While she's writing that up, I also wanted to clarify a point
that was raised by a TA last time at the end of last lecture.
Some of you might have thought about this fact,
and it's important to clarify at least as best we can.
I told you last time that people who inherit a defective copy of the RB,
retinoblastoma tumor susceptibility gene are highly predisposed to the
development of retinoblastoma, a tumor of the eye. Actually, these
patients end up getting bilateral retinoblastoma,
affecting both eyes, and typically have about a dozen
tumors, independent tumors. And, if you recall,
those tumors arise through the loss of the normal copy of the RB gene in
the cells that give rise to these tumors. And I also told you that
the RB gene is a critical regulator of cell cycle progression.
And so you might have wondered why don't these people get all sorts of
tumors? Why are they predisposed only to retinoblastomas?
Why not breast cancer, lung cancer, pancreatic cancer and
so on? We don't actually know in complete detail why that is,
but we suspect that there's a fundamental difference between
retinal cells and other cells with respect to their requirement for RB
gene function. So I told you previously that RB is
a regulator of the cell cycle. Specifically it regulates the entry
of cells from the G1 phase of the cell cycle into S phase.
It blocks. And it has to, itself, be inactivated for tumor
development. Or rather for normal cell cycle
progression. An we think that in retinal cells this is the key
regulator of S phase progression, of S cell cycle entry, so that if
you get rid of it you now have deregulated cell cycle control and
tumor development. And we suspect that in other cells
where RB is almost certainly important --
-- there are probably other factors,
let's call them X, which can also regulate cell cycle progression.
So that even if the cell were to lose RB, there are other factors
that can, in a sense, back it up. And in these cells,
in most of your cells, although RB loss might contribute to tumor
formation, it's not sufficient. In these cells other events must be
necessary to inactivate, one way or another, these X
functions. OK? So hopefully that helps clarify.
Now, I told you last time, the last two times that we now think
of cancer as a clonal progression from normal cells to tumor cells.
The acquisition of mutations in cellular genes,
oncogenes, tumor suppressor genes, and collectively these give rise to
cells that are malignant and potentially life-threatening.
This is interesting information from a scientific point of view,
but is it useful? Why do we want to understand these cancer-associated
genes? Why do we want to understand these
mutations? Well, there are a variety of reasons why.
We're going to focus today on therapy which is directed against
the mutations that arise in cancers. But there are other purposes that I
just want to mention to you.
Early detection. Cancer is most easily treated when
caught early. If we know somebody has cancer, before the cancer has
spread, they have a much better chance of curing that individual.
And so it's desirable to have tests for early detection.
And increasingly there are PCR-based tests looking for cancer
cells in bodily fluids. Sometimes the blood, urine or other
tissues. PCR-based tests looking for mutations in the
cancer-associated genes, looking for cells that have a Ras
mutation or have a p53 mutation or have an RB gene mutation and so on.
So this is not commonplace, but there are now tests,
commercially available tests that are based on PCR looking for such
mutations. There are also blood tests for what we call
cancer markers. You've probably heard of the PSA
test for prostate cancer. There are certain other tests for
other types of cancer. These are blood tests that detect
inappropriate levels of something, often something produced by the
cancer. And, again, increasingly, as we understand what
happens in cancer cells, we'll have more and more precise
cancer makers that will be detectable in the blood in a very
simple screening test so that you can go to the doctor every year,
go through one of these tests and know whether or not you have an
early form of one or another type of cancer.
That's not, again, happening today, at least in a
widespread way, but it will happen in the years to
come. And when it does, we will be in a position to do what
we call cancer prevention. Rather than waiting until somebody
has a full-blown tumor and trying to treat it, which is difficult,
we will hopefully detect those tumors at a very early stage and
then prevent their progression. So this is not treating cancer
really, but treating the hyperplasias I told you about.
Or early lesions,
benign lesions before they progress to true cancer.
And we think that this will be easier to do because those cancer
cells will have acquired fewer mutations. And,
therefore, it will be easier to design very specific agents that
will effectively limit their proliferation or possibly
even kill them. OK. Today we're going to focus on
the use of this information for better therapies,
ways to design more effective, more specific anti-cancer agents.
And I'll come towards the end to using this information and related
information to do better diagnosis to try to distinguish two people who
have clinically similar tumors. But those tumors might actually be
quite different at the molecular level, and we'd like to understand
that. OK. Before we get into sort of the New Age cancer treatments,
I thought I should at least mention to you conventional therapies.
Right now, if you have to have
cancer treatment, you might get one of the drugs that
I'm going to tell you about later in the lecture, but more likely you're
going to get what we call a conventional anti-cancer treatment.
And these anti-cancer treatments have actually been around for quite
some time, and they do work. They do work, but they don't work
as well as we need them to work. Radiation is a very common
anti-cancer agent, as you probably are aware.
And there are a variety of drugs that we list along with radiation
like Adriamycin, Cisplatin. And there are a variety
of other chemical agents, which together are grouped because
they cause DNA damage. These are DNA damaging agents,
and they're also effective anti-cancer agents.
There's another category of anti-cancer agents which is
exemplified by a drug called Taxol, and there is a series of
Taxol-related compounds. And these are microtubule
inhibitors. Microtubule inhibitors. And these therefore, microtubules
are important in mitosis, if you'll remember the mitotic
spindle. So these are anti-mitotic drugs.
And these drugs do work.
And we think that they work in part because cancer cells are rapidly
dividing cells compared to most normal cells in your body.
And, therefore, if you damage their DNA or you block their ability to
divide you'll more effectively block cancer growth compared to
normal cell growth. Now, overall, in the context of
cancer, what we're looking for, and actually in the context of other
diseases as well is something called a therapeutic window.
A therapeutic window is defined as a difference in the concentration of
a drug necessary to kill the cell of interest versus normal cells in the
body. These drugs, anti-mitotics and DNA damaging
agents will kill normal cells. So if you look at a graph of percent
killing versus drug concentration, normal cells will eventually die.
The hope is that cancer cells will die sooner. And this difference is
defined as the therapeutic window.
And that does exist for many of these drugs for many different types
of cancer. And so these agents will, in fact, give initial responses.
Unfortunately, they tend not to be, tend not be durable. That is
patients tend to relapse. Not always but tend to relapse in
response to these agents. This slide just makes the same
point that many of the drugs that we know about affect the cell cycle
either in S phase during DNA synthesis or in M phase
during mitosis. And this also points out that many
of these agents cause the death of cancer cells by inducing apoptosis,
inducing the death of cells. In contrast to most,
but not all, most normal cells in the body, which in response to that
same concentration of drug, will not die. And instead those
cells will arrest at some point in the cell cycle and repair
the damage. And the difference,
what makes up the therapeutic window in many cases,
is that the cancer cells are dying at a given concentration,
the normal cells are staying alive and simply arresting.
However, there are other cells in the body that in response to the
same drug at the same concentration will undergo apoptosis.
And you actually know what those cells are if you've thought about
cancer chemotherapy before. It's the cells that support the
hair follicles. Those cells die in response to these
drugs. And that's why cancer patients lose their hair.
It is cells in the blood, in the bone marrow which will die in
response to these concentrations. And that's why cancer patients get
anemic. And in cells of the lining of the stomach and intestine which
will die in response to these drugs. And that's why cancer patients feel
sick, feel nauseous. So there are side effects in
response to these drugs. And that's because many cells,
some cells in your body will also die by apoptosis.
Now, we've learned, actually my lab has participated in
this process, that the p53 tumor suppressor gene that I've told you
about is actually quite important in guiding the responsive cells to
these drugs. Many normal cells turn on p53 in response to this damage
and arrest. Those other cells that I just told you about will
turn on p53 and die. And cancer cells,
likewise, if they have a functional p53 gene will turn it on.
And this will induce apoptosis. And it's the difference between
cancer cells turning on p53 and dying compared to normal cells
turning on p53 and resting, it gives the therapeutic window.
Unfortunately, as I've mentioned to you, about 50% of human cancers
carry p53 mutations. And given that p53 is important in
this response, if you don't have p53 then you won't
die, or won't die as effectively, and that limits the therapeutic
window. And this is one of the reasons why
cancer therapy is not as good as it should be and why cancer cells will
sometimes come back, because they're now no longer
responsive to the drug, at least especially responsive to
the drug. So we'd like to do better, and we think we can do better by
taking advantage of the information that we've gained over the last 30
years about cancer-associated mutations.
And I'm going to review for you in detail the first three of these new
agents, all three FDA approved in the last five years or so for the
treatment of one or another type of cancer. And I'll also mention
anti-Ras therapies, although we don't have an FDA
approved drug for those. If there's time I'll mention
inhibitors of an enzyme called telomerase, as well as
anti-angiogenesis. There are other therapies,
not drug-based therapies but other therapies that are under
consideration, and in some places in use.
Gene therapy, replacing cancer mutation genes.
Immunotherapy, trying to convince your immune system to attack your
cancer. And also cancer prevention strategies, which I mentioned
actually last time, trying to make vaccines against
viruses that are associated with certain types of cancer including
human papillomavirus and cervical cancer. So Ras is the first one
that I'd like to mention to you. And it's an example of where we
haven't done enough. We don't know enough.
Even though we know that Ras is mutated in 30% of human tumors,
30%, 90% of pancreatic cancers carry Ras mutations.
Pancreatic cancer is one of the worst killers in the cancer category.
If you get pancreatic cancer, of a particular type at least, it's
a very, very, very serious disease. We know that these tumors carry
mutations in the Ras gene but we cannot do anything about
it at the moment. So, as I've told you,
Ras proteins are involved in signaling proliferation.
And this takes place through kinase cascades, phosphorylating enzymes
that phosphorylate other enzymes in a cascade. When you have a mutation
in Ras, it turns the protein on in a constitutive fashion leading to
increased signaling down these pathways and increased
proliferation. We know some of these enzymes.
I've told you about Raf and MEK and MAP kinase. And so many drug
companies are now trying to find inhibitors that might block those
enzymes, small molecule inhibitors, drugs.
And because these are kinases,
the approach is to try to find ATP analogs. Drugs that look like ATP,
can get into the active site of the enzyme and compete for ATP,
and thereby block enzyme function. Some of these drugs work, at least
in cells in culture. There's a bit of a fear that these
pathways are so commonly used in normal cells that the drugs might be
highly toxic and therefore not tolerated. And,
importantly, we don't understand what these arrows mean well enough.
We have some basic ideas, but we don't have enough detail to know
exactly which kinase to inhibit in exactly which type of tumor.
So this is in progress but it's not quite there yet.
I'll come back to another couple of stories related to ATP analogs that
do work and are now in use in cancer treatment.
Before I do, I want to mention another class of inhibitors,
and these are antibodies.
Antibody-directed therapy. Cancer cells often up-regulate
proteins on their surface. I mentioned one last time in the
context of breast cancer. It's a protein called HER2.
I mentioned the fact that 30% of breast cancers have an amplification
of the HER2 gene and, therefore, make more of this HER2
receptor on their cell surface. So, in contrast to normal cells
which will have a certain concentration of this receptor on
their surface, cancer cells, breast cancer cells
that carry this amplification will have a much higher density.
Maybe ten times or a hundred times the level of this receptor on their
surface. And they are using that increased level of receptor to
increase the signal downstream of that receptor to promote
proliferation. Now, the receptor is responding to
ligands as it would normally do. And therapy is based on the fact
that the ligand has to bind to the receptor in order to activate it.
And so what was done by a company called Genentech out in California
was to make antibodies that block to the receptor, that bind to the
receptor and block the binding of the ligand to the receptor.
So these are anti-HER2 antibodies. And this drug, which is now
approved by the FDA, is called Herceptin.
And it works. For those breast
cancer patients who have amplification,
too much of this receptor on their surface, Herceptin works and can
give them months, sometimes years of symptom-free
survival. It's not curative, unfortunately, but it does extend
life. And it's therefore an extremely important drug.
This is just a blocking antibody. There's nothing attached to the
antibody. It's just blocking the binding of the receptor to its
ligand and thereby blocking the function of the receptor.
But antibodies can also be linked to toxins or radionuclides,
and thereby deliver bad stuff to the tumor cell, either a toxin or
something that will irradiate this cell. And these are being tested
currently. There are no FDA approved versions of this,
but I suspect that will change in the years to come.
So Herceptin is an effective antibody-based therapy.
There are a couple more now, but it was the first. And this is
actually from the Genentech website which gives you a little bit of
information about Herceptin and shows you a bottle of Herceptin as
you would see in the pharmacy. And this diagram is just a
reiteration of what I've told you already. Normal cells have low
levels of the receptor on their surface, cancer cells have higher
concentrations of the receptor on their surface,
and the antibody binds to the receptor thereby blocking
its function. OK? So this is a clear example.
We learned that Herceptin was over-expressed in cancer,
breast cancer and ovarian cancer. The company made an antibody and it
works.
Another story, my favorite story relates to a
disease called chronic myelogenous leukemia --
-- or CML. CML is a disease that
affects young adults, adults and children. Child patient
shown here. It is leukemia so it's a disease of
the blood. It affects both the blood, as well as the bone marrow.
And we've learned a lot about this disease over the years.
It's not a very common disease. It only affects about 4,000 or 5,
00 people in this country per year. And it falls in stages. Initially
the person is diagnosed with CML based on relatively low
concentrations of, low levels of white blood cells in
their circulation. And then they progress with that
phase in what's called the chronic phase where there are still
relatively low levels of white blood cells, higher than normal but lower
than are dangerous. However, this can progress over
time through an accelerated phase where there's even higher levels of
white blood cells in the blood to the final phase which is called
blast crisis where the levels of white blood cells really shoot up.
And this is lethal. And these patients invariably
progress through these stages and eventually died.
So what have we done? This is a picture of what the blood
cells look like in a normal individual. This is a white blood
cell you could see in a CML patient. There are higher levels, and they
can be even higher than this. This disease has been studied for a
very long time. And we now know that there's a
signature mutation, a mutation that takes place in
almost all CML cases. It's a translocation that
rearranges two genes called BCR and ABL and places them together on a
translocated chromosome. There's a swapping of genetic
information from chromosomes 9 and 22 such that there's production of a
new gene called BCR-ABL that results in a new protein,
a fusion protein that has a little bit of this BCR protein and a little
bit of this ABL protein. And you can see in the karyotypes of
these individuals that they have an abnormal chromosome 9 which is a
little shorter, sorry, a little longer than it
should be, and an abnormal chromosome 22 which is a little
shorter than it should be. And when you look at cancer cells of
CML patients you always find that translocation.
It's called the Philadelphia translocation because it was
discovered by researchers in Philadelphia.
And it's sometimes referred to as
the Philadelphia chromosome. And, again, it's a translocation
involving chromosome 9 which has a gene called ABL which is
a tyrosine kinase.
And so it's a signaling protein. And chromosome 22 which has a
separate gene called BCR. And, in the development of CML,
breaks take place on these two chromosomes leading to a
translocation and the formation of a new chromosome that has a fusion
gene composed of both BCR and ABL. And this gives rise to a fusion
protein with a piece of BCR and the kinase domain of ABL.
And this leads to increased proliferation,
as well as increased survival of the cells that carry that translocation,
more cells in the blood and eventually leukemia.
And the hope is, the hope was, as this was being worked out,
actually important experiments done at MIT in the early 1980s here.
As this was being worked out that maybe, because it's such a common
mutation in this disease, if you could find an inhibitor --
-- maybe you could block the
proliferation of these cells or perhaps induce their death.
This just gives you a little a bit, a sort of cartoon version of BCR-ABL
signaling. I don't want you to literally pay great attention
to this. Suffice it to say BCR-ABL as a
signaling protein stimulates many of the pathways that you've learned
about already in this class and causes cells to proliferate,
as well as to survive better. So, again, can you find an
inhibitor that blocks the activity of this enzyme and thereby blocks
the proliferation of these cancer cells? This was undertaken by
probably many drug companies in the world, but a drug company now called
Novartis, which has its research headquarters here in Cambridge,
succeeded. They generated this drug which goes
by the name Gleevec. It has a trade name,
the name of which I can never remember, but everybody called it
Gleevec when it was being developed. It was also called STI571 but
Gleevec is the common name. They found this drug through a
screen looking for small molecules that look a little bit like ATP,
although it doesn't look much like ATP anymore, that can specifically
bind to and block the kinase activity of this particular kinase.
And this drug is successful. It does bind to the kinase and
blocks its kinase activity. And importantly in cell lines,
as well as in mouse models, it was found to be effective in killing CML
cells. It was then used in treatment of CML patients and found
to be effective there, too. So the number of white blood
cells in these patients dropped dramatically and the number of
Philadelphia chromosome positive cells likewise.
So if you were to plot the number of
white blood cells in a normal patient it would be low.
In a CML patient, in the early phase of the disease it would be
down here, and then it would go up in the accelerated phase and then it
would go up still further in blast crisis.
And, as I said,
this could take years, several years to progress.
And at this stage, late-stage disease, this person might have
hundreds of thousands of white blood cells per mill.
But when treated with Gleevec the white blood cell counts dropped to
mere normal. And amazingly the drug is extremely well-tolerated.
So even though all of your cells have this same ABL kinase,
not fused to BCR but the same ABL kinase unfused,
and it's probably doing stuff in your cells, those cells
don't need it. But the cancer cells,
in the context of this BCR-ABL fusion, are totally dependent on it.
And if you inhibit it now the cells will not proliferate anymore.
And, indeed, as you can see how precipitous this fall is,
the cells will actually die, undergo apoptosis. So the drug is
extremely effective. As I said, clinical tests were done.
Sorry. This just illustrates a cartoon version of what we've been
talking about. Here's the BCR-ABL protein.
Here it's in its normal state binding to ATP and transferring a
phosphate to some substrate protein in the context of signaling.
And what Gleevec does is binds to the ATP pocket and blocks the access
of ATP to the enzyme and, therefore, blocks the kinase
activity. And this is actual clinical data provided by Novartis
in this case. And what you're looking at here is the number of
Philadelphia chromosome positive cells in the blood.
And what percentage reduction you're seeing, either somewhat or
completely, looking at the accepted therapy before Gleevec came along,
which was not very effective, only 12% of patients showed any response,
or rather a major response, and only 3% showed a complete response.
That is when you looked in their blood by PCR you could find no more
Philadelphia chromosome positive cells.
But now with Gleevec, 75% of patients showed a major
response. And 54% of patients showed a complete response,
you could not find Philadelphia chromosome positive cells by PCR in
the blood of these patients. So it really worked extremely well.
It gave what we call clinical
remissions. Clinical remissions. And these patients survived, had,
you know, dramatically extended lifetimes. This would go on for in
some cases as little as a half a year, in other cases up to ten years
increased survival, especially if the patients were
treated early in the disease. But unfortunately for all the
patients the numbers went back up.
Clinical relapse. An all too familiar problem in
cancer therapy. You might see initial treatments,
they might even last a while, but too many patients undergo relapses
where their disease comes back. So what's going on here? These
patients are continuing to receive Gleevec throughout this course,
and yet the tumors are returning. Why? What might be going on?
Remember that cancer cells acquire mutations? Cancer cells are always
acquiring mutations. So what kind of mutation might be
taking place in these cells that would lead them to be Gleevec
resistant? Well, maybe they're acquiring mutations
within the BCR-ABL gene, that fusion gene, which blocks their
ability to bind the drug. So Charles Sawyers,
investigator at UCLA, took the cancer cells from these
relapsed patients, PCR-ed up the BCR-ABL gene,
sequenced it, and lo and behold he found a bunch of mutations.
Individual tumors had one or another of these point mutations
within the ABL kinase. And the consequence of those
mutations was that the drug Gleevec could no longer bind.
And that's illustrated here. So this is, again, a cutaway view
of the BCR-ABL kinase. Here's Gleevec where it normally
sits, but that red dot is a mutation that sticks an amino acid side chain
right in the way of where Gleevec binds.
So now it cannot bind anymore. The drug cannot bind, it cannot be
effective, cancer cells come back. OK? So that's a problem. What are
you going to do about it? What can be done? What would you
do?
Maybe we could find a drug that will bind even if there is a mutation
there. And that actually works and that's why this Gleevec fits nicely
into that pocket and blocks the activity. So this enzyme is
inhibited. The problem is that apparently invariably mutant
BCR-ABLs arise which are Gleevec resistant.
So you can have Gleevec around,
but it cannot get in there, the enzyme still functions,
it still causes proliferation. But working with a different drug
company, Charles Sawyers screened new drugs. And he found a drug
which has a similar but slightly different shape than Gleevec,
and it's able to bind to the mutant BCR-ABLs.
This drug is called BMS-354825 produced by Bristol-Myers Squibb.
And just in December of this past year Charles Sawyers reported the
first clinical trial with this drug in patients who had failed Gleevec
therapy who had relapsed. And 31 out of 36 responded.
And to my knowledge they are still in remission. And the five who
didn't respond had a particular kind of mutation that actually also
blocked the binding of this drug. But the majority of mutations, even
though there are several mutations that will affect Gleevec resistance,
the majority of them are still sensitive to this new drug.
So this is smart and smart again. Smart, understanding how cells can
be sensitive. Then smart again, finding out how they become
resistance. And then smart for a third time, finding new drugs that
will bind even in the presence of those resistance mutations.
And this, I suspect, is the future of cancer treatments.
Understanding the molecular signature mutations,
finding specific drugs, and then being prepared to find
second-generation drugs that will still work even if resistance
arises. A very similar story,
which I'll have to tell you quickly, comes from the world of lung cancer.
In this case, several drug companies were trying
to find drugs that would block a different tyrosine kinase.
This time a receptor tyrosine kinase by the name of epidermal
growth factor receptor, EGF receptor.
They were motivated to do so because this receptor is over-expressed,
there is too much of it in many types of cancer, including
lung cancer.
And so different companies made different drugs.
One of them is called Iressa which goes by the trade name Gefitinib.
Another made by Genentech is called Tarceva. And these do function as
EGF inhibitors, anti-EGF receptor inhibitors.
They work. They work in the test-tube. However,
when tested in clinical trials they were a spectacular failure.
Even for patients who had high levels of EGF receptor on the
surface of their cancer cells, the drug didn't do anything.
And they were almost not going to be FDA approved for that purpose,
except that a very small number of lung cancer patients responded
extremely well to the drug. about 10% of lung cancer patients
showed responses like the one I'm showing you here,
where this, and outlined in red, is a lung tumor where the tumor is
basically filling the entire lobe of the lung.
Six weeks after treatment with this drug Iressa, you can see massive
resolution of the tumor. The tumor is almost all gone,
and that white stuff is probably just fibrotic tissue.
The tumor cells are practically gone. A dramatic response.
What's going on? Why do those 10% of patients respond so well?
Well, it turns out that those 10% of patients carry a mutation in the
EGF receptor gene. In those 10% of patients,
one of the ways the cancer cells are growing and surviving is that they
have a mutation that activates this gene making those tumor cells highly
dependent on that particular protein in the same way that these cancers
are highly dependent on BCR-ABL. And if you deprive those cancer
cells of that activity by using these drugs, the cells will die.
So this is a good example of what will come in the future of
individualized medicine. If you're a lung cancer patient,
you shouldn't just indiscriminately take Iressa because 95% of the time
it won't do anything for you. But if you're one of those 10% who
has a mutation in this gene, you would benefit dramatically from
having it. And that will happen more and more in cancer and other
diseases. Your tumor will be molecularly typed to find out
exactly what mutations it has to find out which of a collection of
targeted therapies you should be taking.
These patients, just so you know,
tend to be women, non-smokers, and tend to be Asians for reasons
that we don't understand. Any of those three we don't
understand, but the percentage of EGFR mutant lung cancer patients are
higher in those categories of people. And so they have a greater
likelihood of being responsive. But, in fact, nowadays if you have
lung cancer you get your EGFR gene sequenced. And if it has a mutation
you take this drug. And it will work.
It will resolve your tumor. Unfortunately, your tumor will come
back. The same story but faster. These patients tend only to get
three months, six months, maybe a year, two years, three years
extra survival, and then their tumors come back.
Same story, the receptors that are now insensitive to the drug carry a
new mutation that blocks access of the drug to the receptor.
Fortunately, just last month there was a paper that described a new
drug that will still work even if the receptor carries such a
resistance mutation. So there's hope that we'll see a
story similar to this one emerging for lung cancer.
Now, I've told you three of, just a handful of molecularly
targeted agents for therapy in cancer.
There are more to come. Telomerase is an enzyme that cancer
cells need, that normal cells or at least most normal cells don't need.
We won't go into the details of that, but suffice to say this is a
promising area for therapy as well. Angiogenesis, I've mentioned to you
before. Tumors, solid tumors need a new blood supply.
If you can block the ability of the tumor to recruit a blood supply,
you might be able to block the development of the tumor.
And there has recently, Genentech once again, been an FDA
approved anti-angiogenesis drug that blocks, that prevents progression of
colon cancer, and also they just reported breast cancer.
So anti-angiogenesis is a viable therapy strategy as well.
Gene therapy, putting lost genes back. Cancer cells have mutations
in tumor suppressor genes, p53, RB I've told you about,
and others. Perhaps you could just put the gene
back in, the gene that got lost. Make a virus that expresses that
gene and put it back. This is being tried. I'm not super
enthusiastic about whether it will work because I don't know that we
can get the virus carrying the good gene into all the cancer cells.
But, nevertheless, it's something to consider. Immunotherapy is also
a promising area. It's possible that we can convince
your immune system to detect the abnormal proteins that cancer cells
make by virtue of the mutations that they carry.
You can make antibodies or T cells that eliminate those,
and that's underway. And I've mentioned already the cancer
prevention approaches with vaccines. I want to draw your attention to
the fact that the Cancer Center here at MIT will have a symposium in June.
Many of you will have gone home for the summer, but some of you may not
have. June 24th. This is free to MIT students,
and actually features many alums of MIT. Two of these people were
undergraduates here at MIT, including Dan Heber, the guy who did
the EGF lung cancer story that I just showed you.
This is a very great group of people who will be telling you the latest
and greatest about the new science of cancer therapy,
an extension of what I've told you about today. All right.
Before we finish I want to just briefly mention that in addition to
tracking mutations in cancer-associated genes,
we can also track the expression patterns, the levels of expression
of all the genes in a cancer cell. And this is done using a technology
called array technology where all of the genes of a cell,
the 30,000 genes of a cell can be assessed based on how much RNA is
being produced in those cells at any given time or at any given sample.
This is called a GeneChip or a gene expression array.
And increasingly it's being used to diagnose cancers.
Cancer is typically diagnosed by histopathology.
You look at the tumor, or the pathologist looks at the
tumor in a histological section and says it's a this or it's a that.
The problem is that many cancers look very similar to the histologist
or the pathologist, but in the underlying molecular
level they might be quite different. Some of them might be fairly benign.
Others might be really dangerous. And maybe you cannot tell that
apart by looking at the cells, but looking at the activity of the
different genes inside those cells you may be able to get to that.
So this is done by comparing, on a glass slide, the levels of
expression of all the genes from the cancer cell compared to some
reference RNA, let's say the normal cell of that
tissue. And then the signal that you read out by looking at labeled
RNAs, the cancer cell being labeled red, for example,
the normal RNA being labeled green, the signal that you read out from
each of those spots using a laser and a CCD camera to detect the
signal coming off of the chip, the signal that you see can be
quantified. And a red signal would mean there's
more RNA in sample one for that particular gene,
a green signal more RNA for sample two, and a yellow signal roughly
equal. And the pattern that you get from these chips can then give you
information about the state of those cells, and that information might be
extremely important clinically. And in the last two minutes I'll
just tell you a brief story about how it is being used.
This is a collection of 75 breast cancer specimens,
early stage breast cancers, node negative, lymph node negative
breast cancers. These patients,
before this technology, all would undergo removal of the
tumor and then chemotherapy. But it turns out that only some of
them will actually go on to progress. These patients were followed for
ten years after that sample was taken. And it was known that some
of them progressed, and those fall over here,
progressed in the sense that they developed metastatic tumors.
And others didn't progress. And so what was done was is to take
RNA from these samples at this early stage, RNA from these samples and do
one of these GeneChips and ask, is the pattern of expression of
genes correlative to the outcome, the eventual outcome? It might take
some years for it to happen. And what they found was that indeed
-- And you can probably see it from
where you're sitting, that this collection of genes in red
over here is highly expressed in the guys who actually do pretty well and
is relatively lower expressed in the guys that don't do well.
And this collection of genes is highly expressed in the ones who
don't do well compared to the ones who do. And so now there's a
clinical test. You can have your early-stage
breast cancer typed by this analysis and it will tell you with some
degree of certainty, not complete, whether your tumor
will eventually, maybe five year down the road
progress into a metastatic tumor. If you get the signal,
if you get the answer yes, then you have it removed and you
undergo therapy. If you get the answer no,
you have a choice. Perhaps you get the tumor removed,
but you don't undergo what is in fact quite difficult and sometimes
damaging therapy. So this is an example of,
again, stuff to come, molecule medicine, specific patient-oriented
medicine.