[Instructor] Here we're going to talk about
the general approach to targeted therapeutics in oncology
and also some genetic predisposition to oncology.
So here, I'm not, my intention is not to be, not
to cover everything and not to give you all the details
of all the different types of therapies
or all the different genetic tests that people can have done
for genetic predispositions.
It's more to give you a few case examples
of what these targeted therapeutics
and genetic testing results can mean,
so that way you can understand how these processes work.
Because unless you practice regularly in oncology,
knowing all the details about all the different therapeutics
and all the different genetic tests
isn't really gonna be that useful for you.
But hopefully understanding
the concepts of these therapeutics
and the genetic predisposition will actually
be more useful for you.
So somatic versus germline mutations,
this is really what we're talking about.
And somatic mutations are acquired
by individual cells in the body over a person's lifetime.
Remember what somatic cells are,
those are basically all cells in your body
that are not your germline cells.
As a result, cancer cells will have a unique set
of mutations that are not found
in other normal cells in the body.
So while you could say,
all of your cells in the body have the same genome,
that's true, but each cell has accumulated a unique set
of mutations for it.
And in cancer cells, this is especially true
because as you remember, those particular kinds of genes,
those caretaker genes that repair DNA mutations,
DNA damage, well, if they're inactivated
or they're not functioning normally,
those cells that have those caretaker genes mutated,
they're going to accumulate a lot more mutations
very, very quickly compared with other cells in the body.
And some mutations are found in all cells.
And these were inherited, so these are germline cells.
They started out from day one, fertilized egg.
This individual had this particular mutation,
so it's found in every single cell
in their body, exact same mutation.
Why? Because they inherited it.
So it's a germline mutation, something they inherited.
They didn't acquire it over time.
Somatic mutations, which happen in all
of us and all of our cells, those are acquired over time.
And those are gonna be very unique in each cell
within a person's body.
It's not just person to person, but cell to cell.
So these mutations,
the germline mutations may predispose a person to cancer,
but they require additional somatic
mutations before cancer forms.
Remember, it's the, if you kind of go back to the idea
of three strikes, you're out idea then people who start out
with a germline mutation that is in,
say, a tumor suppressor gene
or in a caretaker gene, that person already has one strike.
But then they have to accumulate those other two strikes
in certain parts of, in certain cells in their body.
And those strikes come from acquiring mutations
either randomly, from DNA replication errors,
or they occur from exposure to carcinogens.
In any case, the predisposing germline mutations,
it's not sufficient to actually cause cancer by itself,
but they actually require
some additional somatic mutations to happen.
Germline mutations can be tested using any cells in the body
while somatic mutations causing a person's cancer can only
be found in the tumor itself.
So think about why that's the case.
And germline mutations, those were inherited.
So they're going to be found in every cell in the body,
whereas somatic mutations are gonna be different
in each cell, depending upon what it was exposed to,
how well it was able to repair the damage,
and any other additional mutations
that might have happened in that particular cell
that are gonna be different from any other cell in the body.
Targeted therapies target somatic mutations,
somatic mutations specific to the cancer cells,
while genetic predisposition tests
for mutations in all cells that all cells have,
that might make cells more susceptible to becoming cancer.
Okay, and we'll talk about each of those,
but first, let's look at what types of tissues
or samples are taken.
So an inherited, so that's gonna be a germline mutation.
An inherited mutation versus an acquired mutation.
Acquired is a somatic mutation
because it's acquired over the person's lifetime.
So an inherited versus acquired mutation testing,
the blood sample.
So really, I mean, blood,
it's gonna be a relatively easy sample to take.
You could also just do a cheek swab
or something like that to test for
a mutation found in those cells
because it's found in all cells in the body.
So it's not as though a person needs to have leukemia,
for example, before you can take a blood sample to test
for an inherited mutation,
because that inherited mutation is going
to be found in all cells in their body.
So you just take whatever is easiest type of sample
to take for that.
For acquired mutations, on the other hand,
you have to have the cells that are causing the problem.
So at this point, a person already has some kind of tumor,
and so a biopsy is taken
and tested for which specific mutations
are found in those cells specifically.
And those mutations are not gonna be found
in the other normal cells,
but they're just gonna be found in the tumor cells.
So you need the tumor in order to test for those mutations.
You can't do a blood sample test
and know that well, your colon tumor
or your colon cancer has these has a mutation
in the epidermal growth factor receptor.
And so we're going to start you on this kind of therapy.
It won't tell you that,
you need to actually get a biopsy from the tumor
because it's only in those cells
where they have those specific mutations,
not in all cells in the body.
So targeted therapeutics.
So one other point I want to mention here
is that the genetic testing
for inherited mutations can be done
at any point in a person's life.
I mean, even before they ever have any
signs or symptoms of cancer.
And they may never develop cancer, actually,
even if the genetic test comes back saying
that they do have an inherited mutation
which could lead to cancer,
it's simply that it could lead to cancer.
It's not a diagnosis of cancer.
When you're looking at acquired mutations.
That only happens when a person already has been diagnosed
with some form of a tumor at least.
And they want to know if the two,
like what specifically what mutations are found
in that tumor.
Targeted therapeutics,
of the 57 FDA approved indications, detailing genotype
or gene expression information 47 are in oncology.
So what do I mean by that?
So in the actual indication for 57 drugs
that are approved by the FDA,
those indications actually specify this drug
is to be used in individuals who have this genotype.
And 47 of those.
So the vast majority,
over 80% of those are for drugs in oncology.
So why are oncology therapies particularly well suited
for a targeted genetic approach?
Well, cancer is the most common genetic
disease as we talked about.
There's also inherent variability in cancer genotypes.
And what do I mean by that?
So as we've been talking about these acquired mutations,
they're going to be very different person to person,
or even a person
who might have two different kinds of cancer,
might develop two different kinds of cancer.
Those can be very different from one another
because each of their cells
has acquired different set of mutations.
So it's not as though cancer is one disease
that can be treated with one type of approach.
I mean, cancer is, I mean, it's almost
an infinite number of different kinds of causes
of the disease because you could have mutations
in so many different genes
or regions of the DNA that can lead to cancer.
And so it's important to identify which genes are disrupted
or which pathways are disrupted
in a particular tumor
in order to know how to best target it.
So targeting cancer cells from normal cells is critical
for safe and effective therapeutics,
as I'm sure you're probably aware, that in general,
chemotherapy, the more general type of treatment
for cancer really just targets any kind
of cells that are rapidly dividing and kills them.
Whether those cells are part of the cancer itself
or whether those cells are the normal cells in the body,
which rapidly divide anyway, which would include
the cells that are involved in follicle formation.
So hair cells that line the gut
and many other kinds of cells as well.
And so that's why people
who undergoing chemotherapy, they lose their hair,
they have significant amounts of nausea and vomiting,
and they're just depleted.
And that's because they are exactly that their cells,
any cell, any cell in the body that happens
to be rapidly dividing is killed.
And that's not a great approach
because it leads to the safety issues,
these side effects which are significant for these patients.
So what the idea is in target therapeutics
is let's just target cancer cells.
Let's try not to hurt our normal naturally
occurring healthy cells.
Let's just target cancer cells and let's kill those.
So personalized medicine
is really the approach that's being taken.
And so this time actually is all about you.
We all like it when things are about us.
And I just put a little funny little comic strip there,
but it personalized medicine when we're talking about that,
that's kind of the targeted therapeutic approach.
So which drug is most likely to generate a response in you
and which diseases are you predisposed to?
So that way we can personalize both the therapy
for if when a person,
or when a person does develop a disease,
but also can identify those who are more likely
to develop the disease.
So we can have better approach to surveillance
and to preventive measures as well
to hopefully prevent a person
from ever even developing cancer.
And why are pharmaceutical companies interested
in making targeted therapies?
Well, it's very expensive as you may already be aware,
but it's very expensive to get to bring a drug to market.
And I mean the estimates
for dollars spent per drug approved
are in the billion dollar range per drug.
So to bring a single drug from, for basically
for each new drug that's approved
for these pharmaceutical companies
and you divide the number
of dollars they invest in bringing all their drugs
to through clinical trials, through development divided
by the number of drugs that are actually approved,
you can come up with billions of dollars per drug.
And why is it so expensive?
Well, if you have 6,000
or 6,000 circles here, just stress me on that one.
If you have 6,000 different compounds that start out in say
in early development for in a pharmaceutical company,
how many of those do you think will actually go
on to ever be approved?
Well, it's actually only one of them.
This one, let's say this little guy right here, that one out
of the 6,000 compounds they start out in testing will
actually ever make it all the way through clinical trials
and be approved and sold.
So why do so many fail?
Well, their safety and efficacy fails
to improve over existing standard of care in the population
or the response rates and adverse events rates vary greatly
person to person, largely because of genetic diversity.
But all data are combined in the analyses
and they lose significance.
So while you might think in a clinical trial,
well we have five apples and of the five apples,
well it worked really well in four of them,
but one of them it didn't.
So if we average all that together,
it didn't really work all that great.
But in reality, instead of having five apples,
what you have is four apples and an orange.
And it was the orange where something didn't,
where it didn't work
or there was a major safety concern, say for example.
And that limited the ability to bring that product
through clinical trials.
And the FDA did not approve it
because of the safety concerns.
But if they can identify which
of these apples is actually an orange
through genetic testing, for example,
and say, hey, you are not gonna be likely to respond
to this therapy or you are not gonna be likely to,
you're likely to have a bad response
and a safety concern
or an adverse event that will happen.
That's a lot more likely to happen
because of your particular genotype
than they can identify those people
and they can divide out the data when they're actually doing
the analysis of safety and efficacy data.
They can divide out based upon a patient's particular
genotype, their response rates
and their adverse event rates.
And it'll make it a lot more likely for drugs
to be approved
and be useful not for the general population necessarily,
but for subsets.
And those subsets can be identified through genetic testing.
So in actual clinical practice, genetic testing
for specific somatic mutations
in the tumor help inform therapy selection.
And in oncology it is just as important to know
what will work as what will not work.
And why is that?
I'm sure you're all probably pretty familiar
with why that's important to know in your patients,
but not wasting precious time with therapies
that will not work across all cancer types.
Earlier treatment equals greater clinical success.
Like hands down, that's the most important factor in terms
of success in treating cancer is how early it was detected.
So wasting those precious months trying
a therapy that's not going to work.
You know, as you're probably aware,
there's like first line therapies, second line, third line
that a patient will progress through if they fail each
of those therapies along the way.
But that takes time
and some therapies cannot be co-administered
with other therapies due to reduced safety or efficacy.
So they can't just try everything at once.
They have to do it in a staged approach.
And why also it's important not to know
what will not work but by avoiding
or reducing unnecessary exposure of patients to drugs
with significant side effects
and also avoiding the expense associated with purchasing
and administering targeted cancer therapies
if that particular cancer therapy
is never going to work in that patient.
So here's a quick case study
and please don't bother to know all the details
of the picture I'm showing you here on the right.
That's just to give you a pictorial representation
of the actual pathway
and some of the different proteins involved
in signaling in that pathway.
But not really important for you,
not important at all actually
for you to know the details of this.
This is just a case study to give you an example
of what we're talking about here.
So EGFR,
which is called the epidermal growth factor receptor.
Epidermal growth factor receptor is a receptor
that exists on the surface of the cell.
So remember that receptors are proteins, pretty much all
of these things we're talking about here,
they're all proteins so they're all encoded by genes, right?
They all have gene sequence that is transcribed
and translated into these proteins
that have these different functions.
So they're all subject to mutations in their genes
and those mutations in their genes
might affect their function or their ability
to do what it is they need to do
or even whether or not they're there, okay?
So there's a drug called Cetuximab,
it's a monoclonal antibody
to epidermal growth factor receptor
and it's used to treat colorectal cancer
and EGFR is often highly active in colorectal cancers.
And why is that?
Well, EGFR is one of those types of proteins
that falls into the category
of activating cell proliferation and inhibiting apoptosis.
So it's really, you could think of it as sort
of an oncogene, a proto-oncogene
when it's not been mutated,
it's normal function is to respond
to those growth factors in the environment
and to basically tell the cell let's go.
We need to divide and replicate
and do all those fun things when it is in its normal state,
it's responsive to the external environment
and growth factors that may be around there.
So EGFR is,
so basically why are we targeting EGFR in cancer?
Well again, because it's often highly active
and it's also on the surface of cells
'cause it's a receptor, it senses
and detects what's going on outside the cell.
But because of that, it's really an easier target
for drugs because it's like the drug doesn't actually have
to get into the cell to do its thing.
It can just be on the outside of the cell
and the environment around it and can affect this protein
because this protein is actually going through the cell.
So it's through the cell membrane.
Part of it's on the inside, part of it's on the outside.
So it can be affected
by whatever is on the outside of the cell.
So Cetuximab is a monoclonal antibody.
And what is an antibody?
Remember that from last week.
An antibody is going to bind to its particular antigen.
In this case, this antibody is against EGFR.
And so it will bind to EGFR
and will both block the activity of EGFR
and stimulate immune cells to destroy the cancer cells.
So this is going to elicit that immune response
and have the immune cells come in
and say, oh, you've got a weird antibody on you
and so we are detecting you
as something that needs to be destroyed.
And that's exactly what it does.
So it can specifically target those cells
that have too much EGFR on the surface.
It will bind to and coat those cells with this antibody
and then it'll do two things.
It'll induce the immune cells to destroy the cancer
and it'll block the pathway of EGFR,
which activates cell proliferation, angiogenesis,
inhibiting apoptosis, all of that stuff.
So it really has like a two-pronged approach
and it's actually quite effective therapy
for colorectal cancer in some patients.
However, there are some patients
that have a mutation in a completely, in a different gene,
which is called KRAS.
So we say KRAS not KRAS, but it's KRAS gene
and KRAS is, let's just go back for one quick second.
Again, you don't need to know the details of this,
but just in case you're interested, RAS is right here.
KRAS is a type of RAS,
which is just another protein in the cell within the cell
that responds to EGF receptor being activated.
It then goes on through
and activates a bunch of other stuff
which activates transcription factors
to turn on cell proliferation.
So if there's actually quite a few individuals,
but maybe about 20, 30%
of individuals will have a mutation in KRAS,
which KRAS is normally activated normal KRAS,
unmutated KRAS is activated by EGF receptor
to turn on growth and proliferation.
But there are common mutations in KRAS
which result in its constitutive activation.
What do I mean by that?
It's always on.
So EGF receptor does not need to activate it.
And here you're just seeing basically
where the KRAS gene is located,
it's located on chromosome 12
and there's a single amino acid difference.
It's this glycine, it's normally glycine
at codon 12 is now availing a single base change
from G to T can result in a completely different function
for this protein, which now is always on.
So it doesn't like in normal cells,
this KRAS protein sits around, doesn't do anything
until EGF receptor detects growth factors.
And then EGF receptor says, hey, hey KRAS, guess what?
It's time to go.
It's go time KRAS
and KRAS then becomes activated and it goes on
and turns on a bunch of transcription factors
and then they turn on cell proliferation
and dah da da da da da.
Okay, so that's what happens normally.
KRAS is just like taking a nap until EGF receptor turns
it on and says, hey, guess what?
It's go time.
That's normal, that's what we want.
We want the cell
to be able to respond to growth factors.
But in some cases of colorectal cancers,
some people will have this mutation, this point mutation
which actually will cause the KRAS to always be awake,
always be on, always be hyperactive, and it's zipping around
and it's activating transcription factors
whether or not EGF receptor is present,
whether or not EGF receptor is being turned on
by the presence of a growth factor or not.
It doesn't care, it's not listening anymore,
it's just on all the time is always go time when KRAS
is in a constitutively active form.
So what does that mean in terms of, for these patients?
Well the end results is the same
in that it still results in abnormal growth
and proliferation of those cells leading to cancer,
but the way it got there was quite different.
So the way that we would treat that is different.
So now if you took that particular person
who has, let's say you have two people,
one person has too much EGF receptor present
and so, it's inappropriately activating itself all the time.
And so it's turning on the normal KRAS in the cell.
Well if you shut down EGF receptor in those patients,
if you just turn it off,
if you basically send those antibodies in to bind to it
and you target the immune cells,
you can stop your problem right there.
That's great.
It will target those cells to be killed by the immune system
or at least shut down EGF receptor activity, perfect.
But in those people who have constitutively active KRAS,
you can, they don't have too much EGF receptor.
EGF receptor isn't even in the game anymore
because KRAS has gone rogue.
It's now on all the time whether
or not that EGF receptor is there and turned on
or not, doesn't care, doesn't matter.
KRAS don't care, KRAS is now on all the time.
And so not only do these cells not have too much
EGF receptor on their surface, so if you add that antibody,
it's not going to really bind to anything, right?
So you're not gonna have any response in these patients
'cause it has nothing to do with EGF receptor.
It's downstream of that.
So in 30 to 40% of patients with colorectal cancer,
they have one of these activating mutations in KRAS.
And I think you can pretty much come
to the conclusion of would you be more or lesser
or equally likely to prescribe Cetuximab to patients
with colorectal cancer whose tumor
has an activating KRAS mutation.
Hopefully you can see
that you would be a lot less likely to prescribe it.
Why? Because they're not going to respond,
they don't have too much EGF receptor,
they have too much active KRAS
and that's on the inside of the cell.
So if you shut down EGF receptor,
it's not gonna have any effect on KRAS
because KRAS is acting independently of that
in these individuals with the activating KRAS mutation.
There was a clinical trial called the CRYSTAL trial,
which demonstrated that patients with colorectal tumors
that have activating mutations in KRAS fail to respond
to Cetuximab as part of their therapy.
So in 2009, the FDA added the provision
that Cetuximab is indicated only in patients
with colorectal cancer who have wildtype KRAS.
Remember what wildtype means?
Just the normal version of KRAS,
so not the activating mutation,
which makes a standard practice
to perform a genetic test on colorectal tumor tissue
for activating KRAS mutations to inform treatment approach.
And it's not just to say, well, we're going
to do this genetic test to see what,
whether to basically confirm
that we should give you Cetuximab.
It's to say Cetuximab is just either it is likely
or it is unlikely to work in you.
And if it's unlikely, we're gonna find something
better to start with.
'Cause we're not gonna waste our time.
We're not gonna waste the patient's precious time
to start them on a therapy that's unlikely to work.
So predisposition testing for hereditary cancer,
there's a famous quote from the director
of the National Institutes of Health, Francis Collins
who says, "Genetics loads the gun
and environment pulls the trigger."
And I think that's a good analogy to use here
because it's, again, it's not just
that if you inherit these mutations, you will get cancer.
It's that it loads the gun
and if something else comes along to pull the trigger,
then it pulls the trigger.
And basically again, you're starting out
with at least one strike
and you're more likely to get struck out if you start out
with one strike than if you start out with no strikes.
So that's what we're talking about
when we're talking about predisposition.
Remember that five to 10% of cancers are inherited
and most cancer susceptibility mutations
are actually inherited in a dominant found,
in a dominant way.
There are cosmo mutations in tumor suppressor genes
like TP53, APCP 10, BRCA one and two,
these that regulate cell proliferation differentiation
and DNA repair.
So reasons why mutations in ubiquitously expressed tumor
suppressor genes increase risk of specific types
of cancer is an area of active research.
So what do I mean
by ubiquitously expressed tumor suppressed surgeon genes?
Well these are basically, these are genes
that are expressed in all cells really all the time.
So they're never shut down or turned off.
So why would a, say for example people
who have BRCA one or two mutations,
why do they just have a higher increased
risk for breast cancer or ovarian cancer?
It's not clear why, I mean,
in theory they should have a higher risk
of all kinds of cancers.
We don't understand why that's the case yet,
but that is definitely an active area of research.
So let's take a look at BRCA one and two.
'Cause I think these are two that you've probably heard of
that are some of the most commonly tested genetic mutations.
BRCA one and two are tumor suppressor genes
whose proteins function to repair DNA damage.
And so, we can think of them as tumor suppressor genes
or caretaker genes if you want to use
what the way we were defining them earlier.
They have similar functions
but are two different genes, right?
So when people will talk about BRCA one, two,
well that's not just one gene, it's two different genes.
There's BRCA one and there's BRCA two,
they're actually on two different chromosomes.
They're two separate genes.
BRCA one is located on chromosome 17Q21,
BRCA two is located on chromosome 13Q12.3.
And I just bring this up because sometimes it sounds like
they're one gene, but they're actually two different genes.
BRCA one mutations are associated with increased risk
of breast cancer as well as fallopian tube cancer,
male breast cancer and pancreatic cancer
and BRCA two mutations are associated with increased risk
of breast, ovarian as well as prostate cancer,
pancreatic cancer, fallopian tube cancer,
male breast cancer and melanoma.
And BRCA two is especially associated
with male breast cancer.
But BRCA one certainly has,
it does contribute an increased risk for men breast cancer.
An inherited homozygous mutation in BRCA two leads
to Fanconi anemia type D one as well
as significantly higher rates of cancer.
So it can actually cause a separate genetic disease,
Fanconi anemia, if an individual is homozygous
for mutations in BRCA two,
but that also increases their risk
of different types of cancer.
Genetic tests for BRCA one
and two mutations are widely available
and I'm sure you are probably aware of them.
So BRCA one two mutations in breast cancer.
So it increases the lifetime risk
of breast cancer in women from 12% to 60%.
It increases the lifetime risk of ovarian cancer
from 1.5% to 39%.
Ovarian cancer is, you're probably, you may be familiar,
is really difficult to treat successfully.
And it's usually, I mean, in large part,
that's because it's not diagnosed until commonly
until a late stage.
So knowing a person has a much higher risk
of ovarian cancer, even if a person,
even if a woman decides not to have, for example,
a prophylactic oophorectomy, if nothing else,
knowing this information can be so helpful
because again, ovarian cancer isn't usually diagnosed
until stage three or four,
in which case survival rate is very, very low.
If it's diagnosed early, the survival rate is very high, so,
or much higher I should say.
So being able to diagnose it early, which is the result
of potentially greater surveillance,
getting more ultrasounds
or just being aware of what the signs
and symptoms are of ovarian cancer,
could really significantly improve a person's odds
if she does develop ovarian cancer of survival
because it could lead to earlier diagnosis.
So if we break down the prevalence of these BRCA one
and two mutations in ethnic
and racial groups in the US, Asian Americans about usually
have the lowest rate about half a percent
for BRCA one mutations.
And really it's Caucasians
and Hispanic individuals who have the higher mutation,
have the higher rates of mutations
and then the Ashkenazi Jewish population as well, especially
for BRCA one mutations, is present in about 10%
of individuals of that heritage.
So it certainly varies depending upon the group,
but any person, any woman especially who comes in
who has a family history, as you're all very familiar,
go back to those red flags that we talked about
of inherited genetic disease,
which we talked about I think in module seven
when we were looking at risk factors.
Go back and review those again
if you'd like to really become familiar
with what should pop up as a red flag when you're going
through patient's family history.
So quick summary of the targeted therapeutics
and genetic predisposition.
Targeted therapeutics, target cancer cells specifically.
These require genetic testing
of the somatic mutations in the tumor itself
to identify the right therapy to use
and the therapies unlikely to work.
So the example I gave you was of the individuals
who have the KRAS mutations that was of what not to use.
So you would not want to use Cetuximab.
There are certainly are therapies
where you do a genetic test to tell you
what is likely to work.
And so, but I just gave you one example,
but just know that it goes both directions that way.
The presence of certain mutations
in tumor suppressor genes can predispose someone
to develop cancer at some point in his or her life.
If additional somatic mutations accumulate
and actually cause that basically fire the gun,
fire the gun.
Genetic predisposition can be tested for in blood
or cheek swab while identifying somatic mutations
in the cancer requires a biopsy of the tumors
as we talked about in the previous lecture as well.
All right, well with that I will say goodbye.
And what are we looking forward to in the next module?
We'll dive into the psychiatric disorders
and the genetic components there
and I will tell you straight away, this is a much more
hazy topic because while there may be
some genetic factors which have been linked
to certain psychiatric disorders, it's not as black
and white as some of what we've been looking at before.
But for now, I will say goodbye
and I look forward to talking
with you more about cancer genetics in the discussion board.
Thanks very much.