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Is endometriosis angiogenesis dependent?
Dr Robert Greb and Professor Robert Taylor listen
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Media Player Lone
Hummelshøj:
I’m reporting from the 11th World Congress of Gynaecological
Endocrinology in Firenze, Italy and with me this afternoon is Professor Robert
Taylor, from the University of California, San Francisco, United States, and Dr.
Robert Greb from Münster
University Hospital in Germany. We have been talking about endometriosis and angiogenesis
this afternoon, and Professor Taylor: we have always known that endometriosis
was a hormone-dependent disease but it sounded to me this afternoon as if
there’s a bit more to it than that. Would you like to elaborate? Professor
Robert Taylor:
I’d be happy to, thanks for inviting us to speak with you this
afternoon. Increasingly, over the last decade, there has been a lot
of interest and focus on the vascular aspects of endometriosis and the
importance of angiogenesis, the formation of new blood vessels, in supporting
the tissue that most of us believe arises in the peritoneal cavity as a result
of retrograde menstruation. One of the more interesting new hypotheses, is that
for these implants of tissue to grow, they need to recruit a new blood supply.
Many laboratories now focus their attention on how the endometriotic implant
might recruit this blood supply. Some of the work that’s been done has suggested as Dr.
Greb described at his afternoon presentation, that the superficial epithelial
layer of the endometrium, which is the functionalis layer, is particularly rich
in angiogenic factors. If these are indeed spilled into the peritoneal cavity,
that provides an excellent opportunity for those factors to be released locally
and to recruit new blood vessels. Just how that process is actually regulated is
one of the things that this group of investigators has been quite interested in. Robert, from your point of view, which factors do you
think are most important in allowing this angiogenic process to be initiated? Dr. Robert Greb:
I think a lot of work came from primate studies. It’s always difficult
to study the molecular mechanisms in humans because we can’t control really
for the action of hormones and what their effects are on the endometriotic
tissue in an experimental setting. We have a long-standing interest in how
hormones regulate angiogenic molecules in the normal endometrium and also in
endometriosis. From the studies in primates, I think what is very clear
is that oestrogen has a rapid effect on the up-regulation of VEGF, which is one
of the key mediators of angiogenesis, and this affects gene expression within
hours. Of course in general, there are so many factors, which might be
important. One thing we didn’t talk about today is that there are also
naturally occurring angiogenesis inhibitors, thus the right balance between
activators and inhibitors might finally determine whether the tissue is
angiogenic and recruits new blood vessels, or not. Professor
Robert Taylor:
I think that is an important point to bring out and one that came out of
our discussion. In the nature of the 20-minute presentations that we’ve had,
it’s hard to go into a lot of detail. I think it made sense to focus, as you
did, on the role of vascular endothelial growth factor (VEGF), which is one
that’s received lots of attention in the literature. I think the point that
there are a variety of pro-angiogenic, as well as anti-angiogenic factors, and
these are critical as the state of balance is going to need to be sorted out
before we really understand the complexity of this. Your point about the steroid regulation in acute, versus a
chronic, setting is also quite interesting. You are right, the primate models,
cynomolgus monkeys and rhesus
monkeys, really made for a nice way of looking at that. In many of our other
studies, we used biopsies taken from women and then placed in a culture where we
can do relatively acute experiments. In those settings, I think we’ve been
able to understand quite well how oestradiol can induce the VEGF gene promoter
activity, and study the transcription and expression of VEGF protein in an
isolated in vitro acute setting. But you are right, the complexity in
vivo is substantially greater and now we’ve had an opportunity to look at
some of those factors. Dr. Robert Greb:
That’s right, but I think that hormones are only one side of the coin,
and as clinicians know very well, there’s also the aseptic inflammatory
response, which seems to be very important in maintaining the disease. I think
there is also very good evidence that a lot of cells, macrophages and other
immune cells are mediating these responses, and are sustaining the activity of
the disease like in a vicious cycle. Professor
Robert Taylor:
That’s a very important point. The complexity of the tissue itself, the
endometrioma, the endometriotic tissue, there are multiple cell types, the
endometrial cells per se and the vascular cells of course. But you’re
right, inflammatory cells, which include neutrophils to some extent and
macrophages certainly are extremely important. It’s only really within a whole
tissue that you can study these components again it has been a little difficult
to do in an in vitro type of model.
Lone
Hummelshøj:
So what does all this actually mean for the patient? Where is the
clinical application in this whole scenario and are there different stages of
endometriosis that you have to, attack if you like, in a different way? Dr. Robert Greb:
Well, of course we have the main problems: infertility and pain. Nowadays
with techniques of assisted reproduction there are efficient treatment options
for the infertile patient. But what is really a great burden for women is the
pain – to treat chronic pain adequately over several years. For pain relief we
actually need treatments, which can be administered for a long period of time
without causing too many side-effects; currently effective permanent treatments
are not available because side-effects from standard treatments, GnRH analogues
for example, do not permit their extended use because the hypo-oestrogenism
results in several side-effects like vaginal dryness, hot flushes and
osteoporosis. In oncology anti-angiogenic agents have been added to the
panel of treatment options because they can be administered for several years
for example, without having dramatic side effects like chemotherapy. For
endometriosis I’m also thinking about anti-angiogenic substances like sFlt-1.
That’s one example besides anti-VEGF antibodies, which could be given for a
long period of time, and potentially maintain
endometriosis tissue in an inactive state, eventually at a level
where pain can be relieved sufficiently. Professor
Robert Taylor:
Presumably these would be administered in sequence, or possibly
simultaneously, with other kinds of therapies that we currently have. But we
ought to be able to reduce the side effect profiles by having more targets. I
think that’s the most attractive aspect of focusing on the blood vessels
themselves, and maybe the inflammatory response too. We talked a little bit
about macrophage activation, anti-inflammatory medications, and anti-oxidant
types of vitamins that can be used to target that type of cell as well. I would
anticipate that we will have combination therapies that probably each have
certain side effects, but by mixing them together we ought to be able to,
hopefully, reduce those side effects and still maintain a good therapeutic
potential. Dr. Robert Greb:
However, I think we have to be aware that it will still take some time until we
can really translate this research into clinical practice because many
mechanisms are not well understood. For example, we don’t know which blood
vessel phenotype is susceptible for regression after we apply an anti-angiogenic
treatment, or which substances are most appropriate to reduce the inflammatory
response. I think a lot more basic research studies have still to be done to
understand the biological mechanisms before we can translate this new treatment
options into clinical practice. Professor
Robert Taylor:
It also means some potential risks, particularly in young women who are
anticipating having children later. It will be important to know that we’re
using agents that aren’t going to have prolonged effects that might be
dangerous to future fertility. Pain symptoms should be amenable to this type of
therapy. But I think we also have to be careful that we don’t compromise other
aspects of the treatment, such as life plans. Lone
Hummelshøj:
This all sounds very interesting and very sensible as well, but what are
we talking about when you say timelines, and it’s going to take a while? How
long is a while? Professor
Robert Taylor:
I think we’ll start to see the first therapeutics in cancer treatment
within the next few months, using anti-angiogenic agents that are likely to be
approved quite rapidly, both in the United States, through the FDA, as well, I
believe, through the European Drug Administration program. So I think we’ll be
getting to have access to agents that are quite effective at targeting blood
vessels. My guess is that there will be a period of five years while they are
applied in this setting before we’ll be likely to see an approval for
endometriosis. My suspicion is that it will be in a post-reproductive woman with
endometriosis pain problems that might be the first place we get to see these. Now, a number of therapies are being used, aromatase
inhibitors, in settings that are similar to this. I think we’ll start to see
their application in the next several years. I don’t know if you have clinical
trials planned for some of these agents? Dr. Robert Greb:
That is my best guess, too. What is indirectly also an anti-angiogenic treatment
is the use of selective progesterone receptor modulators and these substances
are already in phase II and phase III clinical trials. These options will become
available, I think, in an even shorter time frame, like in a few years. These
compounds may represent also an anti-angiogenic treatment approach, although via
indirect antiangiogenic action. Professor
Robert Taylor:
Yes, I think that’s a nice point to emphasise. There are a number of
agents that we’ve used clinically for years that we might not think of as
having anti-angiogenic effects. But they in fact do, dramatically, affect the
vasculature and maybe that brings us back a little bit full circle. Endocrine
effects on the uterus, ovaries, and blood vessels in the pelvis are an important
part of the regulation of blood vessel function and anti-angiogenesis. Those
have been the mainstays of our treatments for endometriosis in the past; I think
we already have some hints about how what sorts of drugs can be beneficial in
that setting. I also agree that the new progesterone receptor modulators
are going to be quite interesting to look at in that respect. You’ve done some
nice work actually in the primate model, looking at effects on vasculature as
well, right? Dr. Robert Greb:
Yes, that’s right. Mifepristone, one of the classic progesterone receptor
modulators, showed astonishing effects on the expression of vascular endothelial
growth factor (VEGF), in the glands of the endometrium in monkeys. Lone
Hummelshøj:
Well, it sounds as if we’ve come some way but there’s a way to go
yet. Which messages would you like to leave in conclusion for our listeners this
afternoon? Professor
Robert Taylor:
Again, I think it’s really important for us to try to understand this
as rationally as we can the underpinnings of the cell biology of endometriosis.
To try to understand what cells are involved and how they are regulated to do
some of the things that they do. Then we’ll have a much more, I think,
informed approach as how to develop new therapies. It’s a conservative
approach, and unfortunately it takes more time to do it this way. From my perspective that’s the message that’s most
important to get across. We want to understand both the safety and the efficacy
of the new types of therapies that develop and to try and get them into the
hands of clinicians as rapidly as we possibly can, but without risking the
health and well being of the women for whom they are really intended. Dr. Robert Greb:
Yes, I agree. Even with the enthusiasm we both have, probably, with regards to
these new options, it remains to be seen firstly, whether the drugs will work,
and secondly, whether they are safe. Lone Hummelshøj: Thank you very much. See also angiogenesis therapy for endometriosis
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