While the human genome sequence has transformed our understanding of human biology, it isn’t just the sequence of your DNA that matters, but also how you use it! How are some genes activated and others are silenced? How is this controlled? The answer is epigenetics. Epigenetics has been a hot topic for research over the past decade as it has become clear that aberrant epigenetic control contributes to disease (particularly to cancer). Epigenetic alterations are heritable through cell division, and in some instances are able to behave similarly to mutations in terms of their stability. Importantly, unlike genetic mutations, epigenetic modifications are reversible and therefore have the potential to be manipulated therapeutically. It has also become clear in recent years that epigenetic modifications are sensitive to the environment (for example diet), which has sparked a large amount of public debate and research. This course will give an introduction to the fundamentals of epigenetic control. We will examine epigenetic phenomena that are manifestations of epigenetic control in several organisms, with a focus on mammals. We will examine the interplay between epigenetic control and the environment and finally the role of aberrant epigenetic control in disease. All necessary information will be covered in the lectures, and recommended and required readings will be provided. There are no additional required texts for this course. For those interested, additional information can be obtained in the following textbook. Epigenetics. Allis, Jenuwein, Reinberg and Caparros. Cold Spring Harbour Laboratory Press. ISBN-13: 978-0879697242 | Edition: 1
7.9 Drugs that target the epigenetic machinery as chemotherapeutics
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Compétences que vous apprendrez
Cancer, Molecular Biology, Cancer Epigenetics, Dna Methylation
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BM
Aug 14, 2017
One of the best organized and implemented courses I have taken so far. For someone who had barely any experience with epigenetics, I feel this gave me a proper introduction to the field.
HH
Dec 18, 2016
A quintessential course for Genetics students all over the world. Very nicely prepared and elucidated by Dr. Marnie Blewitt .\n\nMany many thanks to Dr. Marnie Blewitt & Coursera team.
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Week 7 - Cancer Epigenetics
This week we’ll bring together much of what we’ve learned in previous weeks of the course, to understand how the epigenome is affected, and can also affect, cancer development and progression. We’ll then go on to discuss the potential therapeutic benefits that can come from using epigenetic biomarkers, and targeting epigenetic modifiers in cancer.
Enseigné par
Dr. Marnie Blewitt
Head, Molecular Medicine Laboratory
So over the course of the last few lectures, we've spoken about these
epigenetic abnormalities and we've spoken a bit about how they can be used for
diagnostic purposes or they can be used prognostically.
But now, I want to focus this last lecture for this week on thinking about therapy.
So, actually, what's been happening
in the last few years is there's been a really intense push by pharmaceutical
companies to target the epigenetic machinery with small molecule inhibitors.
So that is small molecules, chemical molecules, that can come in and bind very
specifically to epigenetic modifiers and inhibit their function.
So, why would you want to target the epigenetic machinery?
Well, I've just told you that we can see alterations in the expression levels or
alterations in there are mutations in the epigenetic modifiers and that
epigenetic abnormalities are really a hallmark of cancer if you like, they
happen in every cancer. And so, if we could reverse these
epigenetic changes because the epigenetic abnormalities are indeed reversible
unlike the mutations, then potentially we could help treat cancer.
So there have been some areas of the epigenetic community, at least that, have
been relatively weary about being able to treat patients with drugs that disrupt
epigenetic machinery. And this is because we know epigenetic
control is critical for all cell types. So what happens if we disrupt, if we just
give a person a drug that's going to influence all of their tissues and say,
for example, inhibit DNA methylation in all of their tissues?
What will happen in terms of side effects?
What will happen in terms of downstream consequences?
So despite this initial wariness, clinical trials are still gone on for
some particular drugs and the thing is that the drugs often work.
So, sometimes, although we worry or we don't want to have too great an
influence, in terms of we don't want to have terrible side effects.
We know that the current options for drugs for cancer patients already give
them a horrible array of side effects. And so, it's not necessarily true that we
can predict what side effects might be just by thinking about a drug, rather you
need to try. And really, the primary aim is to get
patient survival, so while we want to minimize side effects, the primary aim is
patient survival. So if epigenetic drugs may in fact extend
the survival period, then they would still be a very good thing.
And then sometimes, it, at least for adult cancers, the long term consequences
of the use of these drugs is usually not considered.
This is considered for childhood tumors but the long term consequences of the
drug that you might give to somebody whose already quite elderly, so many
patients with myelodysplastic syndrome are in their 70s.
We don't necessary think so much or clinicians don't think so much about
these long term consequences but rather extending the lifespan and the quality of
life of these patients. So, to begin with these drugs have been
targeting the enzymatic epigenetic regulators.
So the ones with enzymatic function, that is that they actually lay down a
particular epigenetic mark, remove an epigenetic mark or the Swi/Snf type
class of chromatin remodellers, any of the chromatin remodellers
that have enzymatic function. They use ATP and bind ATP and use
ATP to move the nucleosomes around. All of these are enzymes.
And the reason these have been targeted first is that in terms of chemical
biology these are most easily targeted with small molecules.
They can find the active site of that particular enzyme and target that active site.
So if we come back to this picture again
of the various classes of enzymatic epigenetic regulators in this case, we
haven't got the ones that are binding to particular chromatin marks.
I'm just showing you a few of the drugs that are currently either in clinical
trial or FDA approved or the ones that are in pre-clinical trial for various
classes of drugs. There's no way I could fit all of them on
one slide and have you be able to read it, so I just have a select few here.
What you'll notice is that there are drugs against DNA methyltransferase, so
DNA methyltransferase inhibitors, histone deacetylase inhibitors, histone
methyltransferase inhibitors, histone acetyltransferase inhibitors, and
histone, sorry, I've made a mistake, they're histone demethylase inhibitors.
So we have broad classes of these drugs. We're targeting most of the enzymatic
epigenetic regulators, at least for the information that's out there at the moment.
There are just two classes where we don't
yet know of any drugs that are targeting this.
This doesn't mean that pharmaceutical companies aren't doing it, but at least
it's not public information at this stage.
So we don't necessarily know that they're targeting the DNA
demethylases the TET proteins or the chromatin remodelers.
I expect there will be but we haven't yet got the information in the public domain yet.
So what I'd like to point out is that,
say for example, EXH2, which I mentioned was mutated in several types of blood,
cell disorders and amplified in solid malignancies.
There's an EZH2 inhibitor that's currently in pre-clinical trials.
So that means, before it actually goes into a full-blown clinical trial, it's a
very effective EZH2 inhibitor called GSK126.
So this might be extremely useful in those cases, where you have gained a
function of EZH2 but less useful in the cases where you have a loss of function of EZH2.
We know there are many more in
development against others, and there's one in clinical trial against a histone
methyltransferase called Dot1-Like. There are those against histone
acetyltransferases, histone demethylases, that are in pre-clinical trials and many
in development. But at the moment, there are just four
drugs that are already FDA approved. So FDA approved means that it's the Food
and Drugs Administration authority that's in the US that's approved them for use
altough they're in use in other places around the world as well.
So these are the first sets of drugs that are supposed to be targeting the
epigenetic machinery. For the two that are DNA
methyltransferase inhibitors, decitabine and vidaza.
They're approved for use in myelodysplastic syndrome that has
progressed to cute myeloid leukemia or AML.
Whereas, the histone deacetylase inhibitors are approved for a cutaneous
T-cell lymphoma. So this is a very particular type of
lymphoma that is just, that occurs in the skin, where you can see the
build-up of the, the T-cells in the skin. Both of these of course are hematopoietic
malignancies, so malignancies of the blood.
So let's, think first of all about these DNA methyltransferase inhibitors.
So DNA methyltransferase inhibitors, I've mentioned one of them before in the past
when I was talking about X inactivation. And that was 5-azacytidine, which
inhibits DNA methyltransferase one. These drugs, Vidaza and decitabine and
also any of the other that are in pre-clinical trial are kind of very
similar to 5-Azacytidine. They've just had additional modifications
take place, so they're all nucleoside analogs.
So they get incorporated into the DNA upon replication, and then, when the DNA
methyltransferase comes along to bind it, the DNMT1 comes along to bind that
nucleotide to then copy the methylation to the daughter strand, that DNA
methyltransferase is bound irreversibly and it can no longer be released.
And this means that the action of these DNA methyltransferase inhibitors is
division dependent so you have to have the cell replicating.
So this means that cancer cells which are dividing much more rapidly than most
other cells in the body will be more severely affected because they're
replicating more. So these DNA methyltransferase inhibitors
were first used back in the 70s, I think. But at that time point, they were using
them with very high dosages and at very high doses they're just toxic really.
They don't have any specific effects, they're toxic, they have terrible side
effects and the patients become very ill. But they're not actually very good at
getting rid of cancer. And that's because you're not acting in
the range in which they cause DNA demethylation.
So instead, much more recently, they've been used at much lower doses.
And at these much lower doses, far, far, far lower doses, you actually do have a
very good anti-neoplastic effect, in other words, you are killing the tumor
cells. And that's because they seem to be
causing DNA methylation, at least in some cases.
So, the DNA methyltransferase inhibitors, although they are actually inducing
people who had taken them around the world, we still don't really know about
how much is specific about this DNA methyltransferase.
They probably hit all dividing cells to some extent, and so, we don't know what
the long term consequences would be on normal cells, because every, most cells
will divide at some point and if the demethylation transferase have been
taken, then they have the potential to be affected.
While I said this is that they've given it the range now that causes DNA
demethylation, we don't know that, that's their only mechanism of action.
Maybe that they're having an effect through other ways as well.
And at the moment, we're not really clear why it's only myelodysplastic syndrome
where they seem to be most effective. In fact, they're in clinical trial for a
very large number of other malignancies, including solid malignancies.
But it's possible that it's very effective or the reason they found it was
most effective in myelodysplastic syndrome is because, you remember, it
might be dependent on CpG island hypermethylation.
And we know that CpG island hypermethylation, heavy CpG island
hypermethylation, has a poor prognostic outcome for myelodysplastic syndrome.
What's interesting is that these myelodysplastic syndrome patients
tolerate these DNA methyltransferase inhibitors extremely well.
So these do tend to be older patients in their 70s.
They tend to be put onto this drug if they've already failed on other
chemotherapeutics, but they then respond extremely well to the DNA
methyltransferase inhibitors and have a far superior life expectancy.
But also, their quality of life is improved because their side effects don't
seem to be too severe. So this goes against all of those things
I think that we were wary about in the first place with the DMNT inhibitors.
So, for the histone deacetylase inhibitors, there are four different
classes of histone deacetylase inhibitors, and that's because there will
target different types of histone deacetylase. The two that are approved, are actually
pan histone deacetylase inhibitors. In other words, they target all four
classes of histone deacetylase. And at the moment, they profuse in this
particular cutaneous T-cell lymphoma. Although, some events suggest they are
effective in other lymphoid malignancies as well.
So with the histone deacetylase inhibitors they might be considered in
some way more dirty than those DNA methyltransferase inhibitors in terms of
their mode of action. And that's because they really show a set
of pleiotropic effects and that's because they don't only target the histone
deacetylases but also other protein deacetylation as well.
It can happen in the cytoplasm or the nucleus so it's not even necessarily a
nuclear restricted, but it also seems to inhibit the acetylation of other
transcription factors for example that are also important in gene expression.
The histone deacetylase inhibitors just like the DNA methyltransferase inhibitors
aren't selective for the cancer cells. So the precise mechanism action is
unknown for a couple of reasons, because we don't know which cells are really
affected, and we don't really know whether its working in the nucleus or the cytoplasm.
But you do see gene expression changes,
but as I said some of this may be explained by them actually working on,
inhibiting the deacetylation of transcription factors rather than the
histones themselves. At this point, the fact that we don't
really know their mechanism of action, again, isn't terribly important, because
again, they're very well-tolerated by the the patients who receive them for
cutaneous T-cell lymphoma and they are extremely effective for these patients.
At the moment, what's very interesting is thinking about how you could use two
different epigenetic drugs together. So we know that the way that epigenetic
works, if you think about maybe x inactivation as an example, is that you
have several layers of epigenetic marks all coming together to be able to bring
about epigenetic silencing, for example. So perhaps by just targeting one, maybe
with a histone deacetylase inhibitor, you won't have the most effective outcome.
But if you can target the epigenetic machinery twice, say with DNA
methyltransferase inhibitors and with histone deacetylase inhibitors, perhaps
both at much lower doses, you might have the optimal outcome both epigenetically
and in terms of side affects. So there are now many clinical trials
going on looking at these two being used together, but also in combination with
standard chemotherapeutics. So how, perhaps you can use standard
chemotherapeutics, which tend to be associated with terrible side effects and
lots of nausea. Maybe you can use them at much lower
doses with low doses of epigenetic drugs as well.
So, one of the recent developments, in terms of targeting the epigenetic
machinery is that now we're not just targeting, the pharmaceutical companies
aren't just targeting those enzymatic epigenetic regulators, but they've taken
a much broader look now. And so they're beginning to target just
protein-protein interactions. So let's say, for example, chromatin
proteins that bind to an acetylated histone mark or methylated histone
residue. In this case, the ones that have been
released are the ones that target bromodomain proteins, called
BET proteins. So these are called BRD2, 3 and 4.
So, remember bromodomains bind to acetylated histone tails as shown here.
And these BET domain inhibitors are again seem to be very effective.
So in this case, just like with the other two cases, we don't know a huge amount
about their mechanism. But what's interesting here is when you
treat cells with BET inhibitors, they don't have very many gene expression
changes, just a small set. And in particular, you seem to alter and
downregulate the expression of this potent oncogene, MYC.
So perhaps, they're having a very direct effect on MYC-, on MYC.
But in general, it seems like, maybe these BET inhibitors have a role by
altering transcriptional elongation. We still don't know how this might work
mechanistically, but it's possible that's how they have an effect in cancer.
So now, I want to turn to thinking just briefly about the future of targeting the
epigenetic machinery. Well, with every new publication that
comes out, there are new mutations being reported in the epigenetic machinery.
So, this is a very very active area of research for pharmaceutical companies,
and an active area of research on, in the basic end of science as well.
Asking what are these mutations doing, how are they altering the function of
these particular proteins? So, while there was early wariness about
target in the epigenetic machinery and there's still concern, it seems that
these drugs are surprisingly effective. And so, perhaps that early wariness is
going to dissipate with time. So what, what do we expect to see, how
will this change the future for cancer therapies?
Well, probably over time, we'll see that these recurrent mutations that are found,
maybe you'll have drugs targeting specifically that mutated form of the protein.
Now, if it only targets the mutated form
of the protein, it will be a syllable if you like.
It shouldn't affect the the neighboring cells because it will only affect that
mutated protein that's found in the cancer cell.
As I said, they're trying more combinatorial epigenetic drug
treatments, so putting multiple targets together and because we know this is how
epigenetics works normally. If we target multiple components of the
epigenetic machinery that go wrong in cancer, perhaps, you can have a more
effective outcome. And then combining these drugs with
standard chemotherapy. So while the approved drugs that are
being used are only being used at the moment in hematological malignancies,
they're being trialled in a much broader array of cancers.
And so solid cancers and these combinations of drugs and solid cancers
and hematologic malignancies. So probably in the coming years, they'll
be approved for all sorts of other cancers as well.
What's quite interesting is that cancer isn't the only case where we have epigenetic
abnormalities, it's not the only disease, it is the one that affects most people by far.
But maybe these drugs that are being
developed because of the high prevalence of cancer in a community may actually be
useful for other disorders as well, these disorders where we know epigenetic makeup
is altered. And so, indeed, now they are being
considered, these epigenetic drugs are being considered with other cases as well.
And perhaps the wariness that we should
keep those, the wariness that should remember about is that still these drugs
are going to be used throughout the system until every cell has the
potential to be effected by these drugs. So maybe still need to keep in mind that
younger patients, particularly those that have developing germ cells for example in
sensitive periods, we should remember about the sensitive
period so that one very large insult to the environment would be taking a drug
that inhibits the epigenetic machinery. So these sorts of things still need to be
considered, but it seems that the future is bright for targeting the epigenetic
machinery in cancer. So that brings us to the very end of this
7-week course. So congratulations to all of you that
made it all the way through the 7 weeks.
You've done very well to listen to me for that long.
And I hope that you've enjoyed the course.
Hopefully, you feel like you've come away with a better understanding of epigenetic control.
Maybe you'll be able to understand a
little bit about the epigenetics literature when reading scientific
articles, and hopefully, much more when you read something about epigenetic
control in the public press. Maybe you now understand that you are or
you are not what your grandmother ate and you understand a little bit about
epigenetic difference between twins. And I hope there's something you've taken
away that your excited about. Okay.
Thanks, bye.
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