November 7, 2025 • 24 mins
For decades, the fight against cancer has focused on killing the tumour cell. We treated cancer like an isolated entity that needed to be destroyed – but what if we’ve been looking at the wrong target?
In this episode, we delve into the critical insight that cancer is not just a rogue cell – it’s an entire ecosystem – and that ecosystem is the key to unlocking a new class of cures.
We hear from Garvan's Dr Ankur Sharma, who is using precision technology to dissect how the environment around liver cancers allows them to grow unchecked. The ultimate goal for this research is to develop better diagnostics and treatments for this deadly cancer.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Dr Viviane Richter (00:01):
For decades, the fight against cancer has focused on killing
the tumour cell. We treated cancer like an isolated entity
that needed to be destroyed. But what if we've been
looking at the wrong target? In this episode, we delve
into the critical insight that cancer is not just a
rogue cell, it's an entire ecosystem. And that ecosystem is
(00:24):
the key to unlocking a new class of cures. Today,
we meet a researcher at Garvan who is using precision
technology to dissect how the environment around liver cancers allows
them to grow unchecked. The ultimate goal, to develop better
diagnostics and treatments. You're listening to Medical Minds, the podcast
(00:48):
that takes you inside the labs at the Garvan Institute
of Medical Research. I'm your host, Dr Viviane Richter, and
with us today is Dr Ankur Sharma, lab head in
the Translational Genomics program at Garvan. Welcome, Ankur.
Dr Ankur Sharma (01:03):
Thanks Viviane, it's great to be here.
Dr Viviane Richter (01:05):
Ankur, you have published your work on liver cancer in
the most prestigious international science journals. But, before we get
to your research, I'd like to go back a couple
of steps and understand where it all started for you.
Dr Ankur Sharma (01:21):
Well, I did not plan to become a scientist to
begin with. I guess I wanted to become a cricketer.
I grew up in India, and cricket is kind of
a religion, so I also wanted to become a cricketer.
I guess in 8th standard, or somewhere, one of our
science teachers was teaching us about genetics and Mendel's fascinating
experiments on plant genetics. This is where I started getting
(01:43):
a lot more excited about science, and I think it's
kind of a serendipity that a lot of internships which
I did in my undergraduate program, they happened to be
in the genetics departments, like plant genetics and forensic genetics,
and I ended up doing my Master's in human genetics. So,
one of the most fascinating research projects I did before my
(02:04):
PhD was working on forensic genetics. And this was in
a lab which was a wildlife lab. So, they were looking
at endangered species of animals and trying to see if
poachers are looking at animals which are endangered versus common. So,
just by looking at genetic patterns, you can differentiate between
(02:26):
a common cat versus a wild cat, and those were
some of the very, very simple things we were doing
back in the day, 20 years ago.
Dr Viviane Richter (02:34):
So, you were studying genetics just after the sequencing of
the first human genome, is that right?
Dr Ankur Sharma (02:41):
Yep.
Dr Viviane Richter (02:41):
That would have been an incredibly exciting time.
Dr Ankur Sharma (02:43):
It was, it was actually, and again, it was not
by plan. I think the human genome was sequenced, a
first full draft came in 2001, 2003. I started my
Master's in 2006, and I guess that was the best
time to study human genetics as a student because there
was so much unknown, and I think that's what fascinates
(03:04):
all of us
the human genome? And all those factors, cumulatively, might have
impacted me, motivated me to do PhD and do what
I'm doing today.
Dr Viviane Richter (03:18):
Incredible. So you went on to study liver cancer, particularly.
What drew you to cancer research and specifically liver cancer?
Dr Ankur Sharma (03:29):
So, I think I started working on liver cancer sometime
in 2015, but before that, I first started working on
cancer because when I was studying human genetics, or genomics,
I got very fascinated about how some of the cells
in our body just go rogue and we develop cancer.
And it's just by getting these mutations in genes. So,
(03:51):
I wanted to study cancer a little bit more in detail.
I decided to do a PhD in the field of
cancer biology, and my PhD topic was looking into a
particular kind of genes which are very important for our development,
but just get overactivated in cancer. And I decided to
block this overactivity of these genes by developing antibodies. So,
(04:15):
antibodies are molecules which will bind to any other gene,
or basically the product of a gene which is protein,
and could potentially block its function. That's what I was
doing in my PhD
this protein in a way that we can control cancer. So,
I was studying this in the context of breast cancer
(04:37):
and colon cancer. While I was doing these studies, again,
I got very fascinated by things I was observing in
the lab, and one of the simple observations was not
all cells are alike, just like us humans
also very diverse, and they come in different shapes, sizes,
and the level of these genes are also different.
Dr Viviane Richter (05:01):
In cancer, specifically?
Dr Ankur Sharma (05:02):
In cancer, more specifically, but in general, like the level of
the gene in cells is not always the same. And
it's important because if you just think about our skin,
our forehand and backhand have different kinds of skin because
they have different functions. So, genes which are important, such
as melanin, would be different levels in these two things. So,
(05:24):
I wanted to study this process in a little bit more detail,
like why cells have different levels of genes. And again,
those days a new technology was coming, which was single
cell genomics, so you can understand all the genes in
a cell at a very high granular level. This is
what I started looking into during my postdoc, and one
(05:46):
thing led to another. One day I got a call
from a senior clinical colleague who was working on liver cancer.
He knew I worked on single cell genomics, and he said,
"Would you like to look into liver cancer in more detail?"
And I guess I was very much fascinated by this
proposal because before that I was looking into cancer cells,
(06:07):
doing single cell genomics, and understanding how heterogeneous they are.
But I was focusing only on the cancer cells. However,
we know the tumour is not just a malignant cancer cell;
it's much more than that. It's cells which bring blood
supply to tumour. It's the immune cells which try to
kill the cancer cell, but cancer is trying to outmaneuver them.
(06:30):
And then there's a very interesting layer of cells such
as fibroblasts and extracellular matrix where all of this interplay is happening.
I thought this is a good opportunity for me to
look into the complex nature of different cells in cancer microenvironment,
and liver cancer was a good model system for me;
and that's how I got into liver cancer.
Dr Viviane Richter (06:52):
When did researchers first understand this idea that a cancer
isn't just made up of cancer cells, it's made up
of all of these supporting cells, connective tissues that make
up this ecosystem that is a tumour?
Dr Ankur Sharma (07:05):
I guess the importance of microenvironment per se in cancer
has been appreciated since so many decades, I would say. However,
tools were not present which will allow us to look
into this complexity in much more detail.
Dr Viviane Richter (07:20):
Right.
Dr Ankur Sharma (07:20):
So, we could look into fibroblast or we could look
into endothelial cells, but we are studying these cells in isolation. However,
these new technologies allow us to look into all the
pieces of the puzzle in one go, and then we
can try to put them together and try to see
what is happening in the cancer. So, I would say
that in the last 10 to 15 years, our ability
(07:42):
to understand tumour ecosystem has improved much more. We knew
that it is important. Another interesting thing that happened in
this area is immunotherapies, which work really well when they work,
and they work by modulating microenvironment. So, I think we
know that clinically it's very important. We have therapies in
(08:02):
clinic which target microenvironment, and we have tools to study this.
Put the pieces together and you can just look into
the tumour and try to understand where each and every
component of tumour is, what they are making, how similar
or dissimilar they are. So, I think it's an advancement
in the technology and clinical need which has re-emphasised the
(08:24):
importance of tumour microenvironment.
Dr Viviane Richter (08:27):
That's fascinating. What is that level of detail allowing us
to understand about cancers and how is that improving how
we're thinking about treating them?
Dr Ankur Sharma (08:38):
I think in the last one decade, technology has evolved
so much that now we can not only see the
different cells in the tumour, but also see how they
are sitting next to each other. So, think of it like:
we can now understand the neighbourhood looking into various suburbs
of cancer and try to understand who lives there, what
(08:59):
they are doing, how they are talking to each other;
and I think this has allowed us to understand cancer
in much more detail. More importantly, because we can understand
how two different cancers or two patients' tumours are different
from each other, because we know that – and all of
us have heard these examples that there is a cancer
(09:19):
patient who responded really well to therapy and they did
really well – and I think all of us want to
have our patient behave like that. However, some tumours are
very aggressive. We have cancers and patients come back within
a few months, and sometimes patients are aggressively developing their
disease before we can even diagnose it. And I think
(09:41):
these two extremes and cancer exists between this continuum of
some very good responders to some very bad responders. And again,
this is not just only two kinds of tumours, it's
just a mix of continuum between them. And to understand
this in whole detail, we need to understand why some
patients respond so well, and why some patients do not respond.
(10:02):
What is in the tumour? Is it the cancer cells,
or it's the microenvironment, or it's the interaction between these
two which is guiding how therapies may or may not work. So,
I think understanding cancer in full detail, on patient tumour
directly without involving a model system, allows us to understand
why patients behave in clinic the way they behave, so
(10:24):
we can design better therapies.
Dr Viviane Richter (10:26):
So, in a way, taking a real precision approach to
cancer therapy that's really targeted to individual patients.
Dr Ankur Sharma (10:33):
Exactly, yeah.
Dr Viviane Richter (10:35):
So, how many people are affected by liver cancer in Australia?
Dr Ankur Sharma (10:39):
So, liver cancer impacts almost 3000 Australians every year. And
we talked about cancers which respond better to therapies versus
do not respond better to therapies, and liver cancer unfortunately
comes into these cancers who do not respond to therapies.
Five-year survival rate of a patient with liver cancer is
only 20%.
Dr Viviane Richter (10:59):
Wow.
Dr Ankur Sharma (10:59):
Because therapies do not work in these patients
cancers are diagnosed at a little bit later stage, but
also it's such a vital organ where, as soon as
cancer becomes a little bit more aggressive, it's difficult to treat.
We cannot remove the liver completely, and the therapies, we
just have one therapy for advanced liver cancer, and the
(11:19):
second therapy is being approved, hopefully, in the next six
months or so. The options in clinic are very limited.
Disease is very aggressive, which is making it such a
difficult cancer to treat.
Dr Viviane Richter (11:32):
I understand you made a really fundamental discovery about how
liver cancers develop from a genetic perspective. Can you talk
us through that?
Dr Ankur Sharma (11:41):
Yeah. So, what we have identified in our lab is
a fascinating similarity between the development of a human foetus and cancers.
And why this is fascinating? So, if you think about
human development, we all start from one cell, and within
a few months, we have trillions of cells and this
whole body, which lasts for many, many years. Now what
(12:03):
happens in cancer? We have, again, a rapid growth of
cancer cells in the body. The only difference is the
development is very controlled, very precise, while cancer is completely
uncontrolled division of cells. However, it utilises the same mechanisms,
the same kind of foundation, or microenvironment, or "soil" (to
(12:26):
think of), which a growing foetus is using to grow
different organs such as liver, lung, heart. And now the
cancer in these organs utilise the same kind of foundation
and microenvironment for uncontrolled growth. So, this is the one
key mechanism we have identified in our lab, which we
call "oncofoetal microenvironment" or "oncofoetal ecosystem".
Dr Viviane Richter (12:48):
That's fascinating. So, you've discovered, in your lab, certain signatures
within some liver cancers that are very similar or the
same as signatures, genetic signatures, within a developing foetus. How
does that open the field up to a different way
to treat liver cancer?
Dr Ankur Sharma (13:08):
Yeah, that's a good question. So, if you think about
development once more
we are not breathing air, so our lungs are not
used to breathing air. And so, our organs behave differently
when we are in our mother's womb versus when we
come out in this world. So, a lot of genes
which are important for maintenance of foetal part of our life,
(13:31):
which is very growth aggressive, are shut down when we
come out of our mother's womb, and this is very
important for healthy growth of a baby. But what happens
in cancer? All of these genes, which are required for
foetal growth, are somehow reactivated. We don't understand completely yet
how this process happens, but it tells us that the
(13:54):
same mechanism which a growing foetus uses is acquired by cancer. Now,
there is an opportunity here, because all of these genes
or proteins are not required for healthy growth, which means
we can target them. Because we see them in foetus
and we see them again in the tumours in adult
life at the age of 50, 60, 70. So, these
(14:16):
are not important for our day-to-day function. These are important
for cancer cells, which provides us a very unique opportunity
for developing new therapeutics, where we can block the signals,
or kill these cells, which are cancer cells but have
this unique marker on them, so we can put a
target on these cells and destroy these cells. So, this
(14:37):
is a one very unique opportunity which we think we
have in our research area.
Dr Viviane Richter (14:42):
And you've discovered these markers, these targets using single cell genomics.
Can you tell us a little bit more about where
your research has taken you, what specifically you're targeting now
in these cancer cells?
Dr Ankur Sharma (14:56):
So, research is a very, very rapidly evolving field, right?
So what now we are building is machine learning and
artificial intelligence-based approaches, where we can look into the entire
fingerprint of foetal development. We can understand the entire fingerprint
of healthy human development and try to understand which component
(15:17):
is only required for foetal development. And, when we have
this understanding, we ask the question
is used by cancer for its growth?" So, this allows
us to understand what are the unique genes which we
can target so we can target only cancer cells without
(15:37):
harming healthy cells, because I think this is the biggest
problem in cancer research
by targeting rapidly dividing cells, right? These are also present
in our gut, our skin, so that's where a lot
of side effects of cancer therapies are. However, what we
are thinking is changing our approach of targeting cancer, but
(16:00):
by not targeting any rapidly dividing cell, but by targeting
cells which are unique. So, I think this will allow
us to develop therapies which are more specific, have less toxicity,
and much more specificity.
Dr Viviane Richter (16:13):
Ankur, tell us what's next, now that you've discovered these signatures.
Where is your research going now?
Dr Ankur Sharma (16:21):
So, what we want to understand is why cancer has
this feature in the first place. Is it a bug
or feature? We think these developmental programs reappear in humans
because we need to deal with wear and tear every
day in our life. So, we get cuts like skin
wounds and so many other injuries all the time, and
(16:44):
these developmental programs reappear to repair these injuries. However, as
we age, we tend to acclimate mutations by UV radiation
or just by ageing, and when these mutant cells, which
I would call seeds at this stage, find this fertile
ground of foetal-like microenvironment, cancer happens. So, you want to
(17:08):
understand this process a little bit better, how to design,
how to tease apart these two processes, how our body
repairs itself versus how it gets cancer. And, if we
can understand these two processes better, we can develop therapies
which will only target cancer without impacting the repair part
of our body, which is very important as we age
(17:29):
because our ability to repair our body is weakened, and
we don't want to make it further weakened by developing
these therapies.
Dr Viviane Richter (17:37):
How are you now targeting these signatures that you've discovered
to develop better treatments?
Dr Ankur Sharma (17:43):
So, we are working on a couple of approaches. One
of them is biologics. So, I'm working with Rachel Galimidi
from the Biologics Platform at Garvan, and we are working on
a couple of lead molecules, which essentially block the interaction
or communication between these cancer cells and the microenvironment. Besides that,
we are also working on mRNA vaccines, which will allow
(18:05):
us to develop a very specific vaccination approach which will
target only these foetal antigens in tumour without touching any
healthy part in the liver or any other tissue.
Dr Viviane Richter (18:17):
Ankur, I understand that you recently kicked off a clinical trial.
Tell us about that.
Dr Ankur Sharma (18:23):
It's a fascinating journey which we, we are living right now.
We discovered these foetal-like phenomena in tumours five years ago,
and if you asked me five years ago where I
see this field going, I would not imagine that we'd
reach the clinical trial stage. So, it's a fascinating collaboration
of the clinicians across Australia. What we are doing in
(18:45):
this clinical trial is
patients who are at high risk of recurrent disease, which
means surgery alone would not improve the outcome in these patients. So,
we are screening these patients across 13 different clinical centres
in five Australian states, and all the screening is happening
(19:05):
in Garvan Institute in Sydney. So, all these centres send
us the samples. We use a technology called spatial transcriptomics
and try to find the signature in these tumours, and
based on the signature, we divide these patients into high
risk and low risk, and then we report back to
the clinic that a particular patient is high risk or
low risk. If the patient is high risk, it is
(19:28):
further randomised into a preemptive immunotherapy before surgery is given
or a standard of care treatment. In this clinical trial,
we are recruiting 208 patients and, hopefully, by the end
of two years, we might have a new approach of treating
this highly aggressive liver cancer patients by combining immunotherapy and surgery. And,
(19:48):
to my knowledge, this is the first time this kind
of trial is happening in any cancer where a spatial
transcriptome is being used to understand the risk of a
patient and therapy decision.
Dr Viviane Richter (20:00):
Ankur, I understand that you've recently had a very personal
run-in with cancer. Can you tell us about that?
Dr Ankur Sharma (20:08):
So, a few months back, my dad was diagnosed with
a lung cancer, and we did not know what kind
of lung cancer it is because, as we know, cancer
comes in different shapes and forms. Unfortunately, he was diagnosed
with a very aggressive lung cancer, and before we could
get all the diagnostic reports in, his cancer had spread
(20:28):
across the body and he succumbed to the disease. And
I think I have been working on cancer since the
last 17-18 years of my life, and this is the
first time when it struck me so close. But it
also emphasised the importance of the early diagnosis, because once
we know that cancer has happened and started to spread,
(20:51):
sometimes it's too late, and we don't get diagnostic reports
in time. Therapies don't work, and therapies, of course, would
not work unless we understand what kind of cancer it is. So,
I guess what was kind of a curiosity is more
of a personal mission now to understand cancer much more better.
Not what kind of cancer it is, because we know
(21:12):
it's a lung cancer or liver cancer, but what is
the molecular nature of this cancer? Why this cancer is
growing so aggressively? And I'm very optimistic that by a
combination of these high-level molecular technologies and machine learning approaches,
we will be there in the next five to six
(21:33):
years where we start diagnosing tumours a little bit better
with full molecular details.
Dr Viviane Richter (21:39):
That's incredible. We can't wait to hear about the outcomes
of this incredible research in the years to come.
Dr Ankur Sharma (21:45):
Thank you, Viviane.
Dr Viviane Richter (21:47):
Ankur, before we let you get back to your lab
at Garvan, it's time for the Fast Five. What was your
first job?
Dr Ankur Sharma (21:57):
Well, my first job was a postdoctoral scientist at Cincinnati
Children's Hospital in Ohio. That was just after my PhD
in India.
Dr Viviane Richter (22:05):
Do you have a favourite movie?
Dr Ankur Sharma (22:06):
I do. My favourite movie is The Man Who Knew Infinity.
It's about a mathematician called Srinivasa Ramanujan. Very fascinating guy. He
had no formal training of mathematics, wrote to a British mathematician,
went to the UK, worked there for a couple of years,
discovered a lot of things which we are still trying
to understand, and died at the age of 32, and
(22:28):
fascinating mind.
Dr Viviane Richter (22:30):
If you weren't a scientist, what would you be?
Dr Ankur Sharma (22:34):
I think I might have been a chef because, you know,
I think I see a lot of similarity between experimenting
with food, which I do a lot when I cook,
and like wet lab things. So, I think if not
a scientist, I would have been a cook maybe, or
a chef.
Dr Viviane Richter (22:51):
Do you have a favourite food?
Dr Ankur Sharma (22:52):
I think, apart from Indian food which I eat almost
on a daily basis, I love Japanese food and Thai food.
And it helps that I have been to Japan almost 10
times in the last four or five years.
Dr Viviane Richter (23:04):
Oh, wow!
Dr Ankur Sharma (23:04):
Yeah, I love the food and hospitality in Japan in general.
Dr Viviane Richter (23:09):
Who inspires you the most?
Dr Ankur Sharma (23:10):
In day-to-day life, my mum. I lost my mum 10
years ago, but she was such a strong and independent woman.
Dr Viviane Richter (23:18):
Dr Ankur Sharma, thank you so much for joining us
on Medical Minds.
Dr Ankur Sharma (23:22):
Thank you, Viviane, it's been great chatting with you.
Dr Viviane Richter (23:25):
If you'd like to know more about Ankur'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 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.
For decades, the fight against cancer has focused on killing
the tumour cell. We treated cancer like an isolated entity
that needed to be destroyed. But what if we've been
looking at the wrong target? In this episode, we delve
into the critical insight that cancer is not just a
rogue cell, it's an entire ecosystem. And that ecosystem is
(00:24):
the key to unlocking a new class of cures. Today,
we meet a researcher at Garvan who is using precision
technology to dissect how the environment around liver cancers allows
them to grow unchecked. The ultimate goal, to develop better
diagnostics and treatments. You're listening to Medical Minds, the podcast
(00:48):
that takes you inside the labs at the Garvan Institute
of Medical Research. I'm your host, Dr Viviane Richter, and
with us today is Dr Ankur Sharma, lab head in
the Translational Genomics program at Garvan. Welcome, Ankur.
Dr Ankur Sharma (01:03):
Thanks Viviane, it's great to be here.
Dr Viviane Richter (01:05):
Ankur, you have published your work on liver cancer in
the most prestigious international science journals. But, before we get
to your research, I'd like to go back a couple
of steps and understand where it all started for you.
Dr Ankur Sharma (01:21):
Well, I did not plan to become a scientist to
begin with. I guess I wanted to become a cricketer.
I grew up in India, and cricket is kind of
a religion, so I also wanted to become a cricketer.
I guess in 8th standard, or somewhere, one of our
science teachers was teaching us about genetics and Mendel's fascinating
experiments on plant genetics. This is where I started getting
(01:43):
a lot more excited about science, and I think it's
kind of a serendipity that a lot of internships which
I did in my undergraduate program, they happened to be
in the genetics departments, like plant genetics and forensic genetics,
and I ended up doing my Master's in human genetics. So,
one of the most fascinating research projects I did before my
(02:04):
PhD was working on forensic genetics. And this was in
a lab which was a wildlife lab. So, they were looking
at endangered species of animals and trying to see if
poachers are looking at animals which are endangered versus common. So,
just by looking at genetic patterns, you can differentiate between
(02:26):
a common cat versus a wild cat, and those were
some of the very, very simple things we were doing
back in the day, 20 years ago.
Dr Viviane Richter (02:34):
So, you were studying genetics just after the sequencing of
the first human genome, is that right?
Dr Ankur Sharma (02:41):
Yep.
Dr Viviane Richter (02:41):
That would have been an incredibly exciting time.
Dr Ankur Sharma (02:43):
It was, it was actually, and again, it was not
by plan. I think the human genome was sequenced, a
first full draft came in 2001, 2003. I started my
Master's in 2006, and I guess that was the best
time to study human genetics as a student because there
was so much unknown, and I think that's what fascinates
(03:04):
all of us
the human genome? And all those factors, cumulatively, might have
impacted me, motivated me to do PhD and do what
I'm doing today.
Dr Viviane Richter (03:18):
Incredible. So you went on to study liver cancer, particularly.
What drew you to cancer research and specifically liver cancer?
Dr Ankur Sharma (03:29):
So, I think I started working on liver cancer sometime
in 2015, but before that, I first started working on
cancer because when I was studying human genetics, or genomics,
I got very fascinated about how some of the cells
in our body just go rogue and we develop cancer.
And it's just by getting these mutations in genes. So,
(03:51):
I wanted to study cancer a little bit more in detail.
I decided to do a PhD in the field of
cancer biology, and my PhD topic was looking into a
particular kind of genes which are very important for our development,
but just get overactivated in cancer. And I decided to
block this overactivity of these genes by developing antibodies. So,
(04:15):
antibodies are molecules which will bind to any other gene,
or basically the product of a gene which is protein,
and could potentially block its function. That's what I was
doing in my PhD
this protein in a way that we can control cancer. So,
I was studying this in the context of breast cancer
(04:37):
and colon cancer. While I was doing these studies, again,
I got very fascinated by things I was observing in
the lab, and one of the simple observations was not
all cells are alike, just like us humans
also very diverse, and they come in different shapes, sizes,
and the level of these genes are also different.
Dr Viviane Richter (05:01):
In cancer, specifically?
Dr Ankur Sharma (05:02):
In cancer, more specifically, but in general, like the level of
the gene in cells is not always the same. And
it's important because if you just think about our skin,
our forehand and backhand have different kinds of skin because
they have different functions. So, genes which are important, such
as melanin, would be different levels in these two things. So,
(05:24):
I wanted to study this process in a little bit more detail,
like why cells have different levels of genes. And again,
those days a new technology was coming, which was single
cell genomics, so you can understand all the genes in
a cell at a very high granular level. This is
what I started looking into during my postdoc, and one
(05:46):
thing led to another. One day I got a call
from a senior clinical colleague who was working on liver cancer.
He knew I worked on single cell genomics, and he said,
"Would you like to look into liver cancer in more detail?"
And I guess I was very much fascinated by this
proposal because before that I was looking into cancer cells,
(06:07):
doing single cell genomics, and understanding how heterogeneous they are.
But I was focusing only on the cancer cells. However,
we know the tumour is not just a malignant cancer cell;
it's much more than that. It's cells which bring blood
supply to tumour. It's the immune cells which try to
kill the cancer cell, but cancer is trying to outmaneuver them.
(06:30):
And then there's a very interesting layer of cells such
as fibroblasts and extracellular matrix where all of this interplay is happening.
I thought this is a good opportunity for me to
look into the complex nature of different cells in cancer microenvironment,
and liver cancer was a good model system for me;
and that's how I got into liver cancer.
Dr Viviane Richter (06:52):
When did researchers first understand this idea that a cancer
isn't just made up of cancer cells, it's made up
of all of these supporting cells, connective tissues that make
up this ecosystem that is a tumour?
Dr Ankur Sharma (07:05):
I guess the importance of microenvironment per se in cancer
has been appreciated since so many decades, I would say. However,
tools were not present which will allow us to look
into this complexity in much more detail.
Dr Viviane Richter (07:20):
Right.
Dr Ankur Sharma (07:20):
So, we could look into fibroblast or we could look
into endothelial cells, but we are studying these cells in isolation. However,
these new technologies allow us to look into all the
pieces of the puzzle in one go, and then we
can try to put them together and try to see
what is happening in the cancer. So, I would say
that in the last 10 to 15 years, our ability
(07:42):
to understand tumour ecosystem has improved much more. We knew
that it is important. Another interesting thing that happened in
this area is immunotherapies, which work really well when they work,
and they work by modulating microenvironment. So, I think we
know that clinically it's very important. We have therapies in
(08:02):
clinic which target microenvironment, and we have tools to study this.
Put the pieces together and you can just look into
the tumour and try to understand where each and every
component of tumour is, what they are making, how similar
or dissimilar they are. So, I think it's an advancement
in the technology and clinical need which has re-emphasised the
(08:24):
importance of tumour microenvironment.
Dr Viviane Richter (08:27):
That's fascinating. What is that level of detail allowing us
to understand about cancers and how is that improving how
we're thinking about treating them?
Dr Ankur Sharma (08:38):
I think in the last one decade, technology has evolved
so much that now we can not only see the
different cells in the tumour, but also see how they
are sitting next to each other. So, think of it like:
we can now understand the neighbourhood looking into various suburbs
of cancer and try to understand who lives there, what
(08:59):
they are doing, how they are talking to each other;
and I think this has allowed us to understand cancer
in much more detail. More importantly, because we can understand
how two different cancers or two patients' tumours are different
from each other, because we know that – and all of
us have heard these examples that there is a cancer
(09:19):
patient who responded really well to therapy and they did
really well – and I think all of us want to
have our patient behave like that. However, some tumours are
very aggressive. We have cancers and patients come back within
a few months, and sometimes patients are aggressively developing their
disease before we can even diagnose it. And I think
(09:41):
these two extremes and cancer exists between this continuum of
some very good responders to some very bad responders. And again,
this is not just only two kinds of tumours, it's
just a mix of continuum between them. And to understand
this in whole detail, we need to understand why some
patients respond so well, and why some patients do not respond.
(10:02):
What is in the tumour? Is it the cancer cells,
or it's the microenvironment, or it's the interaction between these
two which is guiding how therapies may or may not work. So,
I think understanding cancer in full detail, on patient tumour
directly without involving a model system, allows us to understand
why patients behave in clinic the way they behave, so
(10:24):
we can design better therapies.
Dr Viviane Richter (10:26):
So, in a way, taking a real precision approach to
cancer therapy that's really targeted to individual patients.
Dr Ankur Sharma (10:33):
Exactly, yeah.
Dr Viviane Richter (10:35):
So, how many people are affected by liver cancer in Australia?
Dr Ankur Sharma (10:39):
So, liver cancer impacts almost 3000 Australians every year. And
we talked about cancers which respond better to therapies versus
do not respond better to therapies, and liver cancer unfortunately
comes into these cancers who do not respond to therapies.
Five-year survival rate of a patient with liver cancer is
only 20%.
Dr Viviane Richter (10:59):
Wow.
Dr Ankur Sharma (10:59):
Because therapies do not work in these patients
cancers are diagnosed at a little bit later stage, but
also it's such a vital organ where, as soon as
cancer becomes a little bit more aggressive, it's difficult to treat.
We cannot remove the liver completely, and the therapies, we
just have one therapy for advanced liver cancer, and the
(11:19):
second therapy is being approved, hopefully, in the next six
months or so. The options in clinic are very limited.
Disease is very aggressive, which is making it such a
difficult cancer to treat.
Dr Viviane Richter (11:32):
I understand you made a really fundamental discovery about how
liver cancers develop from a genetic perspective. Can you talk
us through that?
Dr Ankur Sharma (11:41):
Yeah. So, what we have identified in our lab is
a fascinating similarity between the development of a human foetus and cancers.
And why this is fascinating? So, if you think about
human development, we all start from one cell, and within
a few months, we have trillions of cells and this
whole body, which lasts for many, many years. Now what
(12:03):
happens in cancer? We have, again, a rapid growth of
cancer cells in the body. The only difference is the
development is very controlled, very precise, while cancer is completely
uncontrolled division of cells. However, it utilises the same mechanisms,
the same kind of foundation, or microenvironment, or "soil" (to
(12:26):
think of), which a growing foetus is using to grow
different organs such as liver, lung, heart. And now the
cancer in these organs utilise the same kind of foundation
and microenvironment for uncontrolled growth. So, this is the one
key mechanism we have identified in our lab, which we
call "oncofoetal microenvironment" or "oncofoetal ecosystem".
Dr Viviane Richter (12:48):
That's fascinating. So, you've discovered, in your lab, certain signatures
within some liver cancers that are very similar or the
same as signatures, genetic signatures, within a developing foetus. How
does that open the field up to a different way
to treat liver cancer?
Dr Ankur Sharma (13:08):
Yeah, that's a good question. So, if you think about
development once more
we are not breathing air, so our lungs are not
used to breathing air. And so, our organs behave differently
when we are in our mother's womb versus when we
come out in this world. So, a lot of genes
which are important for maintenance of foetal part of our life,
(13:31):
which is very growth aggressive, are shut down when we
come out of our mother's womb, and this is very
important for healthy growth of a baby. But what happens
in cancer? All of these genes, which are required for
foetal growth, are somehow reactivated. We don't understand completely yet
how this process happens, but it tells us that the
(13:54):
same mechanism which a growing foetus uses is acquired by cancer. Now,
there is an opportunity here, because all of these genes
or proteins are not required for healthy growth, which means
we can target them. Because we see them in foetus
and we see them again in the tumours in adult
life at the age of 50, 60, 70. So, these
(14:16):
are not important for our day-to-day function. These are important
for cancer cells, which provides us a very unique opportunity
for developing new therapeutics, where we can block the signals,
or kill these cells, which are cancer cells but have
this unique marker on them, so we can put a
target on these cells and destroy these cells. So, this
(14:37):
is a one very unique opportunity which we think we
have in our research area.
Dr Viviane Richter (14:42):
And you've discovered these markers, these targets using single cell genomics.
Can you tell us a little bit more about where
your research has taken you, what specifically you're targeting now
in these cancer cells?
Dr Ankur Sharma (14:56):
So, research is a very, very rapidly evolving field, right?
So what now we are building is machine learning and
artificial intelligence-based approaches, where we can look into the entire
fingerprint of foetal development. We can understand the entire fingerprint
of healthy human development and try to understand which component
(15:17):
is only required for foetal development. And, when we have
this understanding, we ask the question
is used by cancer for its growth?" So, this allows
us to understand what are the unique genes which we
can target so we can target only cancer cells without
(15:37):
harming healthy cells, because I think this is the biggest
problem in cancer research
by targeting rapidly dividing cells, right? These are also present
in our gut, our skin, so that's where a lot
of side effects of cancer therapies are. However, what we
are thinking is changing our approach of targeting cancer, but
(16:00):
by not targeting any rapidly dividing cell, but by targeting
cells which are unique. So, I think this will allow
us to develop therapies which are more specific, have less toxicity,
and much more specificity.
Dr Viviane Richter (16:13):
Ankur, tell us what's next, now that you've discovered these signatures.
Where is your research going now?
Dr Ankur Sharma (16:21):
So, what we want to understand is why cancer has
this feature in the first place. Is it a bug
or feature? We think these developmental programs reappear in humans
because we need to deal with wear and tear every
day in our life. So, we get cuts like skin
wounds and so many other injuries all the time, and
(16:44):
these developmental programs reappear to repair these injuries. However, as
we age, we tend to acclimate mutations by UV radiation
or just by ageing, and when these mutant cells, which
I would call seeds at this stage, find this fertile
ground of foetal-like microenvironment, cancer happens. So, you want to
(17:08):
understand this process a little bit better, how to design,
how to tease apart these two processes, how our body
repairs itself versus how it gets cancer. And, if we
can understand these two processes better, we can develop therapies
which will only target cancer without impacting the repair part
of our body, which is very important as we age
(17:29):
because our ability to repair our body is weakened, and
we don't want to make it further weakened by developing
these therapies.
Dr Viviane Richter (17:37):
How are you now targeting these signatures that you've discovered
to develop better treatments?
Dr Ankur Sharma (17:43):
So, we are working on a couple of approaches. One
of them is biologics. So, I'm working with Rachel Galimidi
from the Biologics Platform at Garvan, and we are working on
a couple of lead molecules, which essentially block the interaction
or communication between these cancer cells and the microenvironment. Besides that,
we are also working on mRNA vaccines, which will allow
(18:05):
us to develop a very specific vaccination approach which will
target only these foetal antigens in tumour without touching any
healthy part in the liver or any other tissue.
Dr Viviane Richter (18:17):
Ankur, I understand that you recently kicked off a clinical trial.
Tell us about that.
Dr Ankur Sharma (18:23):
It's a fascinating journey which we, we are living right now.
We discovered these foetal-like phenomena in tumours five years ago,
and if you asked me five years ago where I
see this field going, I would not imagine that we'd
reach the clinical trial stage. So, it's a fascinating collaboration
of the clinicians across Australia. What we are doing in
(18:45):
this clinical trial is
patients who are at high risk of recurrent disease, which
means surgery alone would not improve the outcome in these patients. So,
we are screening these patients across 13 different clinical centres
in five Australian states, and all the screening is happening
(19:05):
in Garvan Institute in Sydney. So, all these centres send
us the samples. We use a technology called spatial transcriptomics
and try to find the signature in these tumours, and
based on the signature, we divide these patients into high
risk and low risk, and then we report back to
the clinic that a particular patient is high risk or
low risk. If the patient is high risk, it is
(19:28):
further randomised into a preemptive immunotherapy before surgery is given
or a standard of care treatment. In this clinical trial,
we are recruiting 208 patients and, hopefully, by the end
of two years, we might have a new approach of treating
this highly aggressive liver cancer patients by combining immunotherapy and surgery. And,
(19:48):
to my knowledge, this is the first time this kind
of trial is happening in any cancer where a spatial
transcriptome is being used to understand the risk of a
patient and therapy decision.
Dr Viviane Richter (20:00):
Ankur, I understand that you've recently had a very personal
run-in with cancer. Can you tell us about that?
Dr Ankur Sharma (20:08):
So, a few months back, my dad was diagnosed with
a lung cancer, and we did not know what kind
of lung cancer it is because, as we know, cancer
comes in different shapes and forms. Unfortunately, he was diagnosed
with a very aggressive lung cancer, and before we could
get all the diagnostic reports in, his cancer had spread
(20:28):
across the body and he succumbed to the disease. And
I think I have been working on cancer since the
last 17-18 years of my life, and this is the
first time when it struck me so close. But it
also emphasised the importance of the early diagnosis, because once
we know that cancer has happened and started to spread,
(20:51):
sometimes it's too late, and we don't get diagnostic reports
in time. Therapies don't work, and therapies, of course, would
not work unless we understand what kind of cancer it is. So,
I guess what was kind of a curiosity is more
of a personal mission now to understand cancer much more better.
Not what kind of cancer it is, because we know
(21:12):
it's a lung cancer or liver cancer, but what is
the molecular nature of this cancer? Why this cancer is
growing so aggressively? And I'm very optimistic that by a
combination of these high-level molecular technologies and machine learning approaches,
we will be there in the next five to six
(21:33):
years where we start diagnosing tumours a little bit better
with full molecular details.
Dr Viviane Richter (21:39):
That's incredible. We can't wait to hear about the outcomes
of this incredible research in the years to come.
Dr Ankur Sharma (21:45):
Thank you, Viviane.
Dr Viviane Richter (21:47):
Ankur, before we let you get back to your lab
at Garvan, it's time for the Fast Five. What was your
first job?
Dr Ankur Sharma (21:57):
Well, my first job was a postdoctoral scientist at Cincinnati
Children's Hospital in Ohio. That was just after my PhD
in India.
Dr Viviane Richter (22:05):
Do you have a favourite movie?
Dr Ankur Sharma (22:06):
I do. My favourite movie is The Man Who Knew Infinity.
It's about a mathematician called Srinivasa Ramanujan. Very fascinating guy. He
had no formal training of mathematics, wrote to a British mathematician,
went to the UK, worked there for a couple of years,
discovered a lot of things which we are still trying
to understand, and died at the age of 32, and
(22:28):
fascinating mind.
Dr Viviane Richter (22:30):
If you weren't a scientist, what would you be?
Dr Ankur Sharma (22:34):
I think I might have been a chef because, you know,
I think I see a lot of similarity between experimenting
with food, which I do a lot when I cook,
and like wet lab things. So, I think if not
a scientist, I would have been a cook maybe, or
a chef.
Dr Viviane Richter (22:51):
Do you have a favourite food?
Dr Ankur Sharma (22:52):
I think, apart from Indian food which I eat almost
on a daily basis, I love Japanese food and Thai food.
And it helps that I have been to Japan almost 10
times in the last four or five years.
Dr Viviane Richter (23:04):
Oh, wow!
Dr Ankur Sharma (23:04):
Yeah, I love the food and hospitality in Japan in general.
Dr Viviane Richter (23:09):
Who inspires you the most?
Dr Ankur Sharma (23:10):
In day-to-day life, my mum. I lost my mum 10
years ago, but she was such a strong and independent woman.
Dr Viviane Richter (23:18):
Dr Ankur Sharma, thank you so much for joining us
on Medical Minds.
Dr Ankur Sharma (23:22):
Thank you, Viviane, it's been great chatting with you.
Dr Viviane Richter (23:25):
If you'd like to know more about Ankur'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 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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