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I’d like to take a moment and introduce the faculty that
our joining me tonight. Dr. Alan Sandler is an associate professor
of medicine in hematology/oncology at Vanderbilt University in
Nashville, Tennessee. Vanderbilt really is in Nashville, Tennessee,
although, there is a Nashville, Texas but I haven’t been
there yet.
He is also
the medical director of the Thoracic Oncology Program and the
director of the Vanderbilt-Ingram Cancer Center Affiliate Network,
which is a community oncology network.
Also joining
us this evening is Paula Muehlbauer. She is a clinical nurse specialist
in surgical oncology and biotherapy at the National Institutes
of Health in Bethesda, Maryland. She is also responsible in her
role for research, coordination, and implementation of research
protocols, orienting her staff and helping facilitate clinical
trial coordination on the units, as well as patient and staff
education and assisting and developing care plans and patient
care education tools.
One of the
nice things, also about this evening’s program, is in your
handouts you will find an article that is from this month’s
issue of the Journal of Clinical Oncology. This is one of the
primary topics for which we are here tonight, looking at the combination
of VEGF and EGFR targeted therapies. Dr. Sandler was principal
investigator and very involved in this clinical trial in non-small
cell lung cancer. We thought that would be a benefit to provide
to you since not all of you have access to JCL.
What we also
like to do if you haven’t noticed already, is that you have
the response system there at your table. If you would please grab
one of the gray keypads and pass those around; not that you haven’t
seen them before and you have no clue how to work them, but if
you would be kind enough, we’d like to ask one question
to get us started this evening. And it’s not where Nashville
is located, so we’ll move right on to the real question.
What we’d
like to ask is how knowledgeable are you in the subject of targeted
therapies? You have three responses:
1) Very.
I’m here for an update on the topic.
2) Somewhat. I need new information and more information to
feel comfortable caring for patients on targeted therapies.
3) Not at all. This is the first educational program I’ve
attended on the topic.
If you would
please go ahead and chose your answer and we’ll see responses
in just a moment.
Notice the
music. What you will notice also is that there is a clock that
ticks down. We have ten seconds for the response system.
The answer
is: About 70% of you have knowledge in this area. Several of you
are very knowledgeable and we would definitely appreciate any
input you have if you have suggestions or changes for us at all.
There are 18% of you that are new to this and we do hope that
we provide you information that helps you care for the patients
receiving these therapies. Thanks. Keep those handy. We’ll
have those throughout this evening’s program.
With that having been said, I’d like to go ahead and start
the program. The official program, at this point, looking at VEGF
and EGFR signaling the rationale for targeting multiple therapies.
As we continue to gain information from translational research
and new information and ongoing knowledge through clinical practice,
we are learning more and more about how to combine these therapies,
the rationale behind them, the nursing care, and the physician
care, and the coordination care for patients that are receiving
these novel agents.
When we look
at a cancer cell, we know that malignant and transformation in
cell progression occurs through a variety of processes. We know
that the cancer cell becomes self-sufficient. It can through autocrine
and paracrine growth pathways stimulate its own survival and its
own development. It becomes insensitive to negative growth factors
and negative growth signals, so that is one of the mechanisms
through which cancer cells can progress.
Additionally,
as they progress, you have tumor invasion into peripheral tissues,
into the lymphatic system, the circulatory system, and you get
invasion and metastasis. Cells also then develop a limitless replicative
potential and so we have ongoing cellular paracrine occurring.
And as a result of that, and through walking and interference
with the apoptotic pathway, cells become immortal through the
processe that we’re going to talk about tonight. Tumor cells
are able to initiate and sustain their own angiogenesis and their
own vasculature.
In order for angiogenesis to occur, we know that tumor cells are
dependent on this process. This process occurs as a result of
abnormal signaling pathways being stimulated. These pathways then
stimulate cellular processes and the release of other growth factors
to stimulate abnormal angiogenesis and tumor vascularization.
Also within tumors, cells have heterogeneity; meaning that different
cells within a tumor are going to respond differently to our therapeutic
strategies. So you have a variety of cell types, as far as their
response to therapy, and often times then, using combination strategies
will help overcome that resistance.
When we look at the development of cancer and malignancy, we know
that the inception of malignancy, the tumor and the cells are
so small they are not identifiable through blood test or through
radiology procedures. As the cells multiply and divide, you can
have local, regional metastasis. You can have distant metastasis.
Many of our patients we know are diagnosed at a later stage in
their disease. They have a heavier tumor burden and larger tumors
we know are necrotic. That will be a key thing when we talk about
stimulation and stimulators of angiogenesis. This graph shows
you the tumor development and the TNM staging that is also used
at the time of diagnosis of a patient.
In order for angiogenesis to occur, it is a result of induction
and increased secretion of angiogenesis factors from within the
tumor cell, within the tumor itself, and within the tumor microenvironment.
There is also down regulation of the angiogenesis inhibitors,
so you have a dual process of upregulations of angiogenesis factors
and down regulations of angiogenesis inhibitors. At the same time,
the tumor produces its own angiogenic factors. Within that, you
have interaction between the tumor and the host microenvironment;
and so you have a take and give process going on where there is
cross stimulation and release of products, including beta fibroblast
growth factor, smooth muscle cells are involved, as well as infiltrating
the immune cells and alternating the immune system.
We know for
angiogenesis that tumor hypoxia is a key stimulator for initiation
angiogenesis and the process for which tumors then can get their
own supply. If we think about the previous slide, we know that
small tumors very quickly outgrow their blood supply. The only
way for those tumors to become larger is through that process
of angiogenesis. As a sidebar of that process of angiogenesis,
and we’ll talk about leaky blood vessels, that also facilitates
migration and the movement of cells and so you get the local regional
and distant metastasis.
Endothelial cells must do a variety of things in order for angiogenesis
process to be complete. One of the primary things that must occur
is that endothelial cells must migrate through the capillary basement
membrane towards a stimulus. That occurs as a result of MMPs or
matrix metalloproteinase that degrade the extra cellular membrane
and the extracellular matrix allowing endothelial cell migration
to occur. Once that migration occurs, these cells then proliferate,
they form new capillary tubes, ultimately develop new vasculature
and assist with tumor cell and tumor survival.
In addition
to that, an understanding of that is necessary with the vascular
endothelial growth factor. VEGF plays a key role in stimulating
and maintaining the process of angiogenesis.
This shows the VEGF family receptors and ligands. What you’ll
notice is that you have the placenta growth factor and you have
four ligands that are members of the VEGF family. The primary
ligand that we are going to talk about today is VEGF-A. That’s
the primary ligand that is responsible for angiogenesis and that
is the target of bevacizumab, which we will be speaking about
tonight.
There are three VEGFR receptors, and each of those receptors plays
a slightly different role in angiogenesis. The primary role for
VEGFR-1 is angiogenesis. VEGFR-2 has a dual function and that
is angiogenesis and lymphangiogenesis, whereas VEGFR-3's primary
role is lymphangiogenesis. But, again, we are going to be focusing
on targeting primarily the ligand.
Again, in
looking at it from a little bit different perspective, VEGFR-1
is thought to help and assist with endothelial cell migration.
So that is, again, part of the role of the downstream signaling,
once the VEGF receptor as been activated.
The VEGFR-2
then mediates proliferative activities of VEGF. It enhances vascular
permeability, which is the leakiness within the vasculature allowing
additional migration to occur. This also enhances cell survival.
VEGF-3, as I said before, primarily is responsible for lymphangiogenesis.
In addition to gene mutations, there are a variety of things that
occur within the tumors microenvironment that play a key role
in angiogenesis. Those occur both in the extracellular domain,
as well as down stream signaling domains. What you’ll see
here at the top is that there are upstream activators of vascular
endothelial cell factor synthesis. One of the key things we know
is hypoxia, and that’s critical as we talked about our patients
with larger tumors and larger tumor burdens. Again, hypoxia is
a key stimulator of angiogenesis. We have oncogenes, beta fibroblast
growth factor. We will also be talking about EGFR, the epidermal
growth factor receptor and its role in angiogenesis, which also
helps provide the rationale for dual targeting. Low pH, which
can occur as a result of hypoxia, PDGF alpha or platelet drive
growth factor. There are a variety of mechanisms and there is
interplay within those mechanisms for stimulation downstream signaling.
Once VEGF
finds there is activation of the VEGF receptor and within the
endothelial cell downstream signaling allows enhanced survival
through blockage and interference with apoptotic pathways, cellular
migration and changes within the matrix then allowing a change
in the adhesion abilities within the tumor cells so you get both
leaky vasculature and you get the ability for cells to migrate.
All of these play a significant role in angiogenesis.
Again, hypoxia
induces activation of HIF-1 alpha. Hypoxia Inducible Factor 1,
that is the trigger to initiate angiogenesis in many situations,
as well as the release of pro-angiogenic growth factors, such
as beta fibroblast growth factor and EGFR.
Oncogenes
such as VHL and Bcl-2 also play a role in angiogenesis and they
are involved with different pathways and different process. The
downstream regulating, once VEGFR-1 and 2 become activated, once
the VEGF ligand binds, then there is initiation of downstream
pathways. We can look at the opportunity then to target in a variety
of ways in order to block these downstream pathways.
This graph looks at the process of VEGF activation and vascular
permeability. Again, you see your VEGFR or your VEGF-A ligands.
This stimulates vascular permeability. What you’ll see here
is that instead of a solid capillary membrane, you have breaks
in the capillary membrane allowing endothelial cells to migrate.
You also have plasma protein leakage. That then develops this
extra cellular fibrin gel region, which is an excellent environment
for neovascularization and new vascular bud formation to occur.
There is
a change in the oxygen permeability as a result of these leaky
vessels and you have an inconsistent or erratic exposure of the
tumor cells to our chemotherapy agents. You also then have the
low pH. You have the changes in hypoxia and, therefore, that’s
a vicious circle of an ongoing stimulation of angiogenesis.
The goal then, of our anti-VEGF therapies to normalize the tumor
vasculature by blocking the VEGF or the VEGF receptor, we can
lead then to apoptosis of the endothelial cells, decrease the
vessel permeability, microvessel density, as well as changing
the permeability and allowing our therapies to be more effective.
By increasing the oxygen tension, we stabilize the vasculature.
Those leaky tortuous vessels that are not stable become even more
unstable and fall apart. What you have then is a more stable vasculature
allowing a more effective, more consistent administration of the
tumor to the chemotherapy agents, or your other cytotoxic or cytostatic
agents.
Now we get
to your audio response question. If you would go ahead and put
your fork down and grab your keypad, we’d like to go ahead
at this point and ask the following question:
For angiogenesis to occur, endothelial cells must:
A) Migrate
through the capillary basement membrane.
B) Degrade the extracellular matrix and proliferate.
C) Form new capillary tubes.
D) All of the above.
The answer
is D, all of the above. Very good. You can be very proud of yourself
at the end of a long day. For the majority of you, you have good
understanding of the concept ,and that’s awesome.
What I’d like to do now is switch gears. We are going to
switch from the vascular portion of the program, and this time,
we’re now going to look at the epidermal growth factor.
We are going to look at it both individually and its role in angiogenesis.
What you
see is the EGFR family receptors here. You have HER1, HER2, HER3,
and HER4. What you’ll notice is that HER2 does not have
an extracellular ligand-binding domain. HER3 does not have an
intracellular tyrosine kinase-binding domain. You have your extracellular
binding domain, which is where your monoclonal antibodies would
target and your intracellular binding domain for your tyrosine
kinase inhibitors, your oral medications. Our focus this evening
is going to be on HER1/EGFR tyrosine kinase and its receptors.
The role of EGFR or the epidermal growth factor receptor in malignancy
is critical, because it regulates the cellular processes for both
proliferation, repair, and survival. The receptor activation then
initiates a variety of signaling transduction pathways within
the cell, leading to changes and stimulation of processes within
the nucleus. You have uncontrolled cell proliferation, invasion,
angiogenesis, metastasis, and again, resistance to apoptosis.
There are a variety of agents currently available and in clinical
development that will focus on interrupting and blocking these
processes of the epidermal growth factor.
Specifically for the role of EGFR in angiogenesis, it really has
an effect on downstream signaling and stimulating the production
of pro-angiogenic factors. It stimulates the production of VEGF
and it also stimulates the production of the MMPs, or the matrix
metalloproteinase, which degrade the extracellular matrix and
allow for that leaky vessel effect to occur. We know that angiogenesis
is a common pathway in many of our malignancies. There are multiple
pathways involved and our focus is to try to block those pathways.
Blocking occurs then, both directly targeting the tumor cell and
the tumor cell associated endothelial cells, as well as downregulating
the expression and the production of the angiogenic factors by
the tumor cell; again, that autocrine process for which the tumor
stimulates its own vessel development. Therefore, by combining
modalities by VEGF and EGFR inhibition, it allows us the potential
for both indirect and direct effects on both the tumor - the endothelial
cells, and the microenvironment.
One of the challenges, though, with monotherapies, is that it
may take a long period of time. These agents are cytostatic, in
general, as opposed to being cytotoxic; so it may take longer
than what your patient has for disease to be under control. The
idea, then, of combining therapies, such as what we’ve done
with chemotherapy, may enhance the effectiveness of therapies.
We’ve
learned from some of the previous combination strategies that
we still have a lot to learn. We have new questions to be asked,
but those questions are being asked concurrently with ongoing
clinical trials.
The challenge
is that the target will work. A targeted therapy will work when
the drug can reach the target and when it can inhibit the target’s
activity in therapeutically achievable doses. Many of our drugs
we would have to give in so high a dose that we would not be able
to administer that dose; it would be too toxic. So the key is
finding targets or combination of targeted therapies where we
can give them in therapeutic doses to achieve the maximal effect.
Again, we’re
trying to avoid the potential for recurrence prior to effectiveness.
We’re also asking the question, “How long do we continue
these therapies, can they be re-administered if there’s
progression?” Again, these questions are being asked in
our clinical trial processes.
If we look at high levels of VEGF and EGFR expression within our
tumors, we know that there is the effect of invasion and the process
and metastasis, which is what occurs then through this VEGF and
angiogenesis process. We have rapid tumor growth, patients being
diagnosed at a late stage, which may be more challenging in many
situations to allow these therapies to be given long enough to
have a beneficial affect. We know that the challenge with that
is that our patients are often diagnosed at the time where they
have a poor prognosis. Their disease may be rapidly progressing
and their prognosis may be deteriorating. Therefore, we have reduced
survival. The goals of our therapy are to interfere with these
processes and improve the outcomes for those patients throughout
their therapeutic period.
The rationale then for combining strategies, different targets,
different agents, the biological heterogeneity within the tumor
necessitates multi-target approach. Lack of cross-resistance with
these drugs; we can combine these drugs with minimal overlap in
toxicities. The drugs such as bevacizumab and Erlotinib do not
have overlapping toxicities or myelosuppression, and so there
is the potential then not only to give them at full dose, but
to give full efficacy of each agent while we’re also containing
and potentially having a synergistic affect.
One more audience response question.
The EGFR
pathway contributes to the following processes of angiogenesis:
A) Stimulates
the production of vascular endothelial growth factor.
B) Stimulates the production of capillary tube degradation enzymes.
C) Stimulates the production of matrix metalloproteinase.
D) Both A and C.
The answer
is D, 83% of you have the correct answer. That’s excellent,
very good.
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