The human body has an incredible capacity to heal itself, whether it's a paper cut, a broken bone or your lungs recovering after a chest infection. But not all types of healing are good for us. Some cancers have hijacked the healing process to protect themselves from treatments. In today's episode, we speak to a researcher who will explain how cancers do this and how his research is paving the way for better outcomes for patients. 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 me here is Associate Professor Thomas Cox, head of the Matrix and Metastasis Lab at Garvan. Welcome, Tom.

The human body has an incredible capacity to heal itself, whether it's a paper cut, a broken bone or your lungs recovering after a chest infection. But not all types of healing are good for us. Some cancers have hijacked the healing process to protect themselves from treatments. In today's episode, we speak to a researcher who will explain how cancers do this and how his research is paving the way for better outcomes for patients. 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 me here is Associate Professor Thomas Cox, head of the Matrix and Metastasis Lab at Garvan. Welcome, Tom.

Thanks, Viv. Great to be here.

Thanks, Viv. Great to be here.

Tom, where did this idea come from that cancers and wound healing are linked?

Tom, where did this idea come from that cancers and wound healing are linked?

So, I think a lot of the early work studying cancer was by pathologists. So, similar to what they do today. Looking at the tumours under the microscope and trying to piece together how they're different and why they might be different. Some of this goes back really to the 1800s where the pathologists could see that a cancer wasn't just made up of cancer cells. There was a structure, you know, around it that was holding those cells into place. And that structure is very much the same as what we see in our normal tissues and normal organs. If we think about the heart tissue or we think about muscle tissue, we have heart cells but they're held together by a glue or a scaffold that gives them the shape of the heart. And so what pathologists had noticed was actually that this scaffold, this matrix, as we call it, was changing. It appeared very different, and it was resembling some of the properties that they could see in wound healing and in scarring, for example. And so that really kicked off this idea that you have both a sort of cellular component, the the tumour cells, but also this extracellular sort of outside of the cell, and they work together. And then I guess, a few years down the line, this this concept started to be refined, the idea that well, when we think about normal wound healing, so if you or I cut ourselves or injure ourselves in some way, the body switches on these incredibly powerful programmes that have to repair. They have to restore the normal tissue. And what happens in cancer was that the cancer cells are sort of activating those similar wound healing processes. And what this results in really is this sort of idea of a a healing or wound healing in and around the tumour. But if we think about normal situations, we think about what happens when you cut yourself or you break a leg. That event has finished, and so the body heals. Normally, it restores that tissue back to its normal status. But in a cancer, the tumour is still there. And so what we get is this sort of continual insult to that tissue. So the the programme is switched on, but it's never switched off. And this is something that we do see in other diseases as well. We think about, for example, lung fibrosis. Or we could think about liver fibrosis where there's an insult. For example, it could be smoking or drinking. If you continue to do that, then this tissue has to continually repair. And what that leads to is a tissue fibrosis. So, it's exactly the same as what's happening in cancer is, this body's repair mechanism is inadvertently essentially feeding into the progression of the tumour.

So, I think a lot of the early work studying cancer was by pathologists. So, similar to what they do today. Looking at the tumours under the microscope and trying to piece together how they're different and why they might be different. Some of this goes back really to the 1800s where the pathologists could see that a cancer wasn't just made up of cancer cells. There was a structure, you know, around it that was holding those cells into place. And that structure is very much the same as what we see in our normal tissues and normal organs. If we think about the heart tissue or we think about muscle tissue, we have heart cells but they're held together by a glue or a scaffold that gives them the shape of the heart. And so what pathologists had noticed was actually that this scaffold, this matrix, as we call it, was changing. It appeared very different, and it was resembling some of the properties that they could see in wound healing and in scarring, for example. And so that really kicked off this idea that you have both a sort of cellular component, the the tumour cells, but also this extracellular sort of outside of the cell, and they work together. And then I guess, a few years down the line, this this concept started to be refined, the idea that well, when we think about normal wound healing, so if you or I cut ourselves or injure ourselves in some way, the body switches on these incredibly powerful programmes that have to repair. They have to restore the normal tissue. And what happens in cancer was that the cancer cells are sort of activating those similar wound healing processes. And what this results in really is this sort of idea of a a healing or wound healing in and around the tumour. But if we think about normal situations, we think about what happens when you cut yourself or you break a leg. That event has finished, and so the body heals. Normally, it restores that tissue back to its normal status. But in a cancer, the tumour is still there. And so what we get is this sort of continual insult to that tissue. So the the programme is switched on, but it's never switched off. And this is something that we do see in other diseases as well. We think about, for example, lung fibrosis. Or we could think about liver fibrosis where there's an insult. For example, it could be smoking or drinking. If you continue to do that, then this tissue has to continually repair. And what that leads to is a tissue fibrosis. So, it's exactly the same as what's happening in cancer is, this body's repair mechanism is inadvertently essentially feeding into the progression of the tumour.

What does fibrosis look like? How can we visualise fibrosis?

What does fibrosis look like? How can we visualise fibrosis?

So, our understanding of fibrosis is essentially that tissue repair process that has gone wrong or is not completing its its programme as it should. The easiest way for you and I to to think about it, or even to see that would be scarring. So if we cut ourselves, if we leave it alone, it would hopefully heal without a scar. But of course, in some cases it doesn't. Children are great. They keep picking at them whilst they heal. And it's that repeated sort of injury. And what you then get is this scar tissue, and it's it's made up of this large amount of extracellular matrix, and we see that we see this sort of white line. And so that's what we get really in in tumours is this scarring that forms in and around the tumour. And actually, that's quite important because very early on, one of the ways that tumours are diagnosed is there's a lump. There's something there that wasn't there before, and that's a combination of both tumour cells, which are expanding, obviously tumour cells sort of uncontrollably divide, but also some of that fibrosis that is forming this hard lump. And that's that's often what you can feel as an individual. And obviously the doctors would be the first sign that they maybe need further tests.

So, our understanding of fibrosis is essentially that tissue repair process that has gone wrong or is not completing its its programme as it should. The easiest way for you and I to to think about it, or even to see that would be scarring. So if we cut ourselves, if we leave it alone, it would hopefully heal without a scar. But of course, in some cases it doesn't. Children are great. They keep picking at them whilst they heal. And it's that repeated sort of injury. And what you then get is this scar tissue, and it's it's made up of this large amount of extracellular matrix, and we see that we see this sort of white line. And so that's what we get really in in tumours is this scarring that forms in and around the tumour. And actually, that's quite important because very early on, one of the ways that tumours are diagnosed is there's a lump. There's something there that wasn't there before, and that's a combination of both tumour cells, which are expanding, obviously tumour cells sort of uncontrollably divide, but also some of that fibrosis that is forming this hard lump. And that's that's often what you can feel as an individual. And obviously the doctors would be the first sign that they maybe need further tests.

So, what do we know about fibrosis now? Are there some cancers that are more fibrotic than others? Or is this potentially the key to a breakthrough for all cancers?

So, what do we know about fibrosis now? Are there some cancers that are more fibrotic than others? Or is this potentially the key to a breakthrough for all cancers?

So, what we know now and and I think, have done over the last sort of four or five decades, is begun to really start to understand the biology of this fibrosis. Why is it important? How does it feed into the progression of a cancer? And, more importantly, how might that affect treatments that we give patients? Most cancers, in fact all solid cancers, when we think about a solid tumour versus a blood tumour which will have a matrix will have this fibrotic kind of scar tissue, some are much, much more fibrotic than others. A good example of that would be pancreatic cancer, for example, and what we've begun to understand is the context is incredibly important. So, the tumour cells within that tumour and within the context of that fibrosis, that fibrosis is having a huge path now in how fast they divide, whether or not they move and spread around the body in the process that we call metastasis, whether they respond to a particular treatment or not. And so, what we're starting to do is think about designing therapies that are not just targeting cancer cells. What we want to do is to target both the cancer cells and this support network, or this fibrotic mass, that forms around them. And in doing so, we now treat the whole tumour rather than just the cancer cells. And it's not just that it might be telling a cancer cell to divide more. It also forms a bit of a physical barrier sometimes. We think about scar tissue, it's obviously it's a very dense tissue that can have an effect of stopping some therapies from getting in as well, and so part of that is about stopping the fibrosis from forming. But I think we have to be very careful. We have to do this in a bit of a nuanced manner. And the reason I say that was because a few years ago there was this sort of idea that, well, if this fibrosis is bad, then well, surely if we if we just get rid of it, then we will effectively improve the outcomes in cancer. But what they realised was you can't just get rid of everything. And we think back to to what I mentioned earlier about how all of our tissues in our body have these this matrix, this tissue sort of structure. That actually is very powerful in the normal situation of telling the cells what to do. So, the reason our heart tissue just doesn't continue to get bigger and bigger is because that tissue structure is saying no, you're at the right size, now we carry out the function. So, what we want to do is, rather than get rid of that fibrosis, is look at how do we either identify the really what we call pro-tumorigenic parts of it, or effectively normalise it. So, let's say return it back to what it should be and ultimately try to close that loop of that repair mechanism. And in doing so, I think we're going to be much, much more effective and essentially improve the efficacy of our already approved standard of care therapies. And so that's really the goal, I think.

So, what we know now and and I think, have done over the last sort of four or five decades, is begun to really start to understand the biology of this fibrosis. Why is it important? How does it feed into the progression of a cancer? And, more importantly, how might that affect treatments that we give patients? Most cancers, in fact all solid cancers, when we think about a solid tumour versus a blood tumour which will have a matrix will have this fibrotic kind of scar tissue, some are much, much more fibrotic than others. A good example of that would be pancreatic cancer, for example, and what we've begun to understand is the context is incredibly important. So, the tumour cells within that tumour and within the context of that fibrosis, that fibrosis is having a huge path now in how fast they divide, whether or not they move and spread around the body in the process that we call metastasis, whether they respond to a particular treatment or not. And so, what we're starting to do is think about designing therapies that are not just targeting cancer cells. What we want to do is to target both the cancer cells and this support network, or this fibrotic mass, that forms around them. And in doing so, we now treat the whole tumour rather than just the cancer cells. And it's not just that it might be telling a cancer cell to divide more. It also forms a bit of a physical barrier sometimes. We think about scar tissue, it's obviously it's a very dense tissue that can have an effect of stopping some therapies from getting in as well, and so part of that is about stopping the fibrosis from forming. But I think we have to be very careful. We have to do this in a bit of a nuanced manner. And the reason I say that was because a few years ago there was this sort of idea that, well, if this fibrosis is bad, then well, surely if we if we just get rid of it, then we will effectively improve the outcomes in cancer. But what they realised was you can't just get rid of everything. And we think back to to what I mentioned earlier about how all of our tissues in our body have these this matrix, this tissue sort of structure. That actually is very powerful in the normal situation of telling the cells what to do. So, the reason our heart tissue just doesn't continue to get bigger and bigger is because that tissue structure is saying no, you're at the right size, now we carry out the function. So, what we want to do is, rather than get rid of that fibrosis, is look at how do we either identify the really what we call pro-tumorigenic parts of it, or effectively normalise it. So, let's say return it back to what it should be and ultimately try to close that loop of that repair mechanism. And in doing so, I think we're going to be much, much more effective and essentially improve the efficacy of our already approved standard of care therapies. And so that's really the goal, I think.

Are there any particular cancers you're focusing on?

Are there any particular cancers you're focusing on?

So, we focus primarily in the pancreatic cancer, breast cancer and lung cancer space. There's a lot of overlap in some of these mechanisms when we talk about this tumour fibrosis, whilst even though the tumours themselves are quite different. And so we have a number of programmes of work which are essentially trying to understand both those similarities, but also those differences, and so can we learn from one type of tumour and apply it to another. But this is also important because when you think about a lot of cancers, they spread around the body, uh, and this process of metastasis that makes it very difficult to treat. And so if we think about breast cancer, for example, one of the common sites it spreads to is the lung tissue. And so, actually, by studying across multiple cancers and looking at the tissues, whether it's a primary lung cancer or a metastatic breast cancer that's gone to the lung, we can also start thinking about how we might treat these different tumours based on the organ that they are within, or based on the tissue remodelling programmes that they activate.

So, we focus primarily in the pancreatic cancer, breast cancer and lung cancer space. There's a lot of overlap in some of these mechanisms when we talk about this tumour fibrosis, whilst even though the tumours themselves are quite different. And so we have a number of programmes of work which are essentially trying to understand both those similarities, but also those differences, and so can we learn from one type of tumour and apply it to another. But this is also important because when you think about a lot of cancers, they spread around the body, uh, and this process of metastasis that makes it very difficult to treat. And so if we think about breast cancer, for example, one of the common sites it spreads to is the lung tissue. And so, actually, by studying across multiple cancers and looking at the tissues, whether it's a primary lung cancer or a metastatic breast cancer that's gone to the lung, we can also start thinking about how we might treat these different tumours based on the organ that they are within, or based on the tissue remodelling programmes that they activate.

Why is it so critical to target fibrosis in these cancers in particular? What is the limitation of current treatments?

Why is it so critical to target fibrosis in these cancers in particular? What is the limitation of current treatments?

If we take pancreatic cancer as an example, this is a very fibrotic tumour. Sometimes over 50% of the actual tumour itself might be this scar tissue. And so effectively, if we only target cancer cells, we may only be targeting half of that tumour. But as I mentioned before, one of the things this scar tissue, this matrix, can do is blunt the efficacy of therapies that we're giving, be this a chemotherapy, radiotherapy, even the new immunotherapies.

If we take pancreatic cancer as an example, this is a very fibrotic tumour. Sometimes over 50% of the actual tumour itself might be this scar tissue. And so effectively, if we only target cancer cells, we may only be targeting half of that tumour. But as I mentioned before, one of the things this scar tissue, this matrix, can do is blunt the efficacy of therapies that we're giving, be this a chemotherapy, radiotherapy, even the new immunotherapies.

Like a physical barrier.

Like a physical barrier.

Yes. And what we've started to realise is that as we give a therapy, and this is some of the work from my team, one of the things that happens is you actually cause damage to the tumour, which is that actually the therapy doing what it should do. But of course, that damage, that killing of those cancer cells, then sort of hyperactivates the body's wound healing response because there's obviously damage that now needs to be effectively repaired. And so sometimes your therapies do their job at killing cancer cells. But one of the, I guess, side effects is to trigger more of that fibrotic tissue to be deposited. So this may mean that the tumour goes from 50% to 60% to 70% and this becomes a problem because that can stop the successive rounds of therapy getting into the tumour. It may protect those cancer cells from other, for example, immune cells. If we think about the context of immune therapy, which is a new therapy that's been coming out, and so the idea is, if we can block that fibrosis at the same time as our therapy, do we then essentially allow our therapy to continue to carry its job out effectively? So, another problematic aspect of this tumour fibrosis is when we come to monitoring patient response to a particular therapy, especially for tumours that may be deep inside the body, such as within the pancreas. And this is because, typically, we may use an imaging modality or approach like a CT. We hear about CT scans and what they're doing is they're using these to monitor the size of the tumour as we give a therapy. And in many tumours we see the shrinking of that tumour. And so this is an indicator that we're getting a response. But in some pancreatic cancer patients and other fibrotic tumours, what we actually see is that fibrosis replaces where those cancer cells have been killed. And this means that effectively, the tumour doesn't look like it's actually shrinking, and so it can make it very difficult to stage a a tumour and therefore to determine how effective that treatment might be. And this is where we get that increase going up from, you know, 60% or above. And it's not until surgery and the tumour perhaps comes out that you can then look at it and say, well, actually, it's mostly just fibrosis now. The cancer cells have been killed, but it can make it tricky.

Yes. And what we've started to realise is that as we give a therapy, and this is some of the work from my team, one of the things that happens is you actually cause damage to the tumour, which is that actually the therapy doing what it should do. But of course, that damage, that killing of those cancer cells, then sort of hyperactivates the body's wound healing response because there's obviously damage that now needs to be effectively repaired. And so sometimes your therapies do their job at killing cancer cells. But one of the, I guess, side effects is to trigger more of that fibrotic tissue to be deposited. So this may mean that the tumour goes from 50% to 60% to 70% and this becomes a problem because that can stop the successive rounds of therapy getting into the tumour. It may protect those cancer cells from other, for example, immune cells. If we think about the context of immune therapy, which is a new therapy that's been coming out, and so the idea is, if we can block that fibrosis at the same time as our therapy, do we then essentially allow our therapy to continue to carry its job out effectively? So, another problematic aspect of this tumour fibrosis is when we come to monitoring patient response to a particular therapy, especially for tumours that may be deep inside the body, such as within the pancreas. And this is because, typically, we may use an imaging modality or approach like a CT. We hear about CT scans and what they're doing is they're using these to monitor the size of the tumour as we give a therapy. And in many tumours we see the shrinking of that tumour. And so this is an indicator that we're getting a response. But in some pancreatic cancer patients and other fibrotic tumours, what we actually see is that fibrosis replaces where those cancer cells have been killed. And this means that effectively, the tumour doesn't look like it's actually shrinking, and so it can make it very difficult to stage a a tumour and therefore to determine how effective that treatment might be. And this is where we get that increase going up from, you know, 60% or above. And it's not until surgery and the tumour perhaps comes out that you can then look at it and say, well, actually, it's mostly just fibrosis now. The cancer cells have been killed, but it can make it tricky.

Tell us what you're hoping to achieve through your research.

Tell us what you're hoping to achieve through your research.

One of the key things we're interested in is understanding how do all of those building blocks of fibrosis come together? How do they assemble and and how does that you know scar tissue form within the tumour. So we've got quite a large programme of work where we're targeting different elements of that to try and block that. And the idea behind that is that if we can prevent or slow down that formation of that fibrotic tissue, that scarring within the tumour, whilst we're giving our chemotherapy, then we effectively make chemotherapy better and therefore hopefully improve the response of that patient and therefore outcome. We've taken a number of different approaches to doing this. A lot of what we do partners with industry and biotech and pharma to try to develop novel approaches. So, chemotherapy has been around for for decades. It's tried and tested but this, these anti-stromal therapies that I mentioned, these anti-fibrotics are very new to the field of cancer. And so, by combining the two, we're hoping to show that we can improve outcome in patients.

One of the key things we're interested in is understanding how do all of those building blocks of fibrosis come together? How do they assemble and and how does that you know scar tissue form within the tumour. So we've got quite a large programme of work where we're targeting different elements of that to try and block that. And the idea behind that is that if we can prevent or slow down that formation of that fibrotic tissue, that scarring within the tumour, whilst we're giving our chemotherapy, then we effectively make chemotherapy better and therefore hopefully improve the response of that patient and therefore outcome. We've taken a number of different approaches to doing this. A lot of what we do partners with industry and biotech and pharma to try to develop novel approaches. So, chemotherapy has been around for for decades. It's tried and tested but this, these anti-stromal therapies that I mentioned, these anti-fibrotics are very new to the field of cancer. And so, by combining the two, we're hoping to show that we can improve outcome in patients.

So, how do these treatments work? Because I would imagine that you'd want to not turn off all healing, all wound healing in the body, so you wouldn't want to prevent all of fibrosis from happening, I would assume. How do you specifically target this in a cancer?

So, how do these treatments work? Because I would imagine that you'd want to not turn off all healing, all wound healing in the body, so you wouldn't want to prevent all of fibrosis from happening, I would assume. How do you specifically target this in a cancer?

So, what we do in our different cancer models is we look for things that have been activated in tumours. If you remember back at the beginning of our chat, when we were talking about how when we cut ourselves, the body switches on these repair pathways - very powerful programmes that are designed to repair the body quickly and then they switch them off. But in cancers they've obviously switched on and stay on. And so what we do is look for those that are switched on and that allows us to target those specifically. That means that, ultimately, if a patient's on an anti-fibrotic therapy whilst they have the tumour in their chemotherapy, then we'll be effectively targeting just that. Of course, one of the things we will need to do in the future is to ensure that, if you were to cut yourself at the same time, that there weren't going to be adverse effects. But that's obviously something which we would be doing at that point of clinical translation.

So, what we do in our different cancer models is we look for things that have been activated in tumours. If you remember back at the beginning of our chat, when we were talking about how when we cut ourselves, the body switches on these repair pathways - very powerful programmes that are designed to repair the body quickly and then they switch them off. But in cancers they've obviously switched on and stay on. And so what we do is look for those that are switched on and that allows us to target those specifically. That means that, ultimately, if a patient's on an anti-fibrotic therapy whilst they have the tumour in their chemotherapy, then we'll be effectively targeting just that. Of course, one of the things we will need to do in the future is to ensure that, if you were to cut yourself at the same time, that there weren't going to be adverse effects. But that's obviously something which we would be doing at that point of clinical translation.

Where is your research up to now?

Where is your research up to now?

So, at the moment, we are at what we call the sort of preclinical to clinical translation. So, what that means is we have been working for a number of years now with a Sydney-based pharmaceutical called Syntara working through different generations of small molecule drugs, anti-fibrotics. And so the idea is that we are showing that they work in the Petri dish, as you would expect in a lab, but then transition that into some of our models of pancreatic cancer, in particular some of our mass models. And last year we published some research showing that they work in mass models of pancreatic cancer in combination with a standard of care chemotherapy. And we see that we get, and this is a pancreatic cancer model, so we see that we get a decrease in that fibrosis within those tumours. This actually leads to a slower growth of those tumours. So, we've removed this fibrotic signal that's activating cancer cells to grow faster. We actually saw that it spreads less around the body, which is very, very important because metastasis is one of the most complicated and difficult things to treat in patients. So today, actually, this drug has been tried in what we call phase one trials, which is to make sure that the drug still has its same effects within people, and a trial has been launched in a slightly different type of cancer called myelofibrosis. This is a fibrotic bone marrow cancer, if we can call it that. And so the next step for us is to launch a phase what we call 1c or 2a trial in pancreatic cancer. Uh, and the idea of that is to run that at the Garvan and the Kinghorn Cancer Centre in connection with our clinical partners across Sydney and Australia. And so the first thing we've got to do is check whether or not our new anti-fibrotic drug is going to be safe to give with chemotherapy. And then, once we're happy that it's not going to negatively affect the efficacy of chemotherapy, ask the question of whether or not it improves the effects of chemotherapy. And so that's really where we're sort of poised. We are hoping to launch that in 2025.

So, at the moment, we are at what we call the sort of preclinical to clinical translation. So, what that means is we have been working for a number of years now with a Sydney-based pharmaceutical called Syntara working through different generations of small molecule drugs, anti-fibrotics. And so the idea is that we are showing that they work in the Petri dish, as you would expect in a lab, but then transition that into some of our models of pancreatic cancer, in particular some of our mass models. And last year we published some research showing that they work in mass models of pancreatic cancer in combination with a standard of care chemotherapy. And we see that we get, and this is a pancreatic cancer model, so we see that we get a decrease in that fibrosis within those tumours. This actually leads to a slower growth of those tumours. So, we've removed this fibrotic signal that's activating cancer cells to grow faster. We actually saw that it spreads less around the body, which is very, very important because metastasis is one of the most complicated and difficult things to treat in patients. So today, actually, this drug has been tried in what we call phase one trials, which is to make sure that the drug still has its same effects within people, and a trial has been launched in a slightly different type of cancer called myelofibrosis. This is a fibrotic bone marrow cancer, if we can call it that. And so the next step for us is to launch a phase what we call 1c or 2a trial in pancreatic cancer. Uh, and the idea of that is to run that at the Garvan and the Kinghorn Cancer Centre in connection with our clinical partners across Sydney and Australia. And so the first thing we've got to do is check whether or not our new anti-fibrotic drug is going to be safe to give with chemotherapy. And then, once we're happy that it's not going to negatively affect the efficacy of chemotherapy, ask the question of whether or not it improves the effects of chemotherapy. And so that's really where we're sort of poised. We are hoping to launch that in 2025.

Tom, how does it feel to be on the cusp of launching this clinical trial, which could potentially have a significant impact for patients?

Tom, how does it feel to be on the cusp of launching this clinical trial, which could potentially have a significant impact for patients?

So, it's a really exciting time right now. Obviously, a lot of the work we've been doing is very much understanding the biology of pancreatic cancer. As we know, it's got in a terrible survival rate at the moment. Unfortunately, it's less than 10%. A lot of that is because there aren't that many effective therapies. Uh, and we really do need to come up with new ways and new combinations to, you know, shift that dial to really improve that. And so this is a a really unique opportunity, I think. This idea of anti-fibrotics or anti-stromal therapies, as we call them, is still quite new in the field. There have been a few trials out there with mixed results because we're still learning about how that fibrosis scarring feeds into the cancer. How that might complement, for example, chemotherapy. And at the moment, from where we're sitting, we've got an incredibly strong signal, like it's very exciting for us to see this route to the clinic. And I guess from a personal perspective, I'm a scientist by training. I I'm one of those people, I like to understand how things work, but also why they aren't working. Why are they not doing what they should be doing and which is obviously what happens in cancer. And so this idea that we can now take all that biology, all that understanding that we've generated and the proof of principle, and transition that through to a potential therapeutic that may have beneficial effects. I think it would be hugely rewarding to see a trial kick off that would pale in comparison if it made a difference to just a single patient. I would honestly feel that after about 15 years of, of working in this space almost on this project, that to see that benefit, even a single patient would be enormous.

So, it's a really exciting time right now. Obviously, a lot of the work we've been doing is very much understanding the biology of pancreatic cancer. As we know, it's got in a terrible survival rate at the moment. Unfortunately, it's less than 10%. A lot of that is because there aren't that many effective therapies. Uh, and we really do need to come up with new ways and new combinations to, you know, shift that dial to really improve that. And so this is a a really unique opportunity, I think. This idea of anti-fibrotics or anti-stromal therapies, as we call them, is still quite new in the field. There have been a few trials out there with mixed results because we're still learning about how that fibrosis scarring feeds into the cancer. How that might complement, for example, chemotherapy. And at the moment, from where we're sitting, we've got an incredibly strong signal, like it's very exciting for us to see this route to the clinic. And I guess from a personal perspective, I'm a scientist by training. I I'm one of those people, I like to understand how things work, but also why they aren't working. Why are they not doing what they should be doing and which is obviously what happens in cancer. And so this idea that we can now take all that biology, all that understanding that we've generated and the proof of principle, and transition that through to a potential therapeutic that may have beneficial effects. I think it would be hugely rewarding to see a trial kick off that would pale in comparison if it made a difference to just a single patient. I would honestly feel that after about 15 years of, of working in this space almost on this project, that to see that benefit, even a single patient would be enormous.

So, what are you hoping to see from this clinical trial?

So, what are you hoping to see from this clinical trial?

So, the first thing I mentioned we'll be looking into confirming safety. So, we know that this drug itself is safe to give to people. But we also need to make sure that, when given at the same time as chemotherapy, we don't make any of those classical side effects of chemotherapy. We don't want to make them worse. And we certainly don't want to decrease the efficacy of chemotherapy that we currently have. So, the first is safety. The second is then efficacy to ensure that it is doing that having that antifibrotic role and that that is then improving the response that patients have to chemotherapy.

So, the first thing I mentioned we'll be looking into confirming safety. So, we know that this drug itself is safe to give to people. But we also need to make sure that, when given at the same time as chemotherapy, we don't make any of those classical side effects of chemotherapy. We don't want to make them worse. And we certainly don't want to decrease the efficacy of chemotherapy that we currently have. So, the first is safety. The second is then efficacy to ensure that it is doing that having that antifibrotic role and that that is then improving the response that patients have to chemotherapy.

In this clinical trial, what would be the best possible outcome for patients?

In this clinical trial, what would be the best possible outcome for patients?

What would be the ideal outcome is that we obviously confirm safety, and we see efficacy that would match what we currently are seeing within our animal models, which is that you would effectively get a reduction in that primary tumour, that antifibrotic is reducing the level of fibrosis. And, in the first instance, this would obviously extend the lifetime survival of patients. But it opens up a really interesting possibility, which is, that there are often patients which the tumour has either got too big or has potentially spread locally, meaning that they're not eligible for surgery. And and currently, surgery is is really one of the the major and best options for pancreatic cancer patients. An absolutely fantastic outcome would be that, as we give our anti-fibrotic in combination with the chemotherapy, that we see a reduction in that tumour size, that the tumour does begin to shrink. And that may potentially make patients eligible for surgery. So, rather than just having chemotherapy and not being eligible for surgery, which has a particularly poor survival, being able to shrink a tumour enough that a surgeon could then get in and do what they do best, which is to remove that tumour. I think that's going to be where you'd start to see some really big increases in overall survival. Because, once you've removed that tumour, then it's gone. Often very difficult to do that with chemotherapy alone. So, that would be our perfect scenario.

What would be the ideal outcome is that we obviously confirm safety, and we see efficacy that would match what we currently are seeing within our animal models, which is that you would effectively get a reduction in that primary tumour, that antifibrotic is reducing the level of fibrosis. And, in the first instance, this would obviously extend the lifetime survival of patients. But it opens up a really interesting possibility, which is, that there are often patients which the tumour has either got too big or has potentially spread locally, meaning that they're not eligible for surgery. And and currently, surgery is is really one of the the major and best options for pancreatic cancer patients. An absolutely fantastic outcome would be that, as we give our anti-fibrotic in combination with the chemotherapy, that we see a reduction in that tumour size, that the tumour does begin to shrink. And that may potentially make patients eligible for surgery. So, rather than just having chemotherapy and not being eligible for surgery, which has a particularly poor survival, being able to shrink a tumour enough that a surgeon could then get in and do what they do best, which is to remove that tumour. I think that's going to be where you'd start to see some really big increases in overall survival. Because, once you've removed that tumour, then it's gone. Often very difficult to do that with chemotherapy alone. So, that would be our perfect scenario.

When might we see the results for this clinical trial?

When might we see the results for this clinical trial?

The clinical trials, once they've kicked off, would still take a a reasonable amount of time. Even early results probably wouldn't be until the, you know, a year after you've started. Some of it comes down to patient recruitment. One of the key things we want to be doing is to be selecting the right patients for that potential clinical trial. One of the things that we can do is, and we are doing, is attempting to find biomarkers that would indicate, well, this patient is most likely to respond to the new combination therapy. It does two things. One is it ensures we are treating the biology of that tumour correctly. And so we're not just giving a drug to a patient that we don't think would respond. But it also spares ineffective therapies, and so patients don't have to essentially go through a treatment regime, which wouldn't work. So.

The clinical trials, once they've kicked off, would still take a a reasonable amount of time. Even early results probably wouldn't be until the, you know, a year after you've started. Some of it comes down to patient recruitment. One of the key things we want to be doing is to be selecting the right patients for that potential clinical trial. One of the things that we can do is, and we are doing, is attempting to find biomarkers that would indicate, well, this patient is most likely to respond to the new combination therapy. It does two things. One is it ensures we are treating the biology of that tumour correctly. And so we're not just giving a drug to a patient that we don't think would respond. But it also spares ineffective therapies, and so patients don't have to essentially go through a treatment regime, which wouldn't work. So.

What patients might benefit most from this new treatment approach?

What patients might benefit most from this new treatment approach?

Effectively, any solid tumour patient in which we know that those tumours are accompanied by high levels of fibrosis. So pancreatic cancer? Definitely. But there are other tumours that tend to be quite fibrotic. We could think about head and neck cancer, for example. So, there may well be other cancers that either present with high levels of fibrosis, so at the time of diagnosis they may already be quite fibrotic, but also, as we mentioned earlier in the discussion, sometimes your therapies can trigger more of that fibrosis to be laid down, and not all cancers do that. But but some do. And of course, that would also be another group where we might be keen to look at with the combination with an anti-fibrotic and another therapy. Could be chemotherapy, radiotherapy. Would that also again improve the response to those particular therapies?

Effectively, any solid tumour patient in which we know that those tumours are accompanied by high levels of fibrosis. So pancreatic cancer? Definitely. But there are other tumours that tend to be quite fibrotic. We could think about head and neck cancer, for example. So, there may well be other cancers that either present with high levels of fibrosis, so at the time of diagnosis they may already be quite fibrotic, but also, as we mentioned earlier in the discussion, sometimes your therapies can trigger more of that fibrosis to be laid down, and not all cancers do that. But but some do. And of course, that would also be another group where we might be keen to look at with the combination with an anti-fibrotic and another therapy. Could be chemotherapy, radiotherapy. Would that also again improve the response to those particular therapies?

Tom, you've been at Garvan for nearly eight years. Why is Garvan the right place to do this kind of research?

Tom, you've been at Garvan for nearly eight years. Why is Garvan the right place to do this kind of research?

Garvan is this incredible mix of ridiculously smart scientists, clinicians, because obviously the Garvan is situated within the St Vincent's Hospital precinct. We have the Kinghorn Cancer Centre, which is actually where my my lab is based, which is a partnership between Garvan and and St Vincent's. And what that means is we not only get to interact with scientists from cancer, biology, immunology, genomics, we get to interact and embed clinicians within our research who are two floors down within the patient treatment part. So, they'll be seeing patients on a regular basis but then discussing the science with us. It often brings it home because the building we work in is also a cancer treatment centre. And so we see the patients and you see them coming in for their treatments. Uh, and I think that's really important, and we engage a lot with our consumers. And by consumers, I'm talking about consumer advocates, individuals who have lived experience of cancer, either personally or through close friends and families, and who want to get back involved in the research, want to bring their perspectives. And Garvan is very good at this. We have a number of consumers across different cancer types that give us their input. They're the ones who, I guess, keep us grounded and help us put what we do in perspective. And all of this together I think, you know, including the industry links we we discussed, create this super team that can tackle some of the really difficult problems, such as as pancreatic cancer.

Garvan is this incredible mix of ridiculously smart scientists, clinicians, because obviously the Garvan is situated within the St Vincent's Hospital precinct. We have the Kinghorn Cancer Centre, which is actually where my my lab is based, which is a partnership between Garvan and and St Vincent's. And what that means is we not only get to interact with scientists from cancer, biology, immunology, genomics, we get to interact and embed clinicians within our research who are two floors down within the patient treatment part. So, they'll be seeing patients on a regular basis but then discussing the science with us. It often brings it home because the building we work in is also a cancer treatment centre. And so we see the patients and you see them coming in for their treatments. Uh, and I think that's really important, and we engage a lot with our consumers. And by consumers, I'm talking about consumer advocates, individuals who have lived experience of cancer, either personally or through close friends and families, and who want to get back involved in the research, want to bring their perspectives. And Garvan is very good at this. We have a number of consumers across different cancer types that give us their input. They're the ones who, I guess, keep us grounded and help us put what we do in perspective. And all of this together I think, you know, including the industry links we we discussed, create this super team that can tackle some of the really difficult problems, such as as pancreatic cancer.

What are these patient advocates telling you about this research? How do they feel about what you're doing?

What are these patient advocates telling you about this research? How do they feel about what you're doing?

So, they're really excited as well. In pancreatic cancer, there's not been a lot of movement in terms of improvements in survival. There have been a number of new therapies coming through, but for this one it's just a different way of of tackling it. And I think that's where the excitement is beginning to grow is that, if this is going to to work, this could have a huge impact. And of course, if you're able to double that survival from currently around about 9% to 20% that would be a phenomenal, uh, achievement.

So, they're really excited as well. In pancreatic cancer, there's not been a lot of movement in terms of improvements in survival. There have been a number of new therapies coming through, but for this one it's just a different way of of tackling it. And I think that's where the excitement is beginning to grow is that, if this is going to to work, this could have a huge impact. And of course, if you're able to double that survival from currently around about 9% to 20% that would be a phenomenal, uh, achievement.

Tom, what drives you for this work day to day?

Tom, what drives you for this work day to day?

So, I've always been a really curious person, and I had this very unique opportunity at high school to visit a local laboratory at the University of East Anglia in Norfolk and to spend the summer in a research lab. And that really opened my eyes to biomedical research and academic research. And I absolutely loved that summer. It's something I will always remember, and it really shaped what I thought I wanted to do. And so, obviously after that became undergraduate in biology and then the PhD in cancer biology. And I was very lucky during my PhD. I had both an academic supervisor and a clinical supervisor, and he was very keen to ensure that there was clinical engagement at a very early sort of stage in the career. I would go into surgery with them to collect samples and really began to see what happens to cancer patients as those tumours grow, see this firsthand, and to take valuable samples and then use those back in the lab in my research. And so that really, I think made the first connection about this isn't just research for research's sake. There is actually a person at the end of this that we're trying to do something. Are we trying to either better treat their tumours? And to me, if what we can do in the lab can lead to the improvement in just a single patient's outcome, then I will be incredibly happy with that.

So, I've always been a really curious person, and I had this very unique opportunity at high school to visit a local laboratory at the University of East Anglia in Norfolk and to spend the summer in a research lab. And that really opened my eyes to biomedical research and academic research. And I absolutely loved that summer. It's something I will always remember, and it really shaped what I thought I wanted to do. And so, obviously after that became undergraduate in biology and then the PhD in cancer biology. And I was very lucky during my PhD. I had both an academic supervisor and a clinical supervisor, and he was very keen to ensure that there was clinical engagement at a very early sort of stage in the career. I would go into surgery with them to collect samples and really began to see what happens to cancer patients as those tumours grow, see this firsthand, and to take valuable samples and then use those back in the lab in my research. And so that really, I think made the first connection about this isn't just research for research's sake. There is actually a person at the end of this that we're trying to do something. Are we trying to either better treat their tumours? And to me, if what we can do in the lab can lead to the improvement in just a single patient's outcome, then I will be incredibly happy with that.

Tom, before we let you get back to your research, it's time to run through the fast five. What was your first job?

Tom, before we let you get back to your research, it's time to run through the fast five. What was your first job?

First job was a PC repair technician at a UK chain of stores called PC World.

First job was a PC repair technician at a UK chain of stores called PC World.

Do you have a favourite movie?

Do you have a favourite movie?

Favourite movie. Top Gun. It was something which I watched many times growing up, and I have an absolute love for flying to the extent that, for a while, I actually had my own private gliders. Licence to fly unpowered gliders.

Favourite movie. Top Gun. It was something which I watched many times growing up, and I have an absolute love for flying to the extent that, for a while, I actually had my own private gliders. Licence to fly unpowered gliders.

Do you have a favourite quote or life motto that really resonates with you?

Do you have a favourite quote or life motto that really resonates with you?

Yes. "If you put your mind to it, then anything is possible," which I first heard in the Back To The Future movie by Marty McFly. But I actually believe it comes from a bit earlier than that. I think it was Benjamin Franklin.

Yes. "If you put your mind to it, then anything is possible," which I first heard in the Back To The Future movie by Marty McFly. But I actually believe it comes from a bit earlier than that. I think it was Benjamin Franklin.

What's the current book you're reading?

What's the current book you're reading?

I've actually got two on the go at the moment. The first one is called Thinking Fast and Thinking Slow by the Nobel laureate, Daniel Kahneman, and it sort of explores how we make decisions. And the second one is is, I'm actually rereading the trilogy of five books by Douglas Adams, The Hitchhiker's Guide to the Galaxy. So I'm at book three at the moment, which is Life, the Universe and Everything.

I've actually got two on the go at the moment. The first one is called Thinking Fast and Thinking Slow by the Nobel laureate, Daniel Kahneman, and it sort of explores how we make decisions. And the second one is is, I'm actually rereading the trilogy of five books by Douglas Adams, The Hitchhiker's Guide to the Galaxy. So I'm at book three at the moment, which is Life, the Universe and Everything.

Something that's on your bucket list?

Something that's on your bucket list?

To visit the Galapagos Islands, mainly to go, essentially, to look at where Charles Darwin initially formed some of the work behind the Origin of Species. But also because it's an amazing place to go scuba diving.

To visit the Galapagos Islands, mainly to go, essentially, to look at where Charles Darwin initially formed some of the work behind the Origin of Species. But also because it's an amazing place to go scuba diving.

Associate Professor Thomas Cox, thank you so much for joining us on Medical Minds.

Associate Professor Thomas Cox, thank you so much for joining us on Medical Minds.

Thanks, Viv. It was an absolute pleasure.

Thanks, Viv. It was an absolute pleasure.

If you'd like to know more about Tom'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.

If you'd like to know more about Tom'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.