June 1, 2025 • 27 mins
Pancreatic cancer is one of the toughest cancers to treat – it’s aggressive, often diagnosed late, and doesn’t respond well to standard therapies. In this episode, we meet Professor Marina Pajic who is working at the cutting-edge of science to transform how we understand and treat this disease.
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Dr Viviane Richter (00:01):
Pancreatic cancer is one of the toughest cancers to treat.
It's aggressive, often diagnosed late, and doesn't respond well to
standard therapies. So what hope is there for patients who
are diagnosed with pancreatic cancer? Today, we meet an extraordinary
researcher who is working at the cutting edge of science
(00:21):
to transform how we understand and treat this disease. You're
listening to Medical Minds, the podcast 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
the Co-director of Garvan's Translational Oncology Program and Head of Garvan's Personalised Cancer Therapeutics Lab,
(00:44):
Professor Marina Pajic. Welcome, Marina.
Professor Marina Pajic (00:47):
Hi, Viviane, and hello, everyone. Thanks very much for this invitation.
It's a pleasure to be here with you today.
Dr Viviane Richter (00:55):
Marina, before we talk about pancreatic cancer and your research,
tell us where it all started for you. Did you
always know you were going to be a scientist?
Professor Marina Pajic (01:05):
Well, subconsciously, probably, yes. I have to say that from
a very early age, and I grew up in Serbia,
our teachers really instilled, you know, this sort of drive
for education. And from very early on, we learned, for example,
about one of the famous Serbian inventors called Nikola Tesla,
(01:28):
and just learning about his inventions, about his crazy life,
where it took him all the way to America, it
just was probably one of the really early inspiring moments
for me to kind of start thinking about, you know,
what being a scientist would be like. From then on, obviously,
I also excelled in natural sciences, things like mathematics, biology, chemistry, math, physics.
(01:53):
So it was, it was just natural way to progress.
Dr Viviane Richter (01:57):
So, how did you get from being obsessed with Nikola
Tesla to working on pancreatic cancer?
Professor Marina Pajic (02:04):
So, I would guess probably natural progression. So, I was
fortunate enough, my parents took us to New Zealand, uh,
where I was able to continue my education after high school.
So this is really where, under some really inspirational scientists,
I started to study pharmacology, so I did a degree,
a bachelor's degree and a master's degree in science. Then, again,
(02:27):
moved to Sydney, moved to Australia in the sort of
early 2000s, and then really started to learn about some
of the hardest to treat cancers. So this was the
PhD that I did at University of New South Wales
under Professor Michelle Haber. She is an incredibly inspirational, uh,
scientist in her own right, but I think she's really
(02:50):
helped me sort of begin to develop an understanding of
why studying treatment resistance is so important. And then I
took that early education, well, early to mid education, on
towards postdoctoral studies where I started developing models of triple
negative breast cancer, and particularly again, trying to understand, you know,
(03:14):
the highly treatment resistant nature of that cancer, trying to
find new ways of targeting the disease. Which then, again,
just naturally drove me back to Australia, to Garvan, and
then really, my research then really took off.
Dr Viviane Richter (03:31):
You focused on some of the toughest to treat cancers.
What is it about them that drives you in your research?
Professor Marina Pajic (03:39):
So, what's particularly interesting about these diseases is that they
are so complex, right? So it's not a simple problem
that just one drug or one hit, you know, will
solve the entire problem. There is this incredible complexity that
surrounds these cancers. I mean, this is also why my
(04:00):
big goal is to really try to, A, understand, you know,
what is driving the disease, what's driving the resistance and,
at almost individual level, try to identify the ways of
how to target these cancers, how to make these patients better.
Dr Viviane Richter (04:17):
So, what is it about pancreatic cancer in particular that
makes this disease so difficult to treat?
Professor Marina Pajic (04:23):
Well, look, again, pancreatic cancer, it is a hard cancer because, A, it,
it is diagnosed late, unfortunately. Symptoms are very difficult to
pick up on because, you know, they're not as obvious
as maybe for some of the other cancers. Pancreas is,
you know, buried deep inside our body. It is hard
(04:44):
to detect these cancers at an early stage. And then,
on top of that, this particular cancer seems to be
very capable to, you know, very quickly spread to other sites,
and then it really starts to cause havoc. It is also, uh,
highly intrinsically resistant to, at least to the current sort
(05:04):
of standard of care treatments. So, unfortunately, not many of
us know much about the pancreas or even care about
what the pancreas does, but it is actually a critical organ.
It produces a number of of different hormones, for example,
insulin being the key hormone that is required for processing
(05:26):
the glucose, the sugars, in our body and ensuring that
the right organs get the energy that they need, but
don't get the excessive, you know, sugar circulating in the
blood and then causing additional damage to the body. And
then also some of the other, for example, hormones as well.
It produces like glucagon, which again is really important for digestion. So,
(05:49):
when something goes wrong, this is also why this small
organ buried deep inside our body is clearly connected to
so many other things, other bodily functions, that this is
also why things go very wrong.
Dr Viviane Richter (06:05):
You mentioned pancreatic cancer is often diagnosed at a late stage.
What are some of the early symptoms?
Professor Marina Pajic (06:12):
Some of the earliest symptoms are mid-level back pain that's
often mistaken, you know, for muscular issues. People go through
physio for quite a period of time, for months and months,
until they start to develop some of the more advanced symptoms,
which involves things like jaundice. That's usually when patients actually
present at the hospital. They'll have a range of digestive
(06:34):
issues as well that will just get mistaken for other
types of conditions. You know, it could be, um, IBS or,
or anything else, really. And then it's at that diagnosis
stage that unfortunately, with jaundice, this is usually when the
cancer becomes quite involved because it is impinging on some
of the other organs. Bile ducts, for example. So, this
(06:58):
is also why you start to see these, um, symptoms
come up.
Dr Viviane Richter (07:02):
And I guess at that point, the cancer has usually
already spread beyond the pancreas. Is that right?
Professor Marina Pajic (07:07):
Exactly. I guess if the patient is lucky, it may involve,
it'll be local invasion at that stage, but majority of
the cases do already present with metastatic disease. So, this
is over 80% of patients. The cancer has already spread.
Dr Viviane Richter (07:23):
Wow, that's, that's a huge proportion of patients. So, how
many people are diagnosed with pancreatic cancer?
Professor Marina Pajic (07:30):
The statistics are really dismal around this disease still. Over
430,000 people will, unfortunately, be diagnosed with pancreatic cancer. These,
these are global figures. And the survival rates are currently
sitting around 12%, uh, five years post-diagnosis. These survival rates
(07:51):
actually have shifted in the last 10 to 15 years.
They used to be sitting around 5%. So, look, there
have been improvements, largely to do with the implementation of polychemotherapy,
so these are combination chemotherapies, uh, for the treatment of
patients with this disease, but unfortunately, obviously, there is still
(08:12):
a lot more that we need to do, and that's
really what my lab focuses on.
Dr Viviane Richter (08:18):
So Marina, let's talk about your research now. How is
your team tackling those dismal survival rates?
Professor Marina Pajic (08:26):
My team is really focused on exactly, you know, building
I guess, on the expertise that I have acquired over
the last 20 or so years. We're really trying to
understand the drivers of treatment resistance in the disease and
then trying to pinpoint both tumour-driven mechanisms behind resistance, as
(08:48):
well as these corrupted cells that surround the pancreatic cancer
as well, trying to understand how they might help drive
the disease. And so really, it's all about finding, co-targeting
treatment approaches, how best to really kill the cancer from
a variety of different angles.
Dr Viviane Richter (09:07):
How has the field changed in pancreatic cancer? What do
we know now that we didn't know, say 10 years ago?
Professor Marina Pajic (09:14):
Well, we've actually had some really major advances since I
arrived and decided to join the Garvan. One of the key, actually,
being really understanding this genomic genetic landscape of the disease. And,
you know, what we learned from this – so this is
where we sequenced, so we understood, we tried to understand
(09:36):
the DNA signature of a whole heap of pancreatic cancers. And,
from there, we found that basically pancreatic cancer, on a
genetic level, is not just one disease. It's a whole
range of different cancers. The next obvious answer or, from that,
was that clearly treating this disease with just one type
(09:59):
of therapy is not the right approach. We need a
more personalised treatment approach for this cancer. What my team
has then also developed as part of this research is
a whole suite of patient-derived models. So, this is from
the tumours, from these patient tumours that we have analysed.
We now have models growing in the laboratory that we
(10:21):
can study. So we can, in great detail, study how
each individual genetic change might develop into a potential therapeutic target.
Building on that sort of knowledge that we have generated
now over the last 10 years, for example, we have
shown that a specific subset of pancreatic cancer, there is
(10:41):
particularly highly genetically rearranged, so these are very, very, we
call them unstable tumours, they may respond to a specific
type of therapy that's had really great success in breast cancer.
So these are drugs called PARP inhibitors. They induce a
specific type of DNA damage inside the tumours. And so
(11:03):
what we've shown is that this specific subset of cancers
may respond to this type of drug. So this was
one of the major publications or research publications that came
out of Garvan, came out of our work. And then
from then, both us, but also other people have taken
on that research, then driven it through international clinical trials,
(11:23):
and this particular drug is now FDA-approved for clinical use
for patients with pancreatic cancer, with this specific type of
genetic change. So that's one of the major, I guess,
breakthroughs that has happened in the last 10 to 15 years.
There's certainly a whole lot of other ones coming through
now in the pipeline on the way to clinical application. So,
(11:48):
we are excited about the, cautiously excited about the future,
but there's obviously a lot more that we need to
do to try to understand, you know, what else can
then pop up and cause the resistance in these cancers,
even if they respond initially to a drug.
Dr Viviane Richter (12:04):
Marina, you mentioned subsets. How many subsets of pancreatic cancer
are there?
Professor Marina Pajic (12:10):
So, this is hard to define because, as the technologies
improve and we learn a lot more about the cancer
at a higher resolution, it seems to become more complex. So, initially,
just through doing this whole genome sequencing, so this is, again,
I say just, but this is actually really expensive and
(12:32):
really comprehensive methodology in its own right. But with that,
we were able to identify at least 10 different subtypes
of pancreatic cancer. But now, using newer methodologies and being
able to understand the disease at even a single cell level,
we can see that within a single cancer there is
all this variability, genetic and beyond variability, that exists that
(12:57):
still we need to take into account when we're designing
new treatment approaches.
Dr Viviane Richter (13:03):
You mentioned earlier personalised treatments. What does that mean? What
does that look like when a patient presents to the clinic?
Professor Marina Pajic (13:12):
When the patient presents with pancreatic cancer, ultimately, because it's
that frontline setting, they will be given standard of care
chemotherapy treatment. There's two options. One that's more toxic, one
that's slightly less toxic, but also a bit less effective,
depending on their wellness status. But, at that point, the
oncologist makes sure that these patients get sequenced. We recommend that.
(13:35):
So that's basic sequencing. It's not, you know, so it
doesn't cover everything. At least it covers a specific proportion.
So if they're lucky, they have one of the mutations
that there are existing drugs for. And, I should say, actually, also,
increasingly now, it's the KRAS inhibitors as well. Because the
KRAS is one of the key drivers. It's a mutation.
(13:55):
In pancreatic cancer, it's present in a large proportion of patients,
so there are tests currently, clinical trials happening to understand
how well these patients will respond to that therapy. The
trials also are showing already that it looks like there's
gonna be a need for a combination therapy there, even
though it's a major driver of pancreatic cancer, the KRAS,
(14:16):
just blocking that pathway, likely not to be enough.
Dr Viviane Richter (14:20):
What do you see as the next stage for pancreatic
cancer patients?
Professor Marina Pajic (14:25):
Well, what we're doing is trying to identify targets that
we can then match with specific therapies. And then, on
top of that, we are now adding new information around
how the other cells that are present in the environment
of these tumours, as they grow and develop, how they
might influence the ultimate response to, to therapy, and also
(14:47):
the growth of the cancer and the spread of the cancer.
And so what we are focusing in our lab is
trying to target two different aspects that further drive the disease. So,
these are the non-functional immune cells. So these are corrupted
cells now that we're talking about that no longer function.
They're not able to recognise the cancer and kill it.
(15:08):
And we're trying to find new ways which we can
stimulate these immune cells to now start to fight the cancer.
Those are some of the new discovery projects that are
happening in our lab. And then, in parallel with that,
we're also trying to target one of the key, uh,
surrounding elements of the cancer. So this is this fibrosis,
this dense scar-like tissue that signals, so not only is
(15:31):
it a physical barrier to treatment, but it also creates
these positive signals that further drive the growth of the
cancer and the spread of the cancer. So we have
a few targets that we have developed the fibrotic elements,
so these are antifibrotic therapies that we're now driving into
early stage phase one clinical trials involving, so this is
(15:53):
now involving the New South Wales Early Clinical Trials Alliance
called NECTA, multiple sites across Sydney. We're hoping to open
these trials later this year. So I'm very excited, obviously
also about this work. I want to see these therapies
really shift the survival of patients with this disease. I
(16:14):
guess our immediate goal within the next decade is to
try to shift the survival rates to something like 30%,
looking at five years post-diagnosis. Uh, so this is in
line with the sort of global goal in this area,
but also further down the line, what we're hoping to
have is a patient present at the clinic, we'll be able
(16:36):
to molecularly profile at high resolution, the tumour elements of
that biopsied tumour biospecimen, but also all of these corrupted
normal cells that are present within these tumours. Understand the
biology of these diverse components, tailor the combination therapy using
(16:58):
realistic treatments that are reasonably well tolerated in this setting –
because that's another thing that we really have to carefully
consider for these patients, because the patients with pancreatic cancer
do tend to present already quite sick, uh, within the clinic.
And then, using innovative techniques, some of the non-invasive methodologies
(17:19):
as well that we're trying to develop in our lab,
try to monitor these patients dynamically as they undergo these treatments.
If the patients stop responding to therapy, we should be
able to, at an earlier stage, define that and then
try to identify the next stage of treatments. So I
(17:40):
am hoping that pancreatic cancer becomes, at the very minimum,
if not cured, a manageable disease for the patients. Patients
can live with this disease long term.
Dr Viviane Richter (17:51):
Marina, you came to Garvan in 2010 to do this research.
Why did you pick Garvan?
Professor Marina Pajic (17:57):
So back in 2010, when I decided to come back
to Australia, Garvan was really the only place to be,
and it still is a beacon for this type of
research that we're currently doing. It was a particularly exciting
time because there was this International Cancer Genome Consortium project
that was being set up. So this was around trying
(18:19):
to understand the genetics of a whole heap of different cancers. International, multi-institutional,
thousands of researchers really joining together on this incredible journey.
And I was very fortunate then to join the Garvan
and the Australian Pancreatic Cancer Genome Initiative, which was the
(18:40):
Australian pancreatic cancer arm of this international study. It was
led by Andrew Biankin, pancreatic cancer clinical expert at the Garvan, and, uh,
Sean Grimmond, genomics expert based at UQ. What we did
as part of this project, you know, we were the
first people to start to understand the Australian pancreatic cancers,
(19:04):
the genomes of these tumours, trying to understand that really
complex genetic landscapes, and as I mentioned before, really discovered
a few key things, some of which have now landed
in clinical practise. From that, what my team has then really, uh,
driven is a whole range of different projects centered around
(19:29):
personalising medicine for pancreatic cancer. So again, quite a few
new discoveries from that
new therapies, so including another breast cancer drug that targets
the proliferative nature of these cancers. We've shown also how
that drug actually affects the fibrotic scar-like tissue of pancreatic
(19:51):
cancer and how, potentially, it could be combined with some
of the standard of care treatments. We've also identified targets,
antifibrotic targets, as I mentioned before, that are now entering
early phase trials, and there's a whole heap of more
research that has now come from these initial studies.
Dr Viviane Richter (20:10):
I guess not much was known about the genomics of
pancreatic cancer. Can you take us back to that time?
What did it take to make those discoveries?
Professor Marina Pajic (20:20):
It was a really crazy time. I think a whole
range of enthusiastic individuals working together, clinicians, scientists, clinician PhD trainees –
so these were people who decided to undertake research as
part of their clinical training, who are now directors of
different oncology centres around Sydney, as well as regionally in
(20:45):
New South Wales that I now really closely collaborate with –
we would be, you know, sitting in the lab preparing
things so that when the surgeon takes the pancreatic cancer
specimen out, the pathologist would be right there on site,
immediately analysing the tissue, doing quality control for us to
give us the prime sample that we can then take
(21:06):
into the lab. Sometimes, God knows what hours, you know,
we would be sitting there 1am, 2am in the morning
waiting for the specimens, because, you know, as you, you know,
should understand as well, these surgeries can be quite complex.
The surgeons are in there for hours operating on the patients.
And then we would, you know, be super happy when
we get these specimens out, process them in various ways,
(21:29):
you know, set up, set them up in cultures so
that we can do screening for new treatments. We can
implant them into mice, make new models of the disease.
So all of that was just an amazing time. I
think that we, by working together, we were able to
generate important new insight around the disease, but it has
(21:50):
actually really then also accelerated the research in Australia.
Dr Viviane Richter (21:56):
Marina, what would you say to someone who has been
just recently diagnosed with pancreatic cancer, or whose family member
has been diagnosed?
Professor Marina Pajic (22:05):
We're really fortunate that, you know, we can now build
on the rich history of research, of the discoveries made
at the Garvan, highly collaborative research. So, involves a lot
of now really well established, long-standing links to the clinic,
multi-layered collaborations, international collaborations, national collaborations, whether it's in the
(22:30):
scientific space or clinical space, industry links as well that
we can now really build on to drive these discoveries
that we make into the clinic, start to really analyse
the new sort of clinical specimens that we get. Try
to understand, you know, why specific patients may respond to
(22:52):
these new treatments or not, and then it's back to
the bench with that information for a whole new generation
of discoveries and new therapies that we can then almost, uh,
stimulate this virtual cycle of discovery to clinic and back again.
We have real momentum now. All the technology is there
(23:14):
at the Garvan. All the people are there, we're ready
to go. We're doing it.
Dr Viviane Richter (23:20):
Marina, before we let you get back to the labs,
we'd love to learn just a little bit more about
you in a section called The Fast Five. Are you
up for it?
Professor Marina Pajic (23:30):
Always.
Dr Viviane Richter (23:32):
Marina, do you have any hobbies?
Professor Marina Pajic (23:34):
Besides working on pancreatic cancer, my child, I think. Uh,
really hanging out with my vivacious and amazing nine-year-old, and
mostly running after her.
Dr Viviane Richter (23:45):
Do you play any sports?
Professor Marina Pajic (23:47):
I used to be a black belt in karate, once
upon a time.
Dr Viviane Richter (23:51):
Wow.
Professor Marina Pajic (23:51):
But now it's running really, that, uh, you know, just
helps that mind calm down sometimes after a big day
of work.
Dr Viviane Richter (24:01):
A black belt in karate. I'm afraid.
Professor Marina Pajic (24:04):
You should be.
Dr Viviane Richter (24:06):
How did you come to be a black belt in karate?
Professor Marina Pajic (24:09):
Look, it's, uh, it's really cheesy, I guess. It's the
Bruce Lee, uh, movies. Back in the day, in the 90s,
I begged my parents to send me to karate, and then, um, yeah,
seven years later, got the first done. I loved it.
I loved my sensei. I love the discipline that karate
brings to you, the calm. And then also, it's great
(24:31):
to learn all the fancy techniques.
Dr Viviane Richter (24:34):
What was your first job?
Professor Marina Pajic (24:36):
Oh, this is really exciting. Newspaper delivery on a bicycle.
Loads of heavy newspapers early in the morning before school.
Dr Viviane Richter (24:45):
Do you have a favourite quote or life motto?
Professor Marina Pajic (24:49):
Never give up. It's simple and you need it in science.
Dr Viviane Richter (24:53):
Do you have any secret skills?
Professor Marina Pajic (24:55):
Maybe, um, baking. I mean, it's not particularly secret, but yeah,
I had a recipe in a cookbook printed by UNSW
once upon a time.
Dr Viviane Richter (25:04):
Very cool. What was it?
Professor Marina Pajic (25:06):
Uh, the recipe, chocolate caramel diamonds.
Dr Viviane Richter (25:09):
Most famous person you've ever met?
Professor Marina Pajic (25:12):
Oh, that's easy. That's Bryan Brown, through Garvan. I was
very fortunate to, um, meet him. It was really amazing
how excited he was to learn about the science, uh,
from us.
Dr Viviane Richter (25:25):
What has been your favourite holiday?
Professor Marina Pajic (25:28):
I would say, as a destination, Thailand. Maybe just speaks
to the nature of the, you know, how fast paced
our work is. Thailand, you can just switch off. I,
and I'm talking island destination, full on beach, uh, sports activities,
and just relaxing in the sun.
Dr Viviane Richter (25:47):
Sounds perfect. Current book you're reading?
Professor Marina Pajic (25:50):
Actually, yeah, the book that I'm currently reading is with
my nine-year-old. It's called Nevermore. It's very exciting.
Dr Viviane Richter (25:56):
Who inspires you the most?
Professor Marina Pajic (25:59):
My parents. Again, very simple, but they've made such dramatic changes. Now,
looking back, uh, on it, all positive changes that, you know,
have enabled me to have the life I now have.
So I'm really grateful.
Dr Viviane Richter (26:13):
Have you got a favourite movie?
Professor Marina Pajic (26:15):
Yeah, of course. And actually, and book, Pride and Prejudice.
With Colin Firth!
Dr Viviane Richter (26:21):
I would not have picked that.
Professor Marina Pajic (26:23):
I know.
Dr Viviane Richter (26:24):
What a surprise.
Professor Marina Pajic (26:26):
Right?
Dr Viviane Richter (26:26):
Why, why, why Pride and Prejudice?
Professor Marina Pajic (26:27):
Goes with my karate skills.
Dr Viviane Richter (26:31):
What do you love about it?
I'm a sucker for Jane Austen novels, yeah.
Professor Marina Pajic, thank you so much for joining us
on Medical Minds.
Professor Marina Pajic (26:41):
Thanks, Viviane. It was great fun to be able to
talk to you today.
Dr Viviane Richter (26:46):
If you'd like to know more about Marina'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
(27:07):
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.
Pancreatic cancer is one of the toughest cancers to treat.
It's aggressive, often diagnosed late, and doesn't respond well to
standard therapies. So what hope is there for patients who
are diagnosed with pancreatic cancer? Today, we meet an extraordinary
researcher who is working at the cutting edge of science
(00:21):
to transform how we understand and treat this disease. You're
listening to Medical Minds, the podcast 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
the Co-director of Garvan's Translational Oncology Program and Head of Garvan's Personalised Cancer Therapeutics Lab,
(00:44):
Professor Marina Pajic. Welcome, Marina.
Professor Marina Pajic (00:47):
Hi, Viviane, and hello, everyone. Thanks very much for this invitation.
It's a pleasure to be here with you today.
Dr Viviane Richter (00:55):
Marina, before we talk about pancreatic cancer and your research,
tell us where it all started for you. Did you
always know you were going to be a scientist?
Professor Marina Pajic (01:05):
Well, subconsciously, probably, yes. I have to say that from
a very early age, and I grew up in Serbia,
our teachers really instilled, you know, this sort of drive
for education. And from very early on, we learned, for example,
about one of the famous Serbian inventors called Nikola Tesla,
(01:28):
and just learning about his inventions, about his crazy life,
where it took him all the way to America, it
just was probably one of the really early inspiring moments
for me to kind of start thinking about, you know,
what being a scientist would be like. From then on, obviously,
I also excelled in natural sciences, things like mathematics, biology, chemistry, math, physics.
(01:53):
So it was, it was just natural way to progress.
Dr Viviane Richter (01:57):
So, how did you get from being obsessed with Nikola
Tesla to working on pancreatic cancer?
Professor Marina Pajic (02:04):
So, I would guess probably natural progression. So, I was
fortunate enough, my parents took us to New Zealand, uh,
where I was able to continue my education after high school.
So this is really where, under some really inspirational scientists,
I started to study pharmacology, so I did a degree,
a bachelor's degree and a master's degree in science. Then, again,
(02:27):
moved to Sydney, moved to Australia in the sort of
early 2000s, and then really started to learn about some
of the hardest to treat cancers. So this was the
PhD that I did at University of New South Wales
under Professor Michelle Haber. She is an incredibly inspirational, uh,
scientist in her own right, but I think she's really
(02:50):
helped me sort of begin to develop an understanding of
why studying treatment resistance is so important. And then I
took that early education, well, early to mid education, on
towards postdoctoral studies where I started developing models of triple
negative breast cancer, and particularly again, trying to understand, you know,
(03:14):
the highly treatment resistant nature of that cancer, trying to
find new ways of targeting the disease. Which then, again,
just naturally drove me back to Australia, to Garvan, and
then really, my research then really took off.
Dr Viviane Richter (03:31):
You focused on some of the toughest to treat cancers.
What is it about them that drives you in your research?
Professor Marina Pajic (03:39):
So, what's particularly interesting about these diseases is that they
are so complex, right? So it's not a simple problem
that just one drug or one hit, you know, will
solve the entire problem. There is this incredible complexity that
surrounds these cancers. I mean, this is also why my
(04:00):
big goal is to really try to, A, understand, you know,
what is driving the disease, what's driving the resistance and,
at almost individual level, try to identify the ways of
how to target these cancers, how to make these patients better.
Dr Viviane Richter (04:17):
So, what is it about pancreatic cancer in particular that
makes this disease so difficult to treat?
Professor Marina Pajic (04:23):
Well, look, again, pancreatic cancer, it is a hard cancer because, A, it,
it is diagnosed late, unfortunately. Symptoms are very difficult to
pick up on because, you know, they're not as obvious
as maybe for some of the other cancers. Pancreas is,
you know, buried deep inside our body. It is hard
(04:44):
to detect these cancers at an early stage. And then,
on top of that, this particular cancer seems to be
very capable to, you know, very quickly spread to other sites,
and then it really starts to cause havoc. It is also, uh,
highly intrinsically resistant to, at least to the current sort
(05:04):
of standard of care treatments. So, unfortunately, not many of
us know much about the pancreas or even care about
what the pancreas does, but it is actually a critical organ.
It produces a number of of different hormones, for example,
insulin being the key hormone that is required for processing
(05:26):
the glucose, the sugars, in our body and ensuring that
the right organs get the energy that they need, but
don't get the excessive, you know, sugar circulating in the
blood and then causing additional damage to the body. And
then also some of the other, for example, hormones as well.
It produces like glucagon, which again is really important for digestion. So,
(05:49):
when something goes wrong, this is also why this small
organ buried deep inside our body is clearly connected to
so many other things, other bodily functions, that this is
also why things go very wrong.
Dr Viviane Richter (06:05):
You mentioned pancreatic cancer is often diagnosed at a late stage.
What are some of the early symptoms?
Professor Marina Pajic (06:12):
Some of the earliest symptoms are mid-level back pain that's
often mistaken, you know, for muscular issues. People go through
physio for quite a period of time, for months and months,
until they start to develop some of the more advanced symptoms,
which involves things like jaundice. That's usually when patients actually
present at the hospital. They'll have a range of digestive
(06:34):
issues as well that will just get mistaken for other
types of conditions. You know, it could be, um, IBS or,
or anything else, really. And then it's at that diagnosis
stage that unfortunately, with jaundice, this is usually when the
cancer becomes quite involved because it is impinging on some
of the other organs. Bile ducts, for example. So, this
(06:58):
is also why you start to see these, um, symptoms
come up.
Dr Viviane Richter (07:02):
And I guess at that point, the cancer has usually
already spread beyond the pancreas. Is that right?
Professor Marina Pajic (07:07):
Exactly. I guess if the patient is lucky, it may involve,
it'll be local invasion at that stage, but majority of
the cases do already present with metastatic disease. So, this
is over 80% of patients. The cancer has already spread.
Dr Viviane Richter (07:23):
Wow, that's, that's a huge proportion of patients. So, how
many people are diagnosed with pancreatic cancer?
Professor Marina Pajic (07:30):
The statistics are really dismal around this disease still. Over
430,000 people will, unfortunately, be diagnosed with pancreatic cancer. These,
these are global figures. And the survival rates are currently
sitting around 12%, uh, five years post-diagnosis. These survival rates
(07:51):
actually have shifted in the last 10 to 15 years.
They used to be sitting around 5%. So, look, there
have been improvements, largely to do with the implementation of polychemotherapy,
so these are combination chemotherapies, uh, for the treatment of
patients with this disease, but unfortunately, obviously, there is still
(08:12):
a lot more that we need to do, and that's
really what my lab focuses on.
Dr Viviane Richter (08:18):
So Marina, let's talk about your research now. How is
your team tackling those dismal survival rates?
Professor Marina Pajic (08:26):
My team is really focused on exactly, you know, building
I guess, on the expertise that I have acquired over
the last 20 or so years. We're really trying to
understand the drivers of treatment resistance in the disease and
then trying to pinpoint both tumour-driven mechanisms behind resistance, as
(08:48):
well as these corrupted cells that surround the pancreatic cancer
as well, trying to understand how they might help drive
the disease. And so really, it's all about finding, co-targeting
treatment approaches, how best to really kill the cancer from
a variety of different angles.
Dr Viviane Richter (09:07):
How has the field changed in pancreatic cancer? What do
we know now that we didn't know, say 10 years ago?
Professor Marina Pajic (09:14):
Well, we've actually had some really major advances since I
arrived and decided to join the Garvan. One of the key, actually,
being really understanding this genomic genetic landscape of the disease. And,
you know, what we learned from this – so this is
where we sequenced, so we understood, we tried to understand
(09:36):
the DNA signature of a whole heap of pancreatic cancers. And,
from there, we found that basically pancreatic cancer, on a
genetic level, is not just one disease. It's a whole
range of different cancers. The next obvious answer or, from that,
was that clearly treating this disease with just one type
(09:59):
of therapy is not the right approach. We need a
more personalised treatment approach for this cancer. What my team
has then also developed as part of this research is
a whole suite of patient-derived models. So, this is from
the tumours, from these patient tumours that we have analysed.
We now have models growing in the laboratory that we
(10:21):
can study. So we can, in great detail, study how
each individual genetic change might develop into a potential therapeutic target.
Building on that sort of knowledge that we have generated
now over the last 10 years, for example, we have
shown that a specific subset of pancreatic cancer, there is
(10:41):
particularly highly genetically rearranged, so these are very, very, we
call them unstable tumours, they may respond to a specific
type of therapy that's had really great success in breast cancer.
So these are drugs called PARP inhibitors. They induce a
specific type of DNA damage inside the tumours. And so
(11:03):
what we've shown is that this specific subset of cancers
may respond to this type of drug. So this was
one of the major publications or research publications that came
out of Garvan, came out of our work. And then
from then, both us, but also other people have taken
on that research, then driven it through international clinical trials,
(11:23):
and this particular drug is now FDA-approved for clinical use
for patients with pancreatic cancer, with this specific type of
genetic change. So that's one of the major, I guess,
breakthroughs that has happened in the last 10 to 15 years.
There's certainly a whole lot of other ones coming through
now in the pipeline on the way to clinical application. So,
(11:48):
we are excited about the, cautiously excited about the future,
but there's obviously a lot more that we need to
do to try to understand, you know, what else can
then pop up and cause the resistance in these cancers,
even if they respond initially to a drug.
Dr Viviane Richter (12:04):
Marina, you mentioned subsets. How many subsets of pancreatic cancer
are there?
Professor Marina Pajic (12:10):
So, this is hard to define because, as the technologies
improve and we learn a lot more about the cancer
at a higher resolution, it seems to become more complex. So, initially,
just through doing this whole genome sequencing, so this is, again,
I say just, but this is actually really expensive and
(12:32):
really comprehensive methodology in its own right. But with that,
we were able to identify at least 10 different subtypes
of pancreatic cancer. But now, using newer methodologies and being
able to understand the disease at even a single cell level,
we can see that within a single cancer there is
all this variability, genetic and beyond variability, that exists that
(12:57):
still we need to take into account when we're designing
new treatment approaches.
Dr Viviane Richter (13:03):
You mentioned earlier personalised treatments. What does that mean? What
does that look like when a patient presents to the clinic?
Professor Marina Pajic (13:12):
When the patient presents with pancreatic cancer, ultimately, because it's
that frontline setting, they will be given standard of care
chemotherapy treatment. There's two options. One that's more toxic, one
that's slightly less toxic, but also a bit less effective,
depending on their wellness status. But, at that point, the
oncologist makes sure that these patients get sequenced. We recommend that.
(13:35):
So that's basic sequencing. It's not, you know, so it
doesn't cover everything. At least it covers a specific proportion.
So if they're lucky, they have one of the mutations
that there are existing drugs for. And, I should say, actually, also,
increasingly now, it's the KRAS inhibitors as well. Because the
KRAS is one of the key drivers. It's a mutation.
(13:55):
In pancreatic cancer, it's present in a large proportion of patients,
so there are tests currently, clinical trials happening to understand
how well these patients will respond to that therapy. The
trials also are showing already that it looks like there's
gonna be a need for a combination therapy there, even
though it's a major driver of pancreatic cancer, the KRAS,
(14:16):
just blocking that pathway, likely not to be enough.
Dr Viviane Richter (14:20):
What do you see as the next stage for pancreatic
cancer patients?
Professor Marina Pajic (14:25):
Well, what we're doing is trying to identify targets that
we can then match with specific therapies. And then, on
top of that, we are now adding new information around
how the other cells that are present in the environment
of these tumours, as they grow and develop, how they
might influence the ultimate response to, to therapy, and also
(14:47):
the growth of the cancer and the spread of the cancer.
And so what we are focusing in our lab is
trying to target two different aspects that further drive the disease. So,
these are the non-functional immune cells. So these are corrupted
cells now that we're talking about that no longer function.
They're not able to recognise the cancer and kill it.
(15:08):
And we're trying to find new ways which we can
stimulate these immune cells to now start to fight the cancer.
Those are some of the new discovery projects that are
happening in our lab. And then, in parallel with that,
we're also trying to target one of the key, uh,
surrounding elements of the cancer. So this is this fibrosis,
this dense scar-like tissue that signals, so not only is
(15:31):
it a physical barrier to treatment, but it also creates
these positive signals that further drive the growth of the
cancer and the spread of the cancer. So we have
a few targets that we have developed the fibrotic elements,
so these are antifibrotic therapies that we're now driving into
early stage phase one clinical trials involving, so this is
(15:53):
now involving the New South Wales Early Clinical Trials Alliance
called NECTA, multiple sites across Sydney. We're hoping to open
these trials later this year. So I'm very excited, obviously
also about this work. I want to see these therapies
really shift the survival of patients with this disease. I
(16:14):
guess our immediate goal within the next decade is to
try to shift the survival rates to something like 30%,
looking at five years post-diagnosis. Uh, so this is in
line with the sort of global goal in this area,
but also further down the line, what we're hoping to
have is a patient present at the clinic, we'll be able
(16:36):
to molecularly profile at high resolution, the tumour elements of
that biopsied tumour biospecimen, but also all of these corrupted
normal cells that are present within these tumours. Understand the
biology of these diverse components, tailor the combination therapy using
(16:58):
realistic treatments that are reasonably well tolerated in this setting –
because that's another thing that we really have to carefully
consider for these patients, because the patients with pancreatic cancer
do tend to present already quite sick, uh, within the clinic.
And then, using innovative techniques, some of the non-invasive methodologies
(17:19):
as well that we're trying to develop in our lab,
try to monitor these patients dynamically as they undergo these treatments.
If the patients stop responding to therapy, we should be
able to, at an earlier stage, define that and then
try to identify the next stage of treatments. So I
(17:40):
am hoping that pancreatic cancer becomes, at the very minimum,
if not cured, a manageable disease for the patients. Patients
can live with this disease long term.
Dr Viviane Richter (17:51):
Marina, you came to Garvan in 2010 to do this research.
Why did you pick Garvan?
Professor Marina Pajic (17:57):
So back in 2010, when I decided to come back
to Australia, Garvan was really the only place to be,
and it still is a beacon for this type of
research that we're currently doing. It was a particularly exciting
time because there was this International Cancer Genome Consortium project
that was being set up. So this was around trying
(18:19):
to understand the genetics of a whole heap of different cancers. International, multi-institutional,
thousands of researchers really joining together on this incredible journey.
And I was very fortunate then to join the Garvan
and the Australian Pancreatic Cancer Genome Initiative, which was the
(18:40):
Australian pancreatic cancer arm of this international study. It was
led by Andrew Biankin, pancreatic cancer clinical expert at the Garvan, and, uh,
Sean Grimmond, genomics expert based at UQ. What we did
as part of this project, you know, we were the
first people to start to understand the Australian pancreatic cancers,
(19:04):
the genomes of these tumours, trying to understand that really
complex genetic landscapes, and as I mentioned before, really discovered
a few key things, some of which have now landed
in clinical practise. From that, what my team has then really, uh,
driven is a whole range of different projects centered around
(19:29):
personalising medicine for pancreatic cancer. So again, quite a few
new discoveries from that
new therapies, so including another breast cancer drug that targets
the proliferative nature of these cancers. We've shown also how
that drug actually affects the fibrotic scar-like tissue of pancreatic
(19:51):
cancer and how, potentially, it could be combined with some
of the standard of care treatments. We've also identified targets,
antifibrotic targets, as I mentioned before, that are now entering
early phase trials, and there's a whole heap of more
research that has now come from these initial studies.
Dr Viviane Richter (20:10):
I guess not much was known about the genomics of
pancreatic cancer. Can you take us back to that time?
What did it take to make those discoveries?
Professor Marina Pajic (20:20):
It was a really crazy time. I think a whole
range of enthusiastic individuals working together, clinicians, scientists, clinician PhD trainees –
so these were people who decided to undertake research as
part of their clinical training, who are now directors of
different oncology centres around Sydney, as well as regionally in
(20:45):
New South Wales that I now really closely collaborate with –
we would be, you know, sitting in the lab preparing
things so that when the surgeon takes the pancreatic cancer
specimen out, the pathologist would be right there on site,
immediately analysing the tissue, doing quality control for us to
give us the prime sample that we can then take
(21:06):
into the lab. Sometimes, God knows what hours, you know,
we would be sitting there 1am, 2am in the morning
waiting for the specimens, because, you know, as you, you know,
should understand as well, these surgeries can be quite complex.
The surgeons are in there for hours operating on the patients.
And then we would, you know, be super happy when
we get these specimens out, process them in various ways,
(21:29):
you know, set up, set them up in cultures so
that we can do screening for new treatments. We can
implant them into mice, make new models of the disease.
So all of that was just an amazing time. I
think that we, by working together, we were able to
generate important new insight around the disease, but it has
(21:50):
actually really then also accelerated the research in Australia.
Dr Viviane Richter (21:56):
Marina, what would you say to someone who has been
just recently diagnosed with pancreatic cancer, or whose family member
has been diagnosed?
Professor Marina Pajic (22:05):
We're really fortunate that, you know, we can now build
on the rich history of research, of the discoveries made
at the Garvan, highly collaborative research. So, involves a lot
of now really well established, long-standing links to the clinic,
multi-layered collaborations, international collaborations, national collaborations, whether it's in the
(22:30):
scientific space or clinical space, industry links as well that
we can now really build on to drive these discoveries
that we make into the clinic, start to really analyse
the new sort of clinical specimens that we get. Try
to understand, you know, why specific patients may respond to
(22:52):
these new treatments or not, and then it's back to
the bench with that information for a whole new generation
of discoveries and new therapies that we can then almost, uh,
stimulate this virtual cycle of discovery to clinic and back again.
We have real momentum now. All the technology is there
(23:14):
at the Garvan. All the people are there, we're ready
to go. We're doing it.
Dr Viviane Richter (23:20):
Marina, before we let you get back to the labs,
we'd love to learn just a little bit more about
you in a section called The Fast Five. Are you
up for it?
Professor Marina Pajic (23:30):
Always.
Dr Viviane Richter (23:32):
Marina, do you have any hobbies?
Professor Marina Pajic (23:34):
Besides working on pancreatic cancer, my child, I think. Uh,
really hanging out with my vivacious and amazing nine-year-old, and
mostly running after her.
Dr Viviane Richter (23:45):
Do you play any sports?
Professor Marina Pajic (23:47):
I used to be a black belt in karate, once
upon a time.
Dr Viviane Richter (23:51):
Wow.
Professor Marina Pajic (23:51):
But now it's running really, that, uh, you know, just
helps that mind calm down sometimes after a big day
of work.
Dr Viviane Richter (24:01):
A black belt in karate. I'm afraid.
Professor Marina Pajic (24:04):
You should be.
Dr Viviane Richter (24:06):
How did you come to be a black belt in karate?
Professor Marina Pajic (24:09):
Look, it's, uh, it's really cheesy, I guess. It's the
Bruce Lee, uh, movies. Back in the day, in the 90s,
I begged my parents to send me to karate, and then, um, yeah,
seven years later, got the first done. I loved it.
I loved my sensei. I love the discipline that karate
brings to you, the calm. And then also, it's great
(24:31):
to learn all the fancy techniques.
Dr Viviane Richter (24:34):
What was your first job?
Professor Marina Pajic (24:36):
Oh, this is really exciting. Newspaper delivery on a bicycle.
Loads of heavy newspapers early in the morning before school.
Dr Viviane Richter (24:45):
Do you have a favourite quote or life motto?
Professor Marina Pajic (24:49):
Never give up. It's simple and you need it in science.
Dr Viviane Richter (24:53):
Do you have any secret skills?
Professor Marina Pajic (24:55):
Maybe, um, baking. I mean, it's not particularly secret, but yeah,
I had a recipe in a cookbook printed by UNSW
once upon a time.
Dr Viviane Richter (25:04):
Very cool. What was it?
Professor Marina Pajic (25:06):
Uh, the recipe, chocolate caramel diamonds.
Dr Viviane Richter (25:09):
Most famous person you've ever met?
Professor Marina Pajic (25:12):
Oh, that's easy. That's Bryan Brown, through Garvan. I was
very fortunate to, um, meet him. It was really amazing
how excited he was to learn about the science, uh,
from us.
Dr Viviane Richter (25:25):
What has been your favourite holiday?
Professor Marina Pajic (25:28):
I would say, as a destination, Thailand. Maybe just speaks
to the nature of the, you know, how fast paced
our work is. Thailand, you can just switch off. I,
and I'm talking island destination, full on beach, uh, sports activities,
and just relaxing in the sun.
Dr Viviane Richter (25:47):
Sounds perfect. Current book you're reading?
Professor Marina Pajic (25:50):
Actually, yeah, the book that I'm currently reading is with
my nine-year-old. It's called Nevermore. It's very exciting.
Dr Viviane Richter (25:56):
Who inspires you the most?
Professor Marina Pajic (25:59):
My parents. Again, very simple, but they've made such dramatic changes. Now,
looking back, uh, on it, all positive changes that, you know,
have enabled me to have the life I now have.
So I'm really grateful.
Dr Viviane Richter (26:13):
Have you got a favourite movie?
Professor Marina Pajic (26:15):
Yeah, of course. And actually, and book, Pride and Prejudice.
With Colin Firth!
Dr Viviane Richter (26:21):
I would not have picked that.
Professor Marina Pajic (26:23):
I know.
Dr Viviane Richter (26:24):
What a surprise.
Professor Marina Pajic (26:26):
Right?
Dr Viviane Richter (26:26):
Why, why, why Pride and Prejudice?
Professor Marina Pajic (26:27):
Goes with my karate skills.
Dr Viviane Richter (26:31):
What do you love about it?
I'm a sucker for Jane Austen novels, yeah.
Professor Marina Pajic, thank you so much for joining us
on Medical Minds.
Professor Marina Pajic (26:41):
Thanks, Viviane. It was great fun to be able to
talk to you today.
Dr Viviane Richter (26:46):
If you'd like to know more about Marina'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
(27:07):
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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