March 18, 2024 • 22 mins
The relief of a successful cancer treatment is all too often marred by a distressing, lingering uncertainty of whether a cancer will return. Cancer cells can tuck away and lie dormant for years before waking up to spread once again. In this episode we speak to Professor Peter Croucher who is tackling some of the toughest problems in cancer research – how can we track cancer cells on their way to becoming dormant, how can we stop them from waking up and how can we eradicate them from our system completely?
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Dr Viviane Richter (00:01):
The relief of a successful cancer treatment is all too
often marred by a distressing, lingering uncertainty
come back? The devastating reality is that cancer cells can
run and hide. They can tuck away and lie dormant
in different parts of the body, often inside bone, for
years before waking up to spread once again. In today's episode,
(00:23):
we speak to a Garvan researcher who is tackling one
of the toughest problems in cancer research. How can we
track cancer cells on their way to becoming dormant? How
can we stop them from waking up? And how can
we eradicate them from our system completely? You're listening to
Medical Minds. The podcast that takes you inside the labs
(00:43):
at the Garvan Institute of Medical Research. I'm your host,
Dr Viviane Richter. And with me here is Professor Peter Croucher,
Head of the Bone Biology Lab at Garvan. Welcome, Peter.
Prof Peter Croucher (00:54):
Hi, Viviane. It's great to be here.
Dr Viviane Richter (00:57):
Peter, before we talk about how you're tackling this critical problem
in cancer, could you tell us where your inspiration to
become a scientist came from?
Prof Peter Croucher (01:05):
So I'm a zoologist. I was brought up in the
very south west of the UK. And in my formative
years I spent time collecting animals and had fish tanks
and all sorts of creatures that I used to look after.
And then when I went to university, I did zoology.
And as part of my zoology training, I spent some
time in a lab doing medical research, looking at the
(01:27):
role of cancer drugs in the immune system. So once
I'd finished my time at university, I chose to do
a PhD and was asked, or given the opportunity to
do a PhD in skeletal biology.
Dr Viviane Richter (01:40):
What was it about skeletal biology that really interested you?
Prof Peter Croucher (01:44):
When I was offered this opportunity, I met somebody that
was actually working on osteoporosis, and this is obviously a
pretty devastating disease that affects the skeleton. You lose bone
and have pathological fractures. So it excited me that we
could actually spend time trying to understand this disease and
develop new approaches to treating that. So I started my PhD,
(02:05):
and we were using rather old technology at the time
to investigate how bones changed over time and in in fact,
we we spent time using sort of old fashioned computers
that would fill a room now using histological slides to
try and measure things in those slides and understand how
the cells that control bone take away bone and cause
(02:27):
the sort of devastating effects on the skeleton.
Dr Viviane Richter (02:30):
Can you tell us a little bit more about the
specific project that you were working on?
Prof Peter Croucher (02:35):
So we were interested in the cells that resorb bone
and these are important cells because they take away bone
that's not mechanically competent and need to be replaced. And
these cells are called osteoclasts, and at the time we
had little or few approaches to being able to study
this in people. So we were taking, uh, samples of
(02:55):
bone from people using histological approaches to identify these cells
and then using image analysis tools using very old fashioned
image analysis computers to actually quantitate and measure the changes
in bone that were going on in patients with osteoporosis
and other disorders as well.
Dr Viviane Richter (03:15):
What did you learn?
Prof Peter Croucher (03:16):
Well, we found that different types or different patients would
have different outcomes in terms of osteoclastic bone resorption. So,
for example, if you have postmenopause osteoporosis, you would resorb
more bone than you would do normally, and we found
that the sites where bone resorption was going on. You
had many, many more of those sites, so it opened
(03:37):
up the opportunity to think about how we could actually
start to treat diseases such as osteoporosis.
Dr Viviane Richter (03:43):
So the inside of bone is quite a dynamic environment.
Prof Peter Croucher (03:47):
Now, that's absolutely right. So bone is itself a very
difficult tissue to understand and study. It's a sort of
hard tissue. It's inaccessible. There's an outer layer of bone
that you have to penetrate before you can see inside
a bone and then actually study what's going on in
that environment. So inside a bone you have all your
bone marrow, which is the site of blood cell formation
(04:09):
and where your immune system is developing. And on the
surface of bone are all the cells that are responsible
for controlling bone and changing that bone over time. But
at the time I did my PhD, the only tools
we had were really histological tools. So you've got a
snapshot in time only, and seeing that complexity and the
dynamic changes in bone was always something that was an
(04:31):
aspiration when I started my PhD.
Dr Viviane Richter (04:35):
And where did you go from there?
Prof Peter Croucher (04:36):
So after I completed my PhD I went to Cambridge.
I spent some time working with my PhD supervisor, but
she gave me this opportunity to go and work in
a different lab to gain some different experiences. I went
and worked at the Laboratory for Molecular Biology, which is
a very well known laboratory in Cambridge where people do
(04:58):
a lot of molecular biology. And I spent time working
with a haematologist there, learning molecular biology and applying that
to study the skeleton. And it was while I was
there that we really got interested in cancers that grow
in bone. And one of the most devastating cancers that
grows in bone is a disease called multiple myeloma, which
is a blood cancer and that lives in the skeleton
(05:21):
and hijacks the normal processes that go on in bone.
It causes sort of devastating osteolytic bone disease, and this
is largely mediated by osteoclasts resorbing more bone than they
should do. And it's become a a sort of model
in some ways for an extreme form of bone loss.
Dr Viviane Richter (05:40):
So, Peter, how are you investigating this disease?
Prof Peter Croucher (05:43):
So one of the things we recognised was it was
particularly difficult to study myeloma in patients. So we spent
some time developing animal models of multiple myeloma. And and
this turned out to be a sort of pretty wise
decision because we were able to use these models to
understand how myeloma cells hijack bone, how they cause bone disease.
(06:08):
But we discovered some molecules that the tumour cells had
actually hijacked in the bone environment, and that actually caused
more osteoclasts to form. And that discovery led to the
development of a new treatment that ultimately is one of
the most widely used treatments studied , or in in
the treatment of patients with multiple myeloma.
Dr Viviane Richter (06:27):
What's the treatment?
Prof Peter Croucher (06:29):
So we discovered a molecule called RANK ligand, and this
particular molecule is now being targeted by an antibody called denosumab.
And that's now widely used in the treatment of bone disease,
not just in myeloma but also in patients with osteoporosis.
Dr Viviane Richter (06:45):
That must be an incredible feeling to know that the
research that you were involved with is helping to change
the lives of many people today.
Prof Peter Croucher (06:53):
Yeah, it's super exciting. It's clearly a huge team effort, and many,
many individuals are involved in this, but actually contributing in
some small way is incredibly humbling, really.
Dr Viviane Richter (07:05):
And do you think this treatment has changed the dial?
Prof Peter Croucher (07:09):
I think so. So when I first started research in
multiple myeloma, there were few treatments for the devastating bone
disease that occurs in this particular disease. So I think
over the last decade or so, we've seen the introduction
of two new treatments, both of which we've worked on
and contributed to the development of. Individuals that have myeloma
(07:32):
will commonly present with bone disease. And in fact, almost
all patients will have some form of bone disease during
the course of their myeloma. And prior to working on this,
we had very, very few treatments for those individuals. But
now an individual coming into the clinic will typically receive
one of these treatments. So of the, uh, 1200 individuals
(07:55):
in that present to the clinic each year in Australia
with multiple myeloma, many of those individuals, if not all
of them, will ultimately be offered this particular treatment.
Dr Viviane Richter (08:06):
Peter, where did you take your research from here?
Prof Peter Croucher (08:09):
So, having spent time in the UK, I found myself
as a head of department in a university environment, and
I was considering what my options were, whether to stay
in research or stay in university administration. I was contemplating
this quite considerably and I was phoned one day by
(08:30):
an individual in Australia and he said to me that
the Garvan Institute was looking for a new director of
the bone program. So I was invited to come and
visit the Garvan Institute. I spent some time here and
realised what an exciting opportunity that would be. So about
12 years ago, we made the decision to leave the
(08:51):
UK and move to the Garvan and establish our laboratory
again at the Garvan and take on the responsibility for
what was called the bone program at the time.
Dr Viviane Richter (09:02):
And what problem were you specifically looking to understand?
Prof Peter Croucher (09:06):
So one of the most important problems we were looking
to address was still how do we make bones better
for individuals with multiple myeloma? And ultimately, we'd learned through
the studies in animal models that whenever you targeted the
skeleton to try to treat the bone disease, we would
reduce tumour burden and reduce the development of myeloma in
(09:29):
these animal models. So that gave us some important insights
and clues to how these tumours were growing in the skeleton,
it made us realise that they were probably very, very
dependent upon the environment of the skeleton for their survival.
So we recognise that, really, if we're going to have
true impact, we've got to stop myeloma developing in the
(09:51):
skeleton altogether and the way we felt we could tackle
that is going back to the very, very first cell
when it arrives in the skeleton for the first time
and sits down in that environment and settles into that
place and starts to grow. So when we came to
the Garvan, one of the things we did was we
linked up with some colleagues who were developing so-called intravital microscopy,
(10:15):
and that allows us to move away from looking at
histological sections of bone, which was a very static approach,
but to look in living organisms deep inside the bone
as cells were moving around and arriving in that environment.
And that was a watershed moment, really, because it gave
us this opportunity to see things in real time in
(10:37):
living organisms and seeing them how they actually happened right
in front of your eyes. And as as we sort
of say, seeing is truly believing, and this was the
first opportunity to really see that in action.
Dr Viviane Richter (10:49):
Peter, take us inside what is happening in the bone
when one of these cancer cells sets up shop.
Prof Peter Croucher (10:56):
So using the intravital imaging approach, we were able to
see cancer cells arriving directly into the skeleton. And one
of the exciting things was that we could actually see
them sitting down in bone on the bone surface. And
over a period of time, you could see that some
of these cells would be woken up and give rise
(11:18):
to new cancer, whereas many of these cells would just
sit there in a long term dormant state. So we've
spent quite a long time now trying to understand, firstly,
what holds cells in a dormant state. And then, secondly,
what wakes them up? And one of the first things
we did was discover that the cells that we've always
(11:38):
been interested in osteoclasts are able to degrade bone or
resorb bone, and in doing so, they release these dormant
cells from the control that occurs within that environment and
allows them to grow and form a new cancer. And
this may well explain why in the big clinical trials
that were first done with the drugs that target osteoclasts,
(12:00):
that these individuals were able to live longer. And it
really builds upon a very early hypothesis that was proposed
well over 100 years ago now by somebody called Stephen Paget,
who was an English physician. And he made this observation
that in women with breast cancer, their bones would suffer
in a sort of special way. And he developed something
(12:22):
called the seed and soil hypothesis, where the cancer cell
is the seed and it finds its way into the
bone and bone is a fertile soil that can support
the growth and survival of cancers. If we can actually
understand who has disseminated dormant cancer cells, we can think
about beginning to treat them much, much earlier than we
(12:43):
would do normally. So rather than treat our primary disease
and then think, when a disease relapses, we have to
start to treat that, we may be able to consider
treatments in a different way, firstly, identifying who is going
to do poorly, first of all, and then secondly, developing
approaches that we can use to treat and eradicate dormant
(13:04):
cells before they're woken up to cause relapsing disease. So
you can imagine a scenario where you might come into
the clinic and you're treated for your primary disease. But
at the same time, you're also investigated and then treated
for disseminated disease. And if you can stop that disseminated
disease being woken up, and you may well work towards
(13:25):
a likely cure for some of these difficult-to-treat cancers.
Dr Viviane Richter (13:29):
How many people could this have a potential impact for?
Prof Peter Croucher (13:33):
So it's estimated that 10 million individuals will be living
with cancers that have spread to distant organs, and the
skeleton is obviously one of the most common sites for
that spread. So if we can actually identify which individuals
are gonna experience a cancer that's growing in a distant organ,
we have the potential to have a very positive outcome
(13:55):
on all of those individuals. We do have a long
way to go. You know, we have identified these cells,
and we've done a lot of work trying to identify
and work out the genes that control these cells, and
this is providing opportunities now to think about how we
can develop new types of treatment that either keep these
(14:17):
cells in a long term dormant state so they never
wake up or that we can eradicate them as dormant
tumour cells.
Dr Viviane Richter (14:25):
And what kind of diagnostics and therapies are you hoping
to specifically develop during this work?
Prof Peter Croucher (14:31):
So I think that's a really important question and a
real challenge. I think identifying these dormant cells in distant
organs in the skeleton in particular is particularly challenging. What
we're doing at the moment is now we understand many
of the genes that control these cells. We're looking in
(14:52):
bone marrow aspirates to find individual cells based upon that understanding.
So we're optimistic that that could ultimately be a way
of finding them and developing a test to identify and
find those cells. But the real challenge is developing treatments,
and those treatments might involve utilising the power of the
(15:13):
immune system to actually find these cells and eradicate them.
And our understanding at the moment is somehow these cells
are invisible to the immune system. They take on what
we call a cloak, which is hiding away in the
skeleton so they appear as native cells would do normally
(15:34):
in the skeleton. And if we can reveal these cells
to the immune system. Then we can leverage the power
of the immune system to eradicate them, and that will
be our aspiration.
Dr Viviane Richter (15:44):
And what sort of technologies are helping you get there?
Prof Peter Croucher (15:47):
So I think we've made huge improvements since the time
of using old fashioned image analysis and floppy discs to
store data. We've moved through a period now where the
introduction of intravital imaging has allowed us to study cells
in real time for the very first time. The further
introduction of single-cell genomic technologies is allowing us to understand
(16:12):
these incredibly rare cells and all the genes that are
switched on in that environment. And I think going forward,
we're going to be able to leverage what is turning
into a data science challenge. With many, many millions of
cells involved in the development of a cancer, millions of
cells involved in the interactions that occur between a cancer
(16:33):
cell and its environment. We need sophisticated computational approaches to
enable us to analyse many, many millions of cells, thousands
of genes in living organisms and ultimately in people. So
this is going to be a huge data science challenge,
and one of the things that we're trying to do
(16:54):
is bring together people with different expertises. Is not just
people like myself as a bone biologist or a cancer biologist,
but immunologists, data scientists, genomicists all to the table to
be able to tackle this problem together.
Dr Viviane Richter (17:09):
Are you focusing on any cancer in particular?
Prof Peter Croucher (17:12):
So we're focused on three different cancers. One is multiple myeloma,
and that's where we've done most of our initial discovery work.
But we're also interested in cancers such as breast and
prostate cancer that will disseminate to the skeleton. What we've
already discovered is that these cells arrive in the skeleton
and they localise to a very similar environment, so they
(17:35):
seem to sit in the same space, and when they
sit in that space, they switch on the same repertoire
of genes. And it doesn't matter whether you're a myeloma
cell or a breast cancer cell or a prostate cancer cell.
So this offers the exciting prospect that we may be
able to develop pan cancer treatments that work for all
cancers that are growing in the skeleton and potentially similar
(17:59):
approaches might apply in other organs, such as the lung
or the liver.
Dr Viviane Richter (18:04):
And your work has recently led to a clinical trial?
Prof Peter Croucher (18:08):
So we do have clinical trials. So a lot of
our research now has moved into working much more closely
with patients, whether it's patients providing samples that we can
then analyse and study or it includes new interventions. And
we've definitely made some progress with a further new treatment,
potential treatment for the bone disease in patients with myeloma.
(18:31):
And we have the clinical trial that's just started in
that space and that is looking to replace the bone
that has been previously lost. So whilst the early treatments, uh,
stop your skeleton getting worse, the aspiration is to make
it stronger so that it, actually, uh, is resistant to
future fractures.
Dr Viviane Richter (18:51):
Peter, before learning about your research, I had no idea
that bone was such an active site of activity.
Prof Peter Croucher (18:58):
No, that's absolutely right. It's constantly changing, and as we've
talked about, you have osteoclasts taking bone away and osteoblasts
replacing that bone. So the skeleton that you had when
you first started listening to this podcast will be different
to the one that you leave with, and that's happening
with all of us all of the time. So there's
a unique opportunity there to change your skeleton, and we
(19:20):
should all be very mindful of that.
Dr Viviane Richter (19:22):
So how can we change our skeleton for the better?
Prof Peter Croucher (19:25):
So use it or lose. It is probably an important
concept to consider. So the very fact that our skeleton
is adaptable means that we have the amount of bone
that we need. So if you don't use your skeleton,
then you lose bone. If you use it, then it
will be stronger for it. So if you go up
in space, you lose your skeleton because you're not putting
(19:46):
strain on your skeleton. If you're a tennis player, then
your dominant hand will be stronger than your non-dominant hand.
So the lessons from that have taught us that you
have to use your skeleton, so exercise is a very
positive thing.
Dr Viviane Richter (20:00):
Peter, before we let you get back to the lab,
it's time for the Fast Five. What do you do
in your downtime?
Prof Peter Croucher (20:05):
I'm a runner, so I've always liked running. When I
was in the UK, we used to do fell running,
which is running in the Peak District. The closest you
can do that here is more trail running So I
do a lot of trail running when I get the chance.
Dr Viviane Richter (20:21):
What's the most challenging thing you've ever done?
Prof Peter Croucher (20:23):
Probably the most challenging thing that I've done has been
to take on the acting directorship of the Garvan Institute
when our former director stepped down at short notice. That
was a huge privilege, but also incredibly challenging. You know,
we have some of the most amazing scientists at Garvan
(20:45):
all trying to tackle really fundamentally important questions. Yet we're
doing that in a complex and difficult environment where we
have limited resources and funding. So making decisions around how
we took the organisation forward was particularly challenging.
Dr Viviane Richter (21:02):
Peter, do you have any secret skills?
Prof Peter Croucher (21:04):
I'm not sure it's a skill, but it's something that
I've always felt that I could do quite well, which
was actually read people. And at one level, that's been
advantageous because you can actually understand people's motivations. But another level,
it's a bit of a curse, cos you can often
see the car crashes happening before they occur.
Dr Viviane Richter (21:26):
What's been your best holiday?
Prof Peter Croucher (21:27):
Probably my best holiday was a trip to the Maldives
when later my wife and I first got married we
decided we would spend two weeks in the Maldives. We
were a bit terrified that being on a small island
for essentially two weeks would be... we'd have nothing to do.
So we took loads of books and even took work
(21:49):
with us because we were so worried that this would
be so isolating. But once we got there, all we
did was snorkel for two weeks, and it was probably
the most amazing experience I've had.
Dr Viviane Richter (22:01):
Favourite movie?
Prof Peter Croucher (22:02):
I guess my favourite movie is a movie called Sunshine,
which is a Danny Boyle film, and I've always liked
science fiction movies, and this is a great science fiction movie.
But it also has an amazing soundtrack.
Dr Viviane Richter (22:15):
Professor Peter Croucher, thank you so much for joining us
on Medical Minds.
Prof Peter Croucher (22:20):
Thank you very much for having me.
Dr Viviane Richter (22:22):
If you'd like to know more about Peter's research or
donate to the work we do at Garvan, head to garvan.org.au.
And if you've enjoyed this podcast, please leave a review
and share with other podcast lovers. I'm Dr Viviane Richter.
Thanks for listening. This podcast was recorded on the traditional
(22:42):
country of the Gadigal people of the Eora nation. We
recognise their continuing connection to land, waters and community. We
pay our respects to Aboriginal and Torres Strait Islander cultures
and Elders past, present and emerging.
The relief of a successful cancer treatment is all too
often marred by a distressing, lingering uncertainty
come back? The devastating reality is that cancer cells can
run and hide. They can tuck away and lie dormant
in different parts of the body, often inside bone, for
years before waking up to spread once again. In today's episode,
(00:23):
we speak to a Garvan researcher who is tackling one
of the toughest problems in cancer research. How can we
track cancer cells on their way to becoming dormant? How
can we stop them from waking up? And how can
we eradicate them from our system completely? You're listening to
Medical Minds. The podcast that takes you inside the labs
(00:43):
at the Garvan Institute of Medical Research. I'm your host,
Dr Viviane Richter. And with me here is Professor Peter Croucher,
Head of the Bone Biology Lab at Garvan. Welcome, Peter.
Prof Peter Croucher (00:54):
Hi, Viviane. It's great to be here.
Dr Viviane Richter (00:57):
Peter, before we talk about how you're tackling this critical problem
in cancer, could you tell us where your inspiration to
become a scientist came from?
Prof Peter Croucher (01:05):
So I'm a zoologist. I was brought up in the
very south west of the UK. And in my formative
years I spent time collecting animals and had fish tanks
and all sorts of creatures that I used to look after.
And then when I went to university, I did zoology.
And as part of my zoology training, I spent some
time in a lab doing medical research, looking at the
(01:27):
role of cancer drugs in the immune system. So once
I'd finished my time at university, I chose to do
a PhD and was asked, or given the opportunity to
do a PhD in skeletal biology.
Dr Viviane Richter (01:40):
What was it about skeletal biology that really interested you?
Prof Peter Croucher (01:44):
When I was offered this opportunity, I met somebody that
was actually working on osteoporosis, and this is obviously a
pretty devastating disease that affects the skeleton. You lose bone
and have pathological fractures. So it excited me that we
could actually spend time trying to understand this disease and
develop new approaches to treating that. So I started my PhD,
(02:05):
and we were using rather old technology at the time
to investigate how bones changed over time and in in fact,
we we spent time using sort of old fashioned computers
that would fill a room now using histological slides to
try and measure things in those slides and understand how
the cells that control bone take away bone and cause
(02:27):
the sort of devastating effects on the skeleton.
Dr Viviane Richter (02:30):
Can you tell us a little bit more about the
specific project that you were working on?
Prof Peter Croucher (02:35):
So we were interested in the cells that resorb bone
and these are important cells because they take away bone
that's not mechanically competent and need to be replaced. And
these cells are called osteoclasts, and at the time we
had little or few approaches to being able to study
this in people. So we were taking, uh, samples of
(02:55):
bone from people using histological approaches to identify these cells
and then using image analysis tools using very old fashioned
image analysis computers to actually quantitate and measure the changes
in bone that were going on in patients with osteoporosis
and other disorders as well.
Dr Viviane Richter (03:15):
What did you learn?
Prof Peter Croucher (03:16):
Well, we found that different types or different patients would
have different outcomes in terms of osteoclastic bone resorption. So,
for example, if you have postmenopause osteoporosis, you would resorb
more bone than you would do normally, and we found
that the sites where bone resorption was going on. You
had many, many more of those sites, so it opened
(03:37):
up the opportunity to think about how we could actually
start to treat diseases such as osteoporosis.
Dr Viviane Richter (03:43):
So the inside of bone is quite a dynamic environment.
Prof Peter Croucher (03:47):
Now, that's absolutely right. So bone is itself a very
difficult tissue to understand and study. It's a sort of
hard tissue. It's inaccessible. There's an outer layer of bone
that you have to penetrate before you can see inside
a bone and then actually study what's going on in
that environment. So inside a bone you have all your
bone marrow, which is the site of blood cell formation
(04:09):
and where your immune system is developing. And on the
surface of bone are all the cells that are responsible
for controlling bone and changing that bone over time. But
at the time I did my PhD, the only tools
we had were really histological tools. So you've got a
snapshot in time only, and seeing that complexity and the
dynamic changes in bone was always something that was an
(04:31):
aspiration when I started my PhD.
Dr Viviane Richter (04:35):
And where did you go from there?
Prof Peter Croucher (04:36):
So after I completed my PhD I went to Cambridge.
I spent some time working with my PhD supervisor, but
she gave me this opportunity to go and work in
a different lab to gain some different experiences. I went
and worked at the Laboratory for Molecular Biology, which is
a very well known laboratory in Cambridge where people do
(04:58):
a lot of molecular biology. And I spent time working
with a haematologist there, learning molecular biology and applying that
to study the skeleton. And it was while I was
there that we really got interested in cancers that grow
in bone. And one of the most devastating cancers that
grows in bone is a disease called multiple myeloma, which
is a blood cancer and that lives in the skeleton
(05:21):
and hijacks the normal processes that go on in bone.
It causes sort of devastating osteolytic bone disease, and this
is largely mediated by osteoclasts resorbing more bone than they
should do. And it's become a a sort of model
in some ways for an extreme form of bone loss.
Dr Viviane Richter (05:40):
So, Peter, how are you investigating this disease?
Prof Peter Croucher (05:43):
So one of the things we recognised was it was
particularly difficult to study myeloma in patients. So we spent
some time developing animal models of multiple myeloma. And and
this turned out to be a sort of pretty wise
decision because we were able to use these models to
understand how myeloma cells hijack bone, how they cause bone disease.
(06:08):
But we discovered some molecules that the tumour cells had
actually hijacked in the bone environment, and that actually caused
more osteoclasts to form. And that discovery led to the
development of a new treatment that ultimately is one of
the most widely used treatments studied , or in in
the treatment of patients with multiple myeloma.
Dr Viviane Richter (06:27):
What's the treatment?
Prof Peter Croucher (06:29):
So we discovered a molecule called RANK ligand, and this
particular molecule is now being targeted by an antibody called denosumab.
And that's now widely used in the treatment of bone disease,
not just in myeloma but also in patients with osteoporosis.
Dr Viviane Richter (06:45):
That must be an incredible feeling to know that the
research that you were involved with is helping to change
the lives of many people today.
Prof Peter Croucher (06:53):
Yeah, it's super exciting. It's clearly a huge team effort, and many,
many individuals are involved in this, but actually contributing in
some small way is incredibly humbling, really.
Dr Viviane Richter (07:05):
And do you think this treatment has changed the dial?
Prof Peter Croucher (07:09):
I think so. So when I first started research in
multiple myeloma, there were few treatments for the devastating bone
disease that occurs in this particular disease. So I think
over the last decade or so, we've seen the introduction
of two new treatments, both of which we've worked on
and contributed to the development of. Individuals that have myeloma
(07:32):
will commonly present with bone disease. And in fact, almost
all patients will have some form of bone disease during
the course of their myeloma. And prior to working on this,
we had very, very few treatments for those individuals. But
now an individual coming into the clinic will typically receive
one of these treatments. So of the, uh, 1200 individuals
(07:55):
in that present to the clinic each year in Australia
with multiple myeloma, many of those individuals, if not all
of them, will ultimately be offered this particular treatment.
Dr Viviane Richter (08:06):
Peter, where did you take your research from here?
Prof Peter Croucher (08:09):
So, having spent time in the UK, I found myself
as a head of department in a university environment, and
I was considering what my options were, whether to stay
in research or stay in university administration. I was contemplating
this quite considerably and I was phoned one day by
(08:30):
an individual in Australia and he said to me that
the Garvan Institute was looking for a new director of
the bone program. So I was invited to come and
visit the Garvan Institute. I spent some time here and
realised what an exciting opportunity that would be. So about
12 years ago, we made the decision to leave the
(08:51):
UK and move to the Garvan and establish our laboratory
again at the Garvan and take on the responsibility for
what was called the bone program at the time.
Dr Viviane Richter (09:02):
And what problem were you specifically looking to understand?
Prof Peter Croucher (09:06):
So one of the most important problems we were looking
to address was still how do we make bones better
for individuals with multiple myeloma? And ultimately, we'd learned through
the studies in animal models that whenever you targeted the
skeleton to try to treat the bone disease, we would
reduce tumour burden and reduce the development of myeloma in
(09:29):
these animal models. So that gave us some important insights
and clues to how these tumours were growing in the skeleton,
it made us realise that they were probably very, very
dependent upon the environment of the skeleton for their survival.
So we recognise that, really, if we're going to have
true impact, we've got to stop myeloma developing in the
(09:51):
skeleton altogether and the way we felt we could tackle
that is going back to the very, very first cell
when it arrives in the skeleton for the first time
and sits down in that environment and settles into that
place and starts to grow. So when we came to
the Garvan, one of the things we did was we
linked up with some colleagues who were developing so-called intravital microscopy,
(10:15):
and that allows us to move away from looking at
histological sections of bone, which was a very static approach,
but to look in living organisms deep inside the bone
as cells were moving around and arriving in that environment.
And that was a watershed moment, really, because it gave
us this opportunity to see things in real time in
(10:37):
living organisms and seeing them how they actually happened right
in front of your eyes. And as as we sort
of say, seeing is truly believing, and this was the
first opportunity to really see that in action.
Dr Viviane Richter (10:49):
Peter, take us inside what is happening in the bone
when one of these cancer cells sets up shop.
Prof Peter Croucher (10:56):
So using the intravital imaging approach, we were able to
see cancer cells arriving directly into the skeleton. And one
of the exciting things was that we could actually see
them sitting down in bone on the bone surface. And
over a period of time, you could see that some
of these cells would be woken up and give rise
(11:18):
to new cancer, whereas many of these cells would just
sit there in a long term dormant state. So we've
spent quite a long time now trying to understand, firstly,
what holds cells in a dormant state. And then, secondly,
what wakes them up? And one of the first things
we did was discover that the cells that we've always
(11:38):
been interested in osteoclasts are able to degrade bone or
resorb bone, and in doing so, they release these dormant
cells from the control that occurs within that environment and
allows them to grow and form a new cancer. And
this may well explain why in the big clinical trials
that were first done with the drugs that target osteoclasts,
(12:00):
that these individuals were able to live longer. And it
really builds upon a very early hypothesis that was proposed
well over 100 years ago now by somebody called Stephen Paget,
who was an English physician. And he made this observation
that in women with breast cancer, their bones would suffer
in a sort of special way. And he developed something
(12:22):
called the seed and soil hypothesis, where the cancer cell
is the seed and it finds its way into the
bone and bone is a fertile soil that can support
the growth and survival of cancers. If we can actually
understand who has disseminated dormant cancer cells, we can think
about beginning to treat them much, much earlier than we
(12:43):
would do normally. So rather than treat our primary disease
and then think, when a disease relapses, we have to
start to treat that, we may be able to consider
treatments in a different way, firstly, identifying who is going
to do poorly, first of all, and then secondly, developing
approaches that we can use to treat and eradicate dormant
(13:04):
cells before they're woken up to cause relapsing disease. So
you can imagine a scenario where you might come into
the clinic and you're treated for your primary disease. But
at the same time, you're also investigated and then treated
for disseminated disease. And if you can stop that disseminated
disease being woken up, and you may well work towards
(13:25):
a likely cure for some of these difficult-to-treat cancers.
Dr Viviane Richter (13:29):
How many people could this have a potential impact for?
Prof Peter Croucher (13:33):
So it's estimated that 10 million individuals will be living
with cancers that have spread to distant organs, and the
skeleton is obviously one of the most common sites for
that spread. So if we can actually identify which individuals
are gonna experience a cancer that's growing in a distant organ,
we have the potential to have a very positive outcome
(13:55):
on all of those individuals. We do have a long
way to go. You know, we have identified these cells,
and we've done a lot of work trying to identify
and work out the genes that control these cells, and
this is providing opportunities now to think about how we
can develop new types of treatment that either keep these
(14:17):
cells in a long term dormant state so they never
wake up or that we can eradicate them as dormant
tumour cells.
Dr Viviane Richter (14:25):
And what kind of diagnostics and therapies are you hoping
to specifically develop during this work?
Prof Peter Croucher (14:31):
So I think that's a really important question and a
real challenge. I think identifying these dormant cells in distant
organs in the skeleton in particular is particularly challenging. What
we're doing at the moment is now we understand many
of the genes that control these cells. We're looking in
(14:52):
bone marrow aspirates to find individual cells based upon that understanding.
So we're optimistic that that could ultimately be a way
of finding them and developing a test to identify and
find those cells. But the real challenge is developing treatments,
and those treatments might involve utilising the power of the
(15:13):
immune system to actually find these cells and eradicate them.
And our understanding at the moment is somehow these cells
are invisible to the immune system. They take on what
we call a cloak, which is hiding away in the
skeleton so they appear as native cells would do normally
(15:34):
in the skeleton. And if we can reveal these cells
to the immune system. Then we can leverage the power
of the immune system to eradicate them, and that will
be our aspiration.
Dr Viviane Richter (15:44):
And what sort of technologies are helping you get there?
Prof Peter Croucher (15:47):
So I think we've made huge improvements since the time
of using old fashioned image analysis and floppy discs to
store data. We've moved through a period now where the
introduction of intravital imaging has allowed us to study cells
in real time for the very first time. The further
introduction of single-cell genomic technologies is allowing us to understand
(16:12):
these incredibly rare cells and all the genes that are
switched on in that environment. And I think going forward,
we're going to be able to leverage what is turning
into a data science challenge. With many, many millions of
cells involved in the development of a cancer, millions of
cells involved in the interactions that occur between a cancer
(16:33):
cell and its environment. We need sophisticated computational approaches to
enable us to analyse many, many millions of cells, thousands
of genes in living organisms and ultimately in people. So
this is going to be a huge data science challenge,
and one of the things that we're trying to do
(16:54):
is bring together people with different expertises. Is not just
people like myself as a bone biologist or a cancer biologist,
but immunologists, data scientists, genomicists all to the table to
be able to tackle this problem together.
Dr Viviane Richter (17:09):
Are you focusing on any cancer in particular?
Prof Peter Croucher (17:12):
So we're focused on three different cancers. One is multiple myeloma,
and that's where we've done most of our initial discovery work.
But we're also interested in cancers such as breast and
prostate cancer that will disseminate to the skeleton. What we've
already discovered is that these cells arrive in the skeleton
and they localise to a very similar environment, so they
(17:35):
seem to sit in the same space, and when they
sit in that space, they switch on the same repertoire
of genes. And it doesn't matter whether you're a myeloma
cell or a breast cancer cell or a prostate cancer cell.
So this offers the exciting prospect that we may be
able to develop pan cancer treatments that work for all
cancers that are growing in the skeleton and potentially similar
(17:59):
approaches might apply in other organs, such as the lung
or the liver.
Dr Viviane Richter (18:04):
And your work has recently led to a clinical trial?
Prof Peter Croucher (18:08):
So we do have clinical trials. So a lot of
our research now has moved into working much more closely
with patients, whether it's patients providing samples that we can
then analyse and study or it includes new interventions. And
we've definitely made some progress with a further new treatment,
potential treatment for the bone disease in patients with myeloma.
(18:31):
And we have the clinical trial that's just started in
that space and that is looking to replace the bone
that has been previously lost. So whilst the early treatments, uh,
stop your skeleton getting worse, the aspiration is to make
it stronger so that it, actually, uh, is resistant to
future fractures.
Dr Viviane Richter (18:51):
Peter, before learning about your research, I had no idea
that bone was such an active site of activity.
Prof Peter Croucher (18:58):
No, that's absolutely right. It's constantly changing, and as we've
talked about, you have osteoclasts taking bone away and osteoblasts
replacing that bone. So the skeleton that you had when
you first started listening to this podcast will be different
to the one that you leave with, and that's happening
with all of us all of the time. So there's
a unique opportunity there to change your skeleton, and we
(19:20):
should all be very mindful of that.
Dr Viviane Richter (19:22):
So how can we change our skeleton for the better?
Prof Peter Croucher (19:25):
So use it or lose. It is probably an important
concept to consider. So the very fact that our skeleton
is adaptable means that we have the amount of bone
that we need. So if you don't use your skeleton,
then you lose bone. If you use it, then it
will be stronger for it. So if you go up
in space, you lose your skeleton because you're not putting
(19:46):
strain on your skeleton. If you're a tennis player, then
your dominant hand will be stronger than your non-dominant hand.
So the lessons from that have taught us that you
have to use your skeleton, so exercise is a very
positive thing.
Dr Viviane Richter (20:00):
Peter, before we let you get back to the lab,
it's time for the Fast Five. What do you do
in your downtime?
Prof Peter Croucher (20:05):
I'm a runner, so I've always liked running. When I
was in the UK, we used to do fell running,
which is running in the Peak District. The closest you
can do that here is more trail running So I
do a lot of trail running when I get the chance.
Dr Viviane Richter (20:21):
What's the most challenging thing you've ever done?
Prof Peter Croucher (20:23):
Probably the most challenging thing that I've done has been
to take on the acting directorship of the Garvan Institute
when our former director stepped down at short notice. That
was a huge privilege, but also incredibly challenging. You know,
we have some of the most amazing scientists at Garvan
(20:45):
all trying to tackle really fundamentally important questions. Yet we're
doing that in a complex and difficult environment where we
have limited resources and funding. So making decisions around how
we took the organisation forward was particularly challenging.
Dr Viviane Richter (21:02):
Peter, do you have any secret skills?
Prof Peter Croucher (21:04):
I'm not sure it's a skill, but it's something that
I've always felt that I could do quite well, which
was actually read people. And at one level, that's been
advantageous because you can actually understand people's motivations. But another level,
it's a bit of a curse, cos you can often
see the car crashes happening before they occur.
Dr Viviane Richter (21:26):
What's been your best holiday?
Prof Peter Croucher (21:27):
Probably my best holiday was a trip to the Maldives
when later my wife and I first got married we
decided we would spend two weeks in the Maldives. We
were a bit terrified that being on a small island
for essentially two weeks would be... we'd have nothing to do.
So we took loads of books and even took work
(21:49):
with us because we were so worried that this would
be so isolating. But once we got there, all we
did was snorkel for two weeks, and it was probably
the most amazing experience I've had.
Dr Viviane Richter (22:01):
Favourite movie?
Prof Peter Croucher (22:02):
I guess my favourite movie is a movie called Sunshine,
which is a Danny Boyle film, and I've always liked
science fiction movies, and this is a great science fiction movie.
But it also has an amazing soundtrack.
Dr Viviane Richter (22:15):
Professor Peter Croucher, thank you so much for joining us
on Medical Minds.
Prof Peter Croucher (22:20):
Thank you very much for having me.
Dr Viviane Richter (22:22):
If you'd like to know more about Peter's research or
donate to the work we do at Garvan, head to garvan.org.au.
And if you've enjoyed this podcast, please leave a review
and share with other podcast lovers. I'm Dr Viviane Richter.
Thanks for listening. This podcast was recorded on the traditional
(22:42):
country of the Gadigal people of the Eora nation. We
recognise their continuing connection to land, waters and community. We
pay our respects to Aboriginal and Torres Strait Islander cultures
and Elders past, present and emerging.
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