancer Society website which is listed here.
Just a few facts about cancer that you probably know
something about this, it’s now the most common cause
of death in the U.S. and that’s true in many
developed countries. Cancer and heart disease have
been neck and neck in terms of the number one cause of deaths
in developed countries for many years now.
It looks like cancer is winning and we’ll talk about that in a
minute. Cancer’s caused by mutations in
genes that control cell growth. You know that a cancer or
formation of a tumor is an unwanted or uncontrolled growth
of cells. Cell division runs amuck and
cells don’t stop dividing under circumstances where they’re
supposed to. So, you get–a mass is formed
and that mass is–it represents the unwanted growth of cells.
The mutations that cause cancer, that cause these defects
in cell growth, can be either inherited or
environmental. We know that there are thing in
the environment that cause cancer, some viruses can cause
cancers. One of the clearest links is
between human papillomavirus, a sexually transmitted disease
and cervical cancer in women. There is a new vaccine for HPV,
human papillomavirus and it’s expected that this vaccine which
will prevent spread of the virus will also significantly reduce
cancer cases. Other kinds of viruses are
linked to liver cancers, for example.
Chemicals can also, in the environment,
can also cause cancer, and we’ll talk more about that
in a minute. Most cancers also involve some
genetic changes that can be either acquired or inherited.
You know also that cancer can run in families.
The risk of certain kinds of cancers, there’s a genetic basis
for that. In the U.S.,
the lifetime risk of cancer is 1 in 2 for men.
So, half of men will have some kind of cancer,
and 1 in 3 for women. That’s a pretty impressive
number. The age adjusted mortality rate
for cancer is about the same in the 21st century as it was 50
years ago, that is, the rate of death from
cancer hasn’t changed very much in the last 50 years.
This, in spite of the fact that there’s been a lot of attention
to cancer and learning more about cancer,
and its causes, the basic biology and in trying
to design new methods for diagnosing and treating cancer.
But overall deaths haven’t changed very much;
we’ve made progress in certain kinds of tumors but not in
others. This just, I think,
reflects the fact that both cancer is a heterogeneous
disease. You know that it occurs in a
variety of sites throughout the body, but in each of those sites
cancers can be quite different. It’s not one disease but its
family of diseases. Because of that,
it’s been hard to make progress in treatment because all of them
have slightly different characteristics.
This just illustrates that last point a little more
clearly. Change in U.S.
death rates by cause from 1950 to 2003, so over that period
deaths from heart disease went down dramatically.
Deaths from cerebral vascular diseases, so deaths of the
circulatory system in the brain, so this is mainly stroke and
aneurisms down dramatically. Deaths from infectious
diseases, we talked about vaccines several weeks ago which
has a big impact on mortality from infectious diseases,
also down over that years. Deaths from cancer stay about
the same. While we’ve made great
progress, we’re not yet at the point where we’re changing the
outcomes from cancer very dramatically.
I mentioned a few minutes ago that exposure to chemicals
can cause cancer, and you know this.
One of the most well known exposures that’s clearly a cause
of cancer is tobacco use. This is tobacco use mainly
thinking about cigarette smoking, but the same thing
could be true of any kind of tobacco use.
Smoking in other–cigars or chewing tobacco also causes
cancer because the chemicals in cigarette smoke or in tobacco,
in particular. Some of the tars that are
associated with smoking cause cancer of the lung in
particular. This was first noticed by
looking at epidemiological data. We talked about public health
and epidemiology a few weeks ago where you look at how diseases
appear in populations and you try to figure out why things are
changing. Here’s as cigarettes were
consumed more in the U.S., you can see the trend in
cigarette consumption going up over time from 1900 to 1950.
Then, lagging behind that by about a period of 30 years,
is a dramatic increase in lung cancer.
First among men and then among women, and the reason for that
is because cigarette smoking was initially more popular among men
than among women, but advertising and the women’s
movement changed that. Cigarette smoking became
something that everybody could do.
It was acceptable in polite society for women to smoke,
and they were targeted by manufacturers of cigarettes.
Special cigarettes were made for women, they’re special in
some way but not in their ability to cause cancer,
they’re all the same and so female lung cancer still rising.
You can see we’ve made progress in male lung cancer,
mainly by reducing the number of smokers, but that hasn’t yet
happened in women. Evidence first came from
epidemiology but then after it was realized that there was an
association between cigarettes smoking and cancer.
Then, you can start to look more closely and try to figure
out what the molecular cause of it is.
We now know quite a lot about how the chemicals in smoke
cause these sorts of malignant transformations in cells that
lead to cancer. The evidence is pretty clear.
The main point that exposure to chemicals can cause cancer.
This just to try to put in perspective where cancer occurs,
what are the most frequent causes of cancer that lead to
death, and in both men and women,
lunch cancer is number one. After that it changes the top
three in men being lung, colon and prostate;
in women lung, breast and colon and accounting
for just those top three, the large majority of cancers.
Cancer of the pancreas is much less common but because it’s so
difficult to detect and we’ll talk about methods of detection.
The pancreas is an organ that’s deep within your body and it’s
hard to find when things are going wrong with it.
Because it’s difficult to detect cancer of the pancreas it
very frequently leads to death, and of course this is in the
news now because this is the kind of cancer that Patrick
Swayze has. Life expectancy when you have
pancreatic cancer is–life expectancy is very low because
it’s usually in an advanced stage when it’s discovered.
Cancer cells are different, so what makes all these cancers
at different sites similar is the similar characteristics that
the cells that form cancers have.
I mentioned already that one of the things that characterizes
cancer is that cells divide abnormally.
They divide, usually, more rapidly.
We talked about, several weeks ago when we were
talking about cell culture, we talked about cells that you
would isolate from tissue and they would grow at a rate of
about by doubling their number everyday if you maintained them
in culture. Cancer cells can grow much
faster than that so they have mechanisms for dividing very
rapidly. More importantly probably,
they don’t stop proliferating when they’re supposed too.
You know, from what we’ve talked about before,
that there are cells that are continually dividing and
reproducing within your body. Cells in you intestinal tract
for example, cells in the liver, cells in the kidney continually
dividing, cells in your skin. But ordinarily your skin stays
the same size that it is because are cells are dividing but they
know when to stop. They stop when they reach the
right density, the right shape,
they know where they’re supposed to be.
Cancer cells don’t, they continue to divide even
when they get signals that they’re supposed to stop
dividing. Because of this tumors form,
abnormal growths–the organ of–origin becomes larger than
it ordinarily would. They generally don’t
respond to signals that are provided by neighboring cells,
we talked about cell communication and how important
that was for the life of a tissue.
For your liver to be your liver and your brain to your brain,
they don’t just have the right cells there but they have cells
that are communicating in the right way.
There’s a loss of that normal molecular communication when you
have cancer. They don’t differentiate
normally but tend to remain as immature de-differentiated or
undifferentiated cells. What’s this like?
This is like we talked about stem cells, stem cells are less
mature than differentiated tissue cells.
They grow rapidly; both stem cells which
self-renew and cancer cells. They don’t form mature types of
cells and there’s a lot of linkages know known between stem
cells and cancer. Some people think that within
any individual tumor, there are cancer stem cells
that really are the most important ones to treat.
If you get rid of even the bulk of cancer cells without getting
rid of these very stem like cells in cancers the tumors will
regrow again. So, normal differentiation
like stem cells is a problem with cancer cells.
They don’t adhere readily to other cells and extracellular
matrix, they do not become specialized and die.
Because cells in your skin are continually going through not
just birth, not just growth of new cells but death.
There’s skin cells that are dying and being shed from your
body all the time. Cancer cells don’t undergo
those normal processes of cell death that lead to regulation of
tissue structure. If a cancer forms,
it tends to go through different stages and that this
cell, for example, in this tissue is a
pre-malignant cell. If it becomes malignant,
it will start dividing and growing out of control and you
can see that here. That tumor that forms at the
initial site or the site of the origin of a cancer is called the
primary tumor. These tumors,
if they grew, would ordinarily stop at a size
of about one millimeter, very small.
You wouldn’t even be able to notice them, maybe,
if they’re only a millimeter or so in size.
They don’t grow beyond that as a cell mass because they can’t
get nutrients, oxygen, glucose,
the things that the cell needs, amino acids.
The things that it needs in order to produce new cells can’t
get in because those are normally provided by the
bloodstream. When the cell is just dividing
out of control there’s no blood supply.
Many people think that tumor size would be limited.
Cancer wouldn’t be such a problem, except for the fact
that cancers at this stage, as they move from this primary
stage to invasive cancer, they develop an ability to
stimulate the growth of blood vessels So,
now you can see blood vessels are growing into and through
this tumor, they develop their own blood supply.
They’re able to get nutrients readily, and this is when the
growth of the tumor really starts to take off.
We’ll talk about some therapies that block this process of new
tumor growth called angiogenesis.
Many people think if you could block that process selectively
in tumors then you could halt all tumors to a very small size
that would not cause problems. An additional stage after
angiogenesis that some tumors can go through is a process
called metastasis. That’s where tumor cells
actually leave their site of origin and travel to other
places in the body. That’s shown schematically in
this cartoon here. A tumor cell entering the
circulation, it can flow through the circulation,
and maybe get lodged at some distant site and begin the
process of tumor formation at that distant site.
This is obviously a bad thing because maybe you can treat the
primary tumor in a variety of different ways which we’ll talk
about in just a minute. Once it begins to spread
throughout the body becomes much more difficult to treat.
You have not just one tumor, but potentially hundreds or
thousands of tumors that are forming throughout the body. The treatment for
tumors–for cancer–depends very much on what stage it’s at when
it’s identified. For every kind of cancer
physicians, oncologists, have developed classification
methods for talking about, to each other,
about what stage the cancer is at.
I’ll just show you that in an example of that in bladder
cancer. You might have an initial stage
here which is called TA. T is the tumor rating,
T for tumor. This is a very small tumor
that’s just confined to the lining.
When it gets larger it’s classified as T1.
When it gets up to stage T2 it’s starting to invade from the
lining of the bladder into the other tissues of the bladder,
T3, T4. By the time it’s got to stage
T4, it’s occupying not only the whole thickness of the wall of
the bladder but it’s started to invade other tissues like the
prostate as well. You can see that if you
have a tumor that’s at one of these early stages,
local therapy might work; surgery or radiation,
or local chemotherapy which we’ll talk about.
As it begins to invade other organs, then it becomes more
difficult to treat. They can spread and I don’t
mean for you to–tumors can spread, and I don’t mean for you
to be able to see all this here but you can look at this,
these slides will be posted as usual.
Not only can you classify the normal–the original site of the
tumor and that’s classifications of melanoma from T1 up to T4 and
they’re defined here, but you can classify whether it
has spread locally to lymph nodes.
That’s these end stages here, and whether it has metastasized
to different sites. Ordinarily, a physician will
classify a tumor according to the tumor nodal involvement
metastasis classification that’s appropriate for that kind of
tumor. This allows physicians to
say exactly where your cancer is at in development.
We know, because we’ve been treating cancer for a long time
now, you can select a treatment that’s most likely to work for
the stage that it’s at. This, all to say that
diagnosing specifically where a cancer is at in its development
within a patient is very important for deciding what kind
of a treatment is likely to lead to a good outcome.
One of the things that biomedical engineers have worked
very diligently on over the last 50 years or so is designing new
methods for cancer diagnosis. We’ve talked about some of
these as we’ve gone through the course and I just want to
highlight them here. We talked about X-rays and
using X-ray radiation to look inside the body.
Mammography is a special kind of X-ray imaging that’s used to
look just at the breasts to see if there are abnormal tissues
within the breast. This shows a normal mammogram
and this shows a mammogram with some kind of a dense deposit
here that’s not normal. Mammography is used to screen
for breast cancer and it’s a very important screen.
Now women, when they reach a certain age, are recommended to
have mammography a certain number of times per year or per
decade just to try to detect cancers at an early stage.
This is an example of biomedical engineering for
diagnosis. Pap smears also done during
routine pelvic exams in women, where a swab is used to remove
some cells from the cervical region.
Then you can look at these cells under the microscope and
here’s what a normal Pap smear would look like.
You can see the cells are flat, they have small nuclei,
not a lot of protein and so the cells don’t stain very darkly.
Malignant cells, on the other hand,
cells that indicate there might be cancer present have larger
nuclei, more intense staining, abnormal shapes.
So, someone who looks at cells from cervical Pap smears all the
time can quickly tell if there’s the danger that there might be a
tumor growing within a patient who’s had a smear like this.
Now, this requires a visit to the office and a procedure;
wouldn’t it be nice if there were blood tests that you could
do for cancer? Of all the technologies we
talked about; we talked about ELISA’s for
example and all the ways that we can look into the blood to try
to see what chemicals are present there.
If you could find chemical signatures of cancer that could
be detected in blood, or in urine,
or in some other fluid from the body, that would be a great
there aren’t too many examples of that yet.
We don’t know how to do that very well.
We do know for prostate cancer and for certain other kinds of
cancers there are molecules that you can detect in the blood.
In prostate cancer there’s a very particular molecule called
prostate specific antigen, PSA.
If the levels of PSA rise in your blood, that’s a sign that
there’s something going wrong in your prostate and you get a more
thorough exam. Blood tests are available but
only for certain kinds of cancers and they’re not widely
available yet, although we would like for them
to be. If you have a high–if
you’re a male and you have an abnormally high prostate
specific antigen level in your blood,
you might get a more thorough examination and you might
use–and your physician might use an approach like ultrasound
guided biopsy. Here, if you can see in this
diagram here, this is a much less pleasant
experience then a blood test but there’s a device that’s inserted
through the rectum up to close to where the prostate is.
This device has an ultrasound probe on it.
You can look by ultrasound into this region of the body,
identify where the prostate is, and even where a growth on the
prostate might be and then a needle comes out from this
device and takes a small sample of tissue.
This tissue is then taken to the laboratory and looked at in
the same way that a Pap smear might be looked at.
We talked about using optical microscopy or using
optical instruments to probe inside the body into cavities
that we can’t see. There’s lots of technology
available for this now, including sigmoidoscopes and
colonoscopes, which are fiber optic systems
that can be inserted into the colon.
Can be–if they’re designed properly, inserted very far up
into the colon to actually let you look through a lens at
what’s happening on the surface of the tissue.
This has been a very important advance in terms of identifying
cancer of the colon, for example.
Similar scopes are available to look in the lung for lung cancer
and to look in a variety of other sites in the body to look
for cancer and other diseases. A lot of engineering technology
has been brought to bear on the problem of diagnosing cancer and
diagnosing cancer early. What do you do if a cancer
is present? Well the–arguably the oldest
form of cancer therapy is surgery.
Surgery is used for biopsy to take small samples to see if a
growth, for example, is abnormal.
If you have an abnormal growth on your skin,
the surgeon might cut off some of that tissue and send it to a
laboratory for analysis and to find out if it’s cancer or not.
Also used for looking deeper in the body, surgery is.
Surgery is used for prevention of cancer.
If you have abnormal growths called polyps in the colon,
a surgeon can remove those polyps and prevent them from
progressing into a more serious disease.
Polyps on their own aren’t necessarily cancerous but they
can develop into cancer, there’s an association with
that. So, why not remove them
surgically before they have the chance?
Surgeries often remove–used to remove local tumors in the lung,
in the brain, the colon, the prostate,
so surgery is a well established form of cancer
treatment. Radiation can also be used
to treat cancer. This relates to the subject of
imaging that we talked about several weeks ago.
We talked about using electromagnetic radiation
because it can penetrate into the body and using that to take
pictures of what’s inside. But we also talked about forms
of radiation that had biological effects.
We talked about ionizing radiation, for example,
and ionizing radiation can cause changes in the body.
This is radiation that’s on the high frequency,
short wavelength end of the electromagnetic spectrum.
So, X-rays or gamma rays, high frequency,
small wavelength. They can penetrate through
tissues very easily and they can interact with atoms and nuclei
inside of the molecules inside your body.
Ionizing radiation, these forms of high energy
radiation have biological effects.
We talked about one of those effects is that they can cause
the ejection or the deviation of electrons on atoms within the
skin. These change,
these ionizations that occur as a electrons are ejected from
atoms within the skin, can cause cell damage.
This kind of ionization is happening all the time.
You go out in the sun and radiation impinges on your skin,
it causes some damage. There are forms of ionizing
radiation present at low levels in the environment around us,.
Ordinarily that causes no problem because the cells in
your body are able to repair damage.
You have repair mechanisms, either by producing new cells
or by repairing the DNA that gets damaged in cells,
you can recover from the damage that happens.
But if radiation continues to be delivered to that tissue,
you can overwhelm the body’s ability to repair itself.
You can actually cause sections of tissues or cells within
sections of tissues to die, and that’s the basis for
radiation therapy. This graph which is–which
describes an experiment that was done many decades ago,
shows how radiation can be used to kill cells.
This axis here shows a dose of radiation that’s delivered to
cells in culture. Radiation is focused on a Petri
dish that contains cells and then you expose them to some
amount of radiation. The dose of radiation is going
up as you move this way. Then, you look to see how many
cells survived that procedure, how many cells survived this
dose of radiation. Let’s look at a dose of 6 Gy
here, Gy is a radiation unit called the Gray.
At this dose of Gy’s, if you move up this scale here,
you’ll kill all but .001 fraction or .1% of bone marrow
cells. You would kill most of the bone
marrow cells that were exposed by radiation of this kind.
You would kill about 90% of cells from the breast,
and you would kill even less of these other kinds of cells here.
That illustrates another point, that cells have different
sensitivities to radiation. If you know something about the
type of cells you’re trying to treat by radiation,
then you can adjust the dose that you give so you’re killing
only the ones that you want. Some cells are always going to
be susceptible. Cells of the bone marrow,
for example, very susceptible to radiation.
How do you avoid that problem? That you want to kill cells of
the tumor but you don’t want to kill cells that are also
sensitive to radiation in other parts of the body?
You do that by just focusing the radiation on the site that
you want. You do it by localizing where
the radiation is delivered. So, biomedical engineers
and physicists have developed methods for external beam
radiation. These are devices that look
somewhat like the imaging systems we talked about several
weeks ago. They’re delivering high doses
of ionizing radiation and you can see that perhaps that this
thing is on a cradle that swings back and forth,
and there are lenses in here to focus the radiation.
The physician can move it to whatever site that he wants in
three dimensions and focus the beam so it hits only the tissue
that you want to expose to radiation.
These techniques depend very much on computers and on
mathematical models of what the tissue looks like inside your
body, they’re guided by imaging
methods, but the idea is to deliver only radiation at the
site that you want too. Can you do a perfect job?
No, but you can do a pretty good job in focusing the
radiation at the site that you want.
This is described a little bit more in the chapter in your
book. Another way to get
radiation delivered only where you want is to put the radiation
source inside the body in the location you want and that’s
called Brachytherapy. This is an example of a
prostate tumor that’s filled with what looked like little
stars, or little bright dots. Each one of these bright dots
is a small metal seed that’s filled with a radioactive
material. Those are implanted physically
in the tissue, and then the tissue around it
is exposed to radiation. It’s a special kind of
radiation that only penetrates a certain depth in the tissue.
As it penetrates, it delivers ionizing radiation
to all the cells around it. You can see these small seeds
are arrayed throughout the tissue so that you can treat it
as uniformally as possible. So, radiation can be used to
treat tumors. Another thing I wanted to
show you on this slide here is that some cells can be made to
be more sensitive to radiation and they ordinarily are.
That example is shown here with these human cells that have
been–well, that they lack the normal DNA repair mechanisms.
Cells that lack DNA repair mechanisms, if you expose them
to ionizing radiation; they’re much more sensitive
because they don’t have the mechanisms to repair sub-lethal
damage. One important area of research
is trying to find drugs that you can deliver that will accumulate
in tumor tissue to make them more sensitive to radiation,
which you then deliver in the ways that I’ve described.
There are a variety of different approaches that are
under study here for delivering radiation more carefully,
more selectively, to specific regions of the
body, and to design drugs or other strategies to make tumors
more sensitive to the radiation you deliver.
You know about chemotherapy. Again, this is a slide that I
don’t intend for you to be able to read on your–in your
leisure, you can look at the slide when
it’s posted and just gives you some idea of the breadth of
knowledge that we now have about chemotherapy drugs.
There are many different classes of drugs that have been
developed and studied and employed for treating cancer.
Most of these drugs work in a similar fashion,
by interfering with DNA, or by interfering with the
mechanisms by which cells repair DNA so that you can halt cell
growth. If you crosslink all the DNA
inside of a cell it can’t synthesize any more DNA.
Then, it can’t divide and proliferate and that’s the basis
of action for many of these, although not all,
so I’ll let you look at those at your leisure.
One of the problems with chemotherapy is that these drugs
have effect not only on tumor cells but they have effects on
normal cells. If you deliver chemotherapy
throughout the body, not only do you have an effect
on the tumor, an effect that you want,
but you have an effect on other tissues.
In particular, the kinds of tissues where cell
growth, controlled cell growth is an important part of their
physiology; the intestine,
the bone marrow, your hair, skin.
Patients who have chemotherapy often get digestive problems,
severe digestive problems. T hey get anemia,
or infections because they’re not producing cells in their
bone marrow anymore. They lose their hair because
hair is produced by cells that are dividing,
in the skin. They get rashes and other skin
symptoms because their skin isn’t repairing and remodeling
in the normal way, you know this.
One concept that has emerged over the last 10 years
or so is to deliver chemotherapy drugs locally instead of
delivering them over the whole body.
I gave you this example from my own research lab a few weeks ago
when we were talking about drug delivery.
Just to remind you, here’s a situation where
there’s a tumor in the brain. This can be treated by surgery,
and in this case the surgeons were given drug delivery
systems. These were degradable polymer
wafers that were filled with high concentrations of
chemotherapy. In the operating room,
after they removed the tumor, they can place these drug
delivery systems in the brain. The patient leaves the
operating room with most of the tumor removed,
and with high dose chemotherapy delivered locally over a long
period of time after they leave the operating room.
This should remind you of the Brachytherapy we talked about a
few slides ago. Instead of depositing a dose of
radiation in here, we deposited a dose of drugs.
Deposited it in a way that these drugs could be released
slowly over time, and hopefully locally kill any
residual tumor cells that are remaining.
One of the most impressive, important and exciting new
developments over the last 5 years has been the development
of new chemotherapy agents that work by mechanisms of action
that were not known previously. This is an example of modern
biology and our understanding of cancer biology,
in particular, leading to the design of drugs
that are more specific to cancers,
because they take advantage of mechanisms that only cancer
cells typically use. One of those is a drug called
Gleevec. Remember in the 4^(th) week of
the class we talked about cell communication.
We talked about signal transduction and how messages
get from the outside of a cell into the inside of a cell.
We talked about how important a class of signaling molecules
called tyrosine kinases were to creating intracellular signals.
Well, it turns out that certain kinds of tumors you use
a special tyrosine kinase called BCRABL and that that tyrosine
kinase can be inhibited by a drug that was designed to
inhibit it, called Gleevec.
Now, this is one of the first examples of what’s called
rational drug design, in that biologists have
identified this particular tyrosine kinase.
They knew it was involved in signaling inside certain kinds
of cancers, in particular, a certain kind of lymphoma.
They studied this molecule in its molecular detail and
developed a drug, now called Gleevec,
that would interfere with the action of that molecule.
Interfere only with the action of that molecule and not all the
other tyrosine kinases that are important for healthy cell life
in the rest of your body. This drug prevents kinase
activity; it does it by blocking the
binding site for ATP. Remember that ATP was a second
messenger that kinases use in order to phosphorylate protein.
This is an exciting example because it’s the first–one of
the first examples of rational design of a drug at a very
specific molecular target inside tumors.
Now, unfortunately, it’s limited.
Gleevec is limited in its use to only a couple of subclasses
of tumors that express this tyrosine kinase at high
concentrations, but I think the idea of it is
one that can be translated outside.
Another new drug that’s been developed in the last two
years is called Herceptin. Now, Herceptin is unique in a
number of different ways. One is that it’s an antibody,
and we talked about the role of antibodies in the immune
response several weeks ago. We talked about how vaccines
are often designed in order to get your body to produce
antibodies to an infectious disease.
So, you’re familiar with the concept of using antibodies to
neutralize pathogens. Here’s an antibody that was
designed to bind to a receptor that appears only on cells in
breast cancer. This receptor is called HER2;
it’s a form of a growth factor receptor that is particularly
highly expressed in some kinds of breast cancers.
If you deliver this molecule Herceptin,
it’s an antibody which binds to this receptor and prevents its
normal function. Its normal function is to
signal breast cancer cells to grow.
When this antibody binds, it shuts off that growth signal
that the breast tumor cell is getting from this receptor.
It also promotes the immune response to the tumor.
You can imagine if this is a breast cancer cell that has lots
of these receptor molecules on the surface and now you put in
an antibody, you deliver an antibody which
gets coated on the surface, now this surface is
tagged–this cell is tagged for recognition by your immune
system. The immune system can develop a
response to this tumor as well. These are both exciting new
potential therapies for cancer. They’re real therapies for some
cancer, but point the way towards more broadly applicable
methods that might be used to designing chemotherapy agents.
The problem is that it takes a long time and a lot of money,
and a lot of effort in order to get from the point where you
design a new chemotherapy drug to the point where it can be
used in patients. I thought I would end this
lecture by just reviewing a little bit about that process
and try to get you a sense for why,
in practical terms, there haven’t been more drugs
developed for cancer over the past several decades.
The process occurs in steps and I’m going to look at it over
a time scale of about 20 years here.
It involves both testing in vitro, testing in test tubes
in the laboratory. Testing, often in cell
cultures, to look for drugs that have properties that you think
might make them useful cancer. Usually from the time that you
think about a drug, I have a drug,
say drug X and I think it might inhibit this signaling pathway
in colon cancer. So, what do I do first?
I get some colon cancer cells, I expose it to the drug,
I see if it works in culture. This is all called the
discovery phase. The next stage I might do if I
find that my drug works well in cultured cells and I’m starting
to uncover the molecular mechanisms and how it works,
is test it in animals. I might take animals that have
colon cancer and try to treat them with a drug.
This is still in discovery and this is a phase that–called
animal testing. Now, you begin to refine
your approach. You begin to refine your
approach such that you’re starting to test not only for
the activity in animals because you find that,
‘Yes, your drug X does–is an effective treatment for cancer.’
You trying to think about what’s the optimal dose,
how much dose would I need if this worked the same way in
people. You start testing different
aspects of it in animals in preparation for testing in
people. That’s called,
that first step in vitro is called lead discovery.
My lead drug is X, this is a promising lead that
I’m following, and in animal testing you do
lead optimization. All of this takes a long time,
could take 4 years from the point that you think,
‘Maybe this drug is good,’ to, ‘Yes I’ve shown that really is
effective in animals.’ Then, a process of clinical
testing happens, and the clinical testing occurs
in phases. In order to do testing
clinically, you have to be approved by the government to do
that. In this country an organization
called the Food and Drug Administration,
the FDA, is the only one that can give
you approval to take–to test an experimental medicine in people.
They do that because you file an application called an IND or
Investigational New Drug application.
They look at all the data you’ve collected over the last
four years and they say, ‘Yes you’ve convinced us that
this looks like a good drug, it looks like it’ll be safe,
you can go ahead and start testing it in people.’
You first do small studies, you deliver to a few people,
usually not people that have disease, but people that don’t
have disease. You deliver it in small doses
and you slowly increase the amount of dose that you give
them. What you’re looking for here is
not effectiveness of the drug but you’re looking for safety.
Is it safe? What dose do I begin to see
side effects? This allows you to narrow in
the range that you’re going to use in people to test this drug
for its effectiveness, that’s called Phase I.
Phase II, you start to look in patients that have the disease
in a small number of patients, to just look to see if the drug
is effective or not. Phase I, you’re asking whether
it’s safe, in Phase II you’re asking if it’s effective in the
patients that you would like to use it in.
You do that in a small number of patients first just because
this is the first time it’s been used to test effectiveness in
people and you’re not quite sure what’s going to happen.
So, you do it in a small number of patients just to show that it
works the way that you want. If it does work the way you
want you start Phase III which is a very large clinical study
that is in the number of patients you need to show that
it is effective at treating the kind of cancer you want.
How many patients are involved in studies like this?
Well, it could be hundreds, could be thousands.
Depends on the disease, how prevalent the disease is,
what the normal course of the disease is,
and how many patients you need to look at in order to be
absolutely sure that you saw an effect that wasn’t just due to
chance. These are very complicated
studies to do, and hence very expensive.
Remember when we were talking about vaccines,
we talked about a Phase III study of the polio vaccine that
was invented by Jonas Salk. How many patients were involved
in that clinical study, does anybody remember?
How many patients were involved in that Phase III clinical study
of the polio vaccine? Who could remember that?
I remember; 1.8 million eight year olds
were involved in that study, so clinical studies can be
huge. In the case of an infectious
disease, it’s particularly a large number because you need to
deliver it to enough people to see–a vaccine,
to see that you’ve changed the incidence of disease within a
population. In cancer trials,
they tend to be hundreds or thousands in size.
If this Phase III trial works then you’re allowed to
sell the drug. The FDA gives you permission to
sell the drug, and for physicians to prescribe
it. The study doesn’t end there,
in that all manufacturers of drugs are required to keep track
of what happens as their drug is introduced into the population.
This is called Phase IV, as physicians start using it to
treat cancer they’re required to look at how these things work.
You will have noticed, in the newspaper over the past
few years, some very famous drugs that turned out to have
side effects that weren’t expected after they were
released into the general population.
Once it starts being used by physicians all over the country
in many, many more patients sometimes rare side effects
appear that we didn’t expect before.
So, one continues to do research and study even after
that. The challenge for drug
companies is that this takes a very long time,
it takes a lot of money. There’s lots of places where
your drug can fail. My drug X, which I described as
going neatly through in vitro studies,
animal testing, clinical testing might have
stopped working at some stage. I might have found some problem
with its safety when I started testing it in human volunteers.
I might have found that it didn’t work as well in animals
as I expected it too based on in vitro studies.
People estimate that for every 10,000 compounds,
10,000 X’s that are thought of in laboratories,
only one of them eventually gets approved by the FDA.
This is why drug development costs so much money in this
country, because you have to look at a lot of compounds and
test them pretty extensively to find the one that’s really
useful for treating disease. I don’t think we want to
change that, because this process of FDA approval was
introduced early in this century when people were selling drugs
out of the back of covered wagons and moving from town to
town. They’re called snake oil
salesmen or other things. People could sell anything they
wanted and claimed that it treated a disease.
Now, we have a very highly refined system for asking people
that are going to sell drugs to prove that they work,
but that system costs a lot of money.
There are opportunities, I think, for biomedical
engineers to improve how this works by designing better
methods for in vitro study.
By using techniques we talked about, like in cell culture
early on, to use those techniques more efficiently,
to discover and test properties of drugs.
So, this is going to be an area where I think there is lots of
growth and opportunities in the future.
Just in closing, I just put this website up
there; it’s from Science Magazine
which is a very high-profile scientific journal.
They published a poster which is available online that talks
about sort of modern developments in cancer diagnosis
and treatment. I put a few sort of snapshots
from that poster into the Power Point presentation which will be
available. I encourage you to go to this
website and look at this information.
You can find out more about what are the sort of exciting
pathways for the future in biomedical engineering and
cancer treatment. Great, so I’ll see you on