LGSOC Webinar Professor Charlie Gourley transcript

So welcome everybody on behalf of the lowgrade servarian cancer initiative. It's my absolute pleasure to welcome you here today for our lowgrade servarian cancer awareness day webinar with professor Charlie Gully. So the lowgrade serrus o severian cancer initiative's mission is to radically improve survival through research while providing clear information that enables and empowers people to make informed decisions about their care.

So we partner with local organizations to support dedicated research in Australia, Canada, New Zealand, the UK, and the US. Um, so I'm Dr. Alicia Dbury. I'm a scientist at the University of Aland, and I'm a trustee for the Ovarian Cancer Foundation New Zealand, which leads this global lowgrade cirrus ovarian cancer initiative. Um, and I'm honestly I'm so honored and excited to introduce our presenter today, Professor Charlie Goully, who'll be talking about his research in low-grade cirrus.

So, Professor Goully is a medical oncologist and clinical director of the Cancer Research UK Scotland Center. And I mean among his many achievements, he was the UK lead for the first positive randomized clinical trial in low-grade cirrus. And his lab has conducted a screening study testing more than 1,600 drugs in LG sock cell lines to identify potential treatments for future clinical trials. Um, on a personal note, I had the opportunity to visit Charlie and his team earlier this year, and I have to say it's really quite rare to meet someone with such extraordinary level of scientific achievement who's also so down to earth and so genu generous with his time and genuinely approachable.

It was such a pleasure to spend time with his team and to see firsthand the work that they're doing to advance the research in algae sock. So, we're really very lucky to have Charlie with us here today. At the end of the talk, there's going to be an opportunity for you all to ask Professor Goully questions, but please could you put any questions you have in the Q&A box during the talk um and then that way we can ask him at the end.

And just just a little side note, if you can um please understand that he's not able to provide personalized med medical advice. And so with that, I'd like to hand it over to Charlie to introduce himself and tell us more about his research. Welcome, Charlie. >> Thanks. Thanks very much, Alicia. Thanks for that lovely introduction and I hope that the connection stays well behaves itself. If it doesn't, please let me know because I can switch.

I've got two different connections I can use, but hopefully this one behaves itself. And it's so good to speak to everybody on this call. Um, this initiative has been very helpful to my team over the years. So, thanks very much. Let's see if I can share. Okay. Now, is that in the right format? Is that coming through the right way or are you seeing two two screens? >> We're seeing seeing the note form rather than the um other side. >> Is that it now? >> Nope. >> It's not fixed it. >> Yes, that that's it.

There we go. >> Great. Thank you. Thank you. Now just hide this toolbar if I can. Okay. Hopefully that's okay. Is that's we Is that we thing still in the way a nuisance, isn't it? That little thing. Let's see if I can hide this toolbar. I hide floating. There we go. This should work. Okay. Now, let me just see. Um, great. So, yeah, thanks very much. What I'm going to talk about today is Logarian cancer, where we came from, where we are now, and where we want to be.

And um, these are my conflicts of interest. So what I'm going to talk about I'm going to talk a little bit about the background to low gradede servarian cancer and why it is a different cancer going to talk about recent discoveries about the biology of low gradede servarian cancer then about recent therapeutic advances and then about some of the hope for the future both scientific and related to treatment. So this arrow here kind of really plots the progress over the last 25 years since the turn of the century and in the year 2000s all ovarian cancer was being treated the same.

It was just around about 2004 when low gradede serious started to be described as a separate entity. some of the team at the MD Anderson um identified that ser ovarian cancer which we previously thought was grade one, grade two, grade three, well actually it shouldn't be thought of like that should be thought of as high grade and low grade and that those are completely different and I'm going to speak a bit more about that but this was first identified in 2004 was identified as a separate entity and then it was realized that low gradede sears actually is much more resistant chemotherapy than high-grade serious ovarian cancer.

And then I would say there was a while when really there weren't many developments. And then in 2007 there was a big paper um from David Gersonson. It was what we call a retrospective analysis looking backwards but showed that endocrine therapy with drugs such as let was a good thing to do. Then in 2022, we had the study that showed that traumatanib improved progression free survival when it was used rather than standard of care chemotherapy and hormone therapy in relapsed low-grade cirrus.

And then most recently we've had this combination of autametanib and de facto which has demonstrated some efficacy and was given accelerated FDA approval. So is now available in the USA, not many other places just now. And then very very recently this study of chemotherapy and let versus let the results were announced uh just a few months ago and I'm going to mention that and so that that was quite an important thing because that tells us what's the best first line therapy for lowgrade cirrus.

So the background and if we compare it to high-grade seers because previously these were felt to be the same thing and as I've said high-grade seirs is generally chemosensitive. This is something called a waterfall plot and each bar represents the change in size of a patient's tumor. And if the bar goes down the way, the tumors got smaller on chemotherapy. And if it goes up the way, the tumors got bigger. And if a tumor gets smaller by more than 30%, we call that a response.

And when you give neoagivant chemotherapy, so that's when you don't do an operation first, but instead of doing an operation first of all, you give chemo. When you do that in high-grade cirrus, 75% of the tumors get smaller. when you do it in low-grade cirrus only 11% gets smaller. I think this is perhaps the best illustration that um low gradede cirrus is relatively cheoresistant compared to high-grade cirrus. High-grade cirrus we're now pretty sure it originates from the end of the fallopian tube.

Low gradede cirrus is still a bit of uncertainty regarding origin. Some people think also think it comes from the fallopian tube. What we do know is that some patients have borderline ovarian cancer first and that then that progresses in some cases to low-grade cirrus but that doesn't always happen and so there's clearly another mechanism as well. High-grade cirrus generally affects older women mostly over 55 in fact mostly over 60 whereas low-grade cirrus can affect women 20 years earlier and indeed you know if I see a patient who's 19 20 in their 20s or even early 30s with ovarian cancer I'm starting to think lowgrade cirrus or maybe another form called clear cell in highgrade cirrus the molecular biology has been really well characterized.

What I mean by the molecular biology is the biology that's driving the cancer. And there's this thing called whole genome sequencing which is the best sort of sequencing we can do. And in high-grade Sears there have been maybe a thousand whole genomes have been sequenced but in low grade SE it's only about 50 and actually we need a lot more whole genome sequencing and I'm going to mention that later. And um the other thing to say is that high-grade cirrus is driven by this thing called copy number change.

And so this figure here is basically got all the chromosomes lined up. And um you usually expect a uniform number of copies of each chromosome. But the upward spikes show where there are more copies than there should be. And the downward spikes are when there are less copies than there should be because there are deletions. And in high-grade stain cancer, there's all these basically, you know, mountains and valleys because of um amplifications of genes and deletions of genes.

That doesn't really happen so much in low grade. It actually happens a bit. I'm going to mention that. But what generally drives lowgrade serving cancer are mutations in this pathway. So the way that a cell behaves is controlled by its nucleus, but the way that the nucleus behaves and the genes that it switches on and off is controlled by what's going on outside the cell. And this is a receptor at the cell surface and it gets stimulated.

It sends a signal into the cell which goes into the nucleus and tells it to divide. But what happens in um lowgrade cirrus is some of these proteins are mutated so they send a signal into the cell telling it to divide even when there's no signal at the cell surface. And this is a pathway called the map kynise pathway. And the genes that are important are ras wrath and neck. And these are the genes. You'll hear me mentioning these because these are important in this cancer.

They're not important in high-grade sears. So hopefully it's clear these are completely different things. There have been recent discoveries about the biology of logos and you know there've been quite a few and it's not just my group. There are lots of groups particularly some in Australia and in North America. Um you know I'm going to mention mostly our work because that's obviously what I'm most familiar with but there have been lots of other discoveries made.

So one of the things that we found is that when you do sequence these tumors about half of them have got mutations in the genes kraf and nraz and these are all part of this map kynise pathway and about a fifth of all patients are what we call mkynise wild type with no mutations in genes associated with that pathway but about a quarter have mutations that aren't the classical Kraz BFF or NRA but which biologically we think may be related to the pathway and when we look at how these patients get on the patients with mutations in KAS or whose tumors have mutations in KAS BF and NRA have the best survival those who are wild type unfortunately have the worst survival and the ones in the These map kind of associated mutations have an intermediate survival and I think that's because some of them truly stimulate the pathway and therefore behave a bit like these three and other ones don't.

We've not quite worked out which is which just yet. So I showed you this figure earlier because this is the copy number change in high-grade cirrus with all the peaks and troughs. This is low gradede cirrus and this is much more like what you'd expect to see in the normal cell with two copies of each gene pretty much most of the way along. But the particularly eagleeyed of you will notice that it's not two copies all the way along.

So in chromosome one for example there's quite a lot of loss of one of the arms of chromosome one and quite a lot of gain of the other one. This is when it goes below that line it's loss. So when it goes above there's gain and there's some other areas where there's changes in cob number. Now these are m been much less well interrogated in low gradede than they have in high grade. But we're now getting the stage where we can look to see what is actually going on here.

And actually when we looked at this in our coha cohort of patients from the Edinburgh and from Netherlands, we found that patients who who had this change in chromosome one with loss of one P and gain of one Q that they actually had a different survival. They actually did worse. And so we really want to get to the bottom of this and try and work out what's causing it. We need whole genome sequencing in order to do it.

But we're in the process of acquiring some whole genome data so that we can try and work out what's driving this because sometimes when you can work out what's driving it, you can then work out a way of treating it. And then a slightly more mundane level but still important is the fact that a lot of cancers have got estrogen receptors on them or progesterone receptors. Now low-grade serious ovarian cancer actually almost ubiquitously so almost all low gradede servarian cancers have a lot of estrogen receptors on them.

However, progesterone receptor that's a different hormone its expression is much more variable. And when we looked at progesterone receptor expression we found that patients who had low expression did much worse. So again, we need to work out what's driving this in the hope that we can do something about it. Okay. So one other thing that I wanted to mention because it's been done by a few labs. I'm going to talk about some of the stuff that's been done in our lab, but um Dean Cheesley in Australia has done a fantastic study that was published just a couple of months ago um doing drug screening because what you can do nowadays is you can grow these cancer cells in the lab.

So we can you can make these cell lines which are basically the cancer cells growing in the lab. And there's somebody from Vancouver called Mark Kerry who's spent a lot of his career developing these lowgrade serious ovarian cancer cell lines. He's very been very generous and he's handed these round and he's let other people use them. He's let us use them. We've developed some cell lines ourselves and the Australians have developed some and you know we share these.

But what you can do is you can put them in a plate that's got, you know, between three and 400 cells growing on it and then you can expose them to different drugs and you can actually test thousands of drugs and then you can see which drugs kill the cells most effectively and then you can look more closely at those drugs. So we previously did a drug screen and we identified some drugs that were useful but more recently one of my um postocs Sarah Taylor has been trying to find drugs that work particularly well when they're combined with traumatanib because you may be aware that tmetanib is one of the drugs that works very well in low-grade serving cancer.

The only problem is it does have some toxicity. So if we could find drugs that worked particularly well when they worked with tmetanib then it might be possible to give that drug and also reduced the dose of the tmetanib. So we actually screened 330 drugs along with tmetanibin and we looked for something called synergy and they can do plots and basically the redder it is then the more synergy there is between your two drugs.

Now I'm not going to bore you with some of the details but essentially she went through she used a number of cell lines some of which had these KRAS or NRA mutations but some which were wild type because actually it's the patients who don't have those mutations that we need to work out better treatments for. and she basically put them through an imaging system and she looked for in some cases drugs that cause cell death because obviously that's good.

But she also is is in the process of identifying drugs that do other things that don't kill the cancer cell but might also be useful. Anyway, she then looked for drugs that um that combined well that had synergy. So, so a zed score is something that she used to identify synergy. And don't worry too much about this. I'm going to skip through it because it's a bit complicated. But essentially, she went from 330 compounds to 46 initial hits and then she prioritized 10 of these.

So, she had this sort of list, but she prioritized 10 drugs. And the interesting thing was that some of these drugs worked in the same way and they hit the same target and that is something called the EGF receptor and that's a receptor at the cell surface. And when she tried three EGF receptors dcommittanib a fatinib and erotinib two of them worked particularly well across a number of the different lowgrade cirrus cell lines.

So we think these may be drugs that are going to be worth testing going forward. Some of her other hits didn't work so well. There were these mTor inhibitors. Only one out of three worked. And then she had some other inhibitors which didn't work so well. But then she found two other drugs, a PI3 kynise inhibitor and some quite dirty drug that hits a number of targets. And both of those seem to work quite well. I'm going to skip that one.

But I want to tell you that after she tested these in the cell lines, which are cancer cells that become immortal in the lab, she then tested in in a different sort of cellular culture, which is something called an organoid. And you make an organoid by taking a sample from the patient and taking it and making it fresh and growing it in the lab. And an organoid is a different from a cell line because a cell line only has cancer cells in it.

But an organoid has some of the other cells that grow along with the cancer cells and help the cancer grow. And so these are more three-dimensional and we think they're a better representation of human cancer. And so what Sarah wanted to do was then the drugs that had come out of her heads, she wanted to then test them in these organoids which she's become very good at developing from patients. In some cancers, it's quite hard to grow organoids.

For example, in high-grade ser o searian cancer, it's quite hard to grow them. But it turns out that certainly in Sarah's hands, in low gradede sane cancer, she can grow an organoid from pretty much any patient that she gets material from. So anyway, she tested these drugs in the organoids to look to see whether they killed some of the cells and certainly the drugs that she was initially very excited about damitanib and the fatinib do show evidence of efficacy in these organoids.

So, the next thing that we want to do is test these in patients. And a bit later, I'm going to tell you how we're going to take some of these scientific discoveries and put them into a clinical trial that we're setting up with colleagues from the United States. So, we're going to talk about recent therapeutic advances. Obviously, chemotherapy is not a recent advance. That's been um that's that's been something that um you know, it's been going on for a long time.

There's been a fair bit of debate about the extent to which it works in high grade in sorry in low gradede serious ovarian cancer because there are some patients who present with disease that you can't operate on up front. So what do you do in these patients? And we're going to talk a bit about that again later on. But this causes a debate because people look back through the literature to try and work out what exactly the percentage of patients who respond to chemotherapy is here.

We've got five different studies and the response rate is very different across them all. But there's a very important distinction to make. the top three studies the patients didn't get this drug bevicab bevicismab is a a clever drug that blocks the blood supply to the tumor and it's a drug that can be given with chemotherapy initially but when you don't give bevicismab the response rate is pretty poor 4% 23% or 11% but when you do give bevicismab and that's the bottom two trials contain patients who got bevicismab the response rate is quite a bit higher and that fits with some data that we we've seen in relapsed low-grade servant cancer where approximately 50% of patients when they're given chemo and bevvisismab do respond and so it seems to me that bevicismab does increase the response rate to chemotherapy a lot.

Chemotherapy in its own I don't think is particularly effective but adding the bevicismab makes a big difference. So wherever possible if I'm talking to a patient with low gradede CS vein cancer about um chemotherapy I want to try and give them bevicismab as well although it's not always possible because sometimes there are contraindications if for example there's bowel obstruction or there's a lot of disease affecting the tumor.

We know from some of our big studies um in um that have randomized in relapse disease we know that some of the other chemotherapy drugs are also not that effective. In one of the studies Milo the percentage of patients whose tumor shrunk significantly on the chemo drug PLD was 14% and on pitaxel it was 15%. In the GG2A1 study, which I'm going to mention, it was even lower. So these studies, the percentage of patients who respond is not great.

I'm not wanting to depress anybody. Basically, what it means is that we essentially need better treatments. And some of the things I'm going to talk to you today about are better treatments. This study that I mentioned earlier of hormone treatments, this was um in North America. It was from the MD Anderson and they looked back at all their low-grade patients and they looked at those who'd received endocrine therapy, so drugs like let there was an increased time until the cancer came back if they got the letter compared to patients who didn't get hormone treatment.

And in patients who had persistent disease post chemotherapy, it actually also improved the overall survival. So this led some people to think that maybe it would be better to give hormone treatment than to give chemo. Well, there's been a study that's been reported very recently, I'm going to tell you about later, that um suggests that actually we probably ought to give chemo as well. And that goes against what we thought for a while because of this sort of data albeit it never been looked at properly.

Um so we think that probably the best thing to do is give chemo and then at the end of chemo give hormone treatment. And one thing I would say is that I wouldn't recommend tmoxifen as the hormone treatment. drugs like letol or anastrizole are the better treatments because we don't think temoxifen works so well in low-grade serious ovarian cancer. So let's talk about the treatments that we think do work quite well. So um mech inhibitors the first study of a mech inhibitor that reported was this milo study.

It was a big study. It compared binametanib to physician's choice of chemotherapy. Mech inhibitors block this pathway here. If you remember that a lot of this path a lot of low gradede serving cancers come about because this pathway is switched on because of mutations in ras or raph. So you can block the switched on pathway by putting an inhibitor of this enzyme and that's what benametanib is. Now unfortunately this was a negative study because the progression free survival was very similar between the control arm and the chemo arm.

But what it did show was that a significant percentage of patients 16% their tumor shrunk with bametan and that really gave us a hint that these sort of drugs might be useful. But there was another trial going on at the same time. this GOG281 or log study and this randomized patients with relapse low-grade serving cancer to the drug tummet which is also a mech inhibitor or chemotherapy or so they were randomized against that versus standard of care and the standard of care could be let or tmoxifen or chemotherapy and when the patients who receive tremend ended in this study their um cancer stayed away or it came back half as quickly.

So it was able to essentially double the time till the cancer came back. But not not only that, it also turns out it's improved the survival for those patients. So to me it seems that this is a good treatment and giving it early in the patient journey is a good thing to do. It does have some toxicities as I mentioned earlier which is why we're trying to find other drugs that we can use along with it and some of the toxicities can affect the eyes.

It can affect how strongly the heart contracts but um that's usually reversible. So there just a few things you have to look out for. Um and it's not always plain sailing although some patients manage it very well and don't have many side effects. And you can also titrate the dose a bit. You can change the dose. This is a bit of a complex slide, but I think what I'd point out is that in the patients with KAS, BFF or NRA mutations that were driving their tumors, the response to the tetanib was 50%.

But when it was wild type, it was only 8%. So that suggests patients who've got that pathway switched on, if you block the pathway, they do particularly well. That's kind of what you would expect, but we still don't have an ideal biioarker for mech inhibitor sensitivity. So, mech inhibitors look great. Certainly in some patients, they work really well, but often after a while, the cancer will find a way around it. So, what what then is required is something to block the resistance.

So this pathway here is the map kynise pathway. But the thing is in the cell and this is the cell surface. There are other pathways that run parallel. And the feeling is sometimes if you block this pathway you'll get a signal going down one of the other pathways. And so in this trial of deactinib which is something called a fak inhibitor and a vutoanib which is essentially another mech inhibitor although it also inhibits wrath.

It's felt that the combination might prevent the signal that goes down the other pathway. And so the idea was that using these two drugs together might be better than using the vuttanib on its own. And certainly when the two drugs were used in a in in an early phase study the percentage of patients whose cancer shrunk was pretty high. You remember in this waterfall plot if the tumor shrinks by more than 30% then we call that a response.

And what's interesting is that some of the patients those with um the hatchings in the bar had received a mech inhibitor before. So it seemed to also work in some patients who' previously received a mech inhibitor which was exciting. Now the ramp 2011 study looked at either the vuttanib on its own or the vuttanib with defactinib and um when it was used on its own the percentage of patients whose tumor shrunk was 17% when the two drugs were used together it was 31%.

And indeed in patients who had K raz mutations it was even higher at 44%. So it did seem that there was mileage in this and um and these are the waterfall plots from ramp 2011 and uh this is the one you should look at and you can see a significant percentage of the patients their tumor shrinking more than 30 30%. And actually even in some in whom it doesn't shrink 30% it's still shrinking quite a bit. So that led to the FDA granting accelerated approval for this combination of drugs although only in patients whose tumors have got kas mutations.

So this was a real a real um positive and actually um this combination's now been validated in a phase three study called ramp 301. So you may remember I mentioned earlier about chemotherapy and also about let the fact that the retrospective study seemed le seem to suggest let was pretty good. We've got some doubts about how good chemotherapy was. So it led to this study in patients who' stage two to four low-grade ser o se o se o se o se o se o se o se o se o se o searian cancer and they had an operation to remove their cancer and then half of them got pottitaxel and caroplatin for six cycles then let another half just got let alone and I think a lot of us felt that these two things might be about the same but actually it was announced just two or three months ago and I'm sorry I don't have the figures to show you.

It was at a conference and it's not been possible to get these. It's not been published yet, but essentially let alone was not quite as good. There wasn't a huge difference, but it did seem that let chemotherapy was better. So when I speak to my patients about this now I'm suggesting chemotherapy and let unless under their specific circumstances I feel that perhaps let alone might be the bit better option but that is only under particular specific circumstances and really the evidence suggests that chemo and let is probably the best but for example if you get somebody who's had chemo before for some reason and they found it really really tough and they say to you I really don't want to go through that again and we know letter is always pretty good and under those circumstances I think that's reasonable.

You may also remember that I said sometimes if a patient presents with a irresectable tumor and in high grade we give them chemo because we know there'd be a good chance of the cancer shrinking but in low grade chance the cancer shrinking is not as good. So what do we do? Well, often we still give chemo, but this study suggested that giving endocrine treatment CDK46 inhibitors such as a drug called ayclacy plus an endocrine therapy called pulvestrin in this study and it's a small study but the patients didn't have reectable disease.

So they got eight weeks of this combination of hormone treatments and if their cancer shrunk enough then they could go and get an operation and if it didn't shrink um then they would go back to standard care and essentially you know 60% of the patients are cancer shrunk and some of them were able to go on and have an operation. suggests that this might be a strategy that we should explore a bit more and certainly the use of these sort of drugs or these sort of combinations in other studies in relapse disease do seem to be effective.

So this was a study in patients whose cancer had come back and they got a CDK46 inhibitor called ribocyc plus letol that's the aromatase inhibitor you may be getting accustomed to looking at these now but you can see a significant percentage of the patients their cancer shrunk a lot so this is looks like a pretty decent strategy so I'm just going to finish by um talking a little bit about hope for the future both scientific and treatment wise.

So I hope that going forward we can do whole genome sequencing in a lot of our patients and there are people out there who would argue that maybe it's not necessary for lowgrade serious ovarian cancer but there's been recent evidence to the contrary. So this is a case report of a patient who received celometib in a study that was done many years ago. It was a phase two study of cell metamid which is a mech inhibitor and this was this this paper was published in 2015 in the journal of clinical oncology and it's a case report and it's very difficult to get a case report in the journal of clinical oncology but this was so striking because it was a patient who received this celametanib for their because their low-grade serving cancer had come back and the tumor not only shrank and stayed away but it stayed away for more than 5 years.

It was 5 years at the time this was reported. It may still be away. So this is something that we call a super responder or a patient that we call a super responder. And the important thing about super responders is you want to work out why they were a super responder. So they sequenced their tumor and they found that they had a very specific change in a gene that meant this pathway was always switched on. This is the pathway I've showed you a few times.

And this causes something called enkaggene addiction. And that means that it's unlikely that the cancer cell can survive without this pathway being switched on all the time. And so if you give a mech inhibitor in this situation where you've got something that's directly driving mech, which is what's happening here, then you get this sort of super response. So when I saw this I thought well maybe this is a one-off but it is very interesting.

However I got referred a patient recently who was lucky enough to get whole genome sequencing performed by Genomics England and they had a similar thing something called a gene fusion in one of these genes. It's not identical and we can't say with certainty it'll respond the same way. But I'm pretty sure that her cancer has come about because of this gene fusion. And it makes me wonder how many other patients who don't have mutations in KAZ or BFF have this sort of thing going on.

And the only way we can work that out is by doing whole genome sequencing. So we really want to do more whole genome sequencing in more of our patients. And we're currently looking at ways to get hold of that data, analyze that data. I believe the Australians are about to publish some of that data and we'll certainly be wanting to look at their paper and hopefully if they allow us look at their data. There are other strategies coming over the horizon.

You've probably heard of these antibbody drug conjugates. So, these are clever drugs that have got an antibbody that hits a target on the cancer cell and use that as a Trojan horse to get a payload into the cancer cell to then kill the cancer cell. These are people in my lab, Joanna Porter. Well, Joanna's in my lab. Sorry, I couldn't say that about Rob Hollis. Rob Hollis you may of you may have heard of is an independent investigator but his group and my group are working on this together where we're looking at different sorts of ovarian cancers and we're looking at some of the targets on the cancer cells and um Joanna this is her PhD to do this and the cancer type that she's working on now is lowgrade cirrus she's got a number of very exciting hits a number of targets that look like they could be really they they signify that we should try antibbody drug conjugates um in low gradede serious ovarian cancer particular antibbody drug conjugates I'm not showing those today because it's quite early for these but we are excited about some of them I might mention one or two of them later but we are excited about them and we're also very lucky because one of the main tools for analyzing this data so they're basically Joanna is analyzing um about a thousand tumors And she's looking at how often the targets for these drugs are present on clear cell, endometrioid, high-grade cirrus, low gradede cirrus, mucinous, ovarian cancer.

But she's using AI and the AI tool she's used using is used a lot of places around the world, but the developer is actually based in Edinburgh and he's helping her. Um, this is a chap called Peter Bankhead. And then the other thing that really excites me is the fact that Sarah down here, who I've mentioned already can grow these organoids so readily. And so what I'd really like to do going forward is create something called an avatar study where we take a biopsy of a patient's tumor and we grow it in the lab as an organoid, but we also treat the the patient the patient the walking living patient with a drug in a trial, but we use the same drug on the organoid to see whether we can work out from the organoids the best treatments for the patient.

So that's a wee bit off yet, but we think we've got the technology to do that and we just need to really put it all together. And this is one of the last things I'm going to mention. This is something called a platform study because we mentioned these drugs that are coming through our drug screens. the drug screens we're doing, the drug screens that are being done by Dean Cheesley, um drug screens that are being done in the US and in Canada, um and other drugs that are coming through that look like they're good, for example, antibbody drug conjugates.

So what we want to do is we've got this um platform study that we're setting up with colleagues in North America in the hope that patients whose low gradede serving cancer comes back can undergo screening and then go into a particular trial arm according to the biology of their tumor in the hope of shrinking it down. And then if that doesn't work, they can come back through the process and hopefully go on a different arm.

This is something we want to set up because it could set it could potentially run at many centers across the world. It could potentially give us quick answers regarding which drugs work and which don't. And most of all, it could help patients. And then this is the last thing I wanted to say and it's about the patient voice. We've been incredibly lucky because low grace is a very rare or it's not very rare but it's rare ovarian cancer.

There are other rare ovarian cancers that I think are somewhat behind us um in terms of the progress the collaboration we've got and part of that is because of the lowgrade serious surveilling cancer initiative. Part of it's because the great individuals that behind it um pushing it forward and these other groups star and not these overays, you know, that really help the community come together. They've allowed us to make a global collaboration of investigators that investigate the science, investigate new drugs, are trying to create databases, and it's the patients that have driven this.

I mean, there's one patient in particular who's really driven this hugely, but there are now a lot of other patients that are driving it. And indeed, just yesterday, I had a patient um travel to Edinburgh to explain to our community how sequencing really helped um her deal with her diagnosis of low-grade serious ovarian cancer. So I really appreciate everything that all our patient partners and advocates do and some of the pictures are here are from um adverts in time square picadilli circus and low gradede serve cancer conference attendees.

So I want to thank you all for everything you're doing and then this is just a summary. You know I think the things I would point out is chemotherapy is of limited utility but is of some utility. Endocrine therapy as a role bevicismab if you can get it I think is good. Mech inhibitors are very good should be part of this but we've got other things coming through that I think will really help particularly if we explore the science in a bit more detail.

Uh and I must finish by thanking patients and our relatives who've donated um to all of this. Um all our funders including um inter international collaboration for low gradede serious ovarian cancer um target of ovarian cancer nickel Murray Foundation um you'll see them all listed here and all the collaborators that did all the work in the lab and um thank you for your attention. Thanks so much, Charlie. That was just it, you know, the the breadth of um the work that you're doing, but also making it so accessible um to all of us listening.

Just absolutely fantastic. We've got questions really a huge number of questions pouring in. >> Um so, if you don't mind, we'll we'll spend a few minutes going through some of them. >> Yes. Yes. Yes. of course >> and and a lot of them are obviously going to be around chemotherapy and and recurrence and those sorts of sorts of things but thinking about um you know the trial that you've just talked about that came out this year um indicating that there is somewhat of a role for chemotherapy but I think that the community ethoses has been oh actually chemotherapy doesn't work for us so h how do how are we going to navigate that in terms of getting onto clinical trials um and also communicating that to our community that you know some people were telling them that they shouldn't be on it, some people are telling them that they should.

How what's your strategy for that? >> Yeah, it's a good question. So um so that trial was something called a non-inferiority trial. So it was powered to demonstrate that let alone was not inferior to chemotherapy and let as it turned out it was not not inferior. So it was inferior. >> Yeah. >> But actually when you look at the survival curves the difference isn't that great. However, I think it's enough that I would be tempted to say patients should get chemotherapy unless they feel strongly otherwise.

Now, we've only seen that data presented. We've not seen it in a paper. We've not seen it stripped apart according to say the biology of the tumor. >> You know what was Kaz and Bav? What were these biological markers doing? What did the stage have any role here? You know, are there patients who don't necessarily need chemo? Now, it may be that when you start slicing up the population of the study like that that there's not enough power to say that with any certainty.

So, so the way I deal with this now is I say to patients, I think there is a benefit from chemo and if there's any way we can give you bevicismab with the chemo, then I definitely think there's a benefit from chemo and that's what I want to do. If I can't give you bevicysmab, then I still think there's a benefit from chemo. But if patients are feel very strongly that they don't want chemo, then I am willing to talk to them about hormone treatment alone. >> That's how I deal with it. >> Thank you.

Yeah. And and so for um say access to clinical trials because it is standard of care, do you mostly have to have received chemotherapy to then be able to enroll on other clinical trials? So historically historically that's how it's been anyway. So even before that data came out you know and you know the trial that you know that platform study I showed you at the end that we're putting together with Rachel Gisham and David Gersinson and others anal sud um you know we were planning to write that so that patients didn't have to have had chemo first.

So we may have to readress that but you know we may be pragmatic about that and say you don't have to because you know I guess the big question is >> whether we should be doing a trial of a mech inhibitor versus chemo first line. Yeah, >> that would be. Now, obviously, we can't give that just now because that trial's not been done. >> But, you know, >> if you were going to put a bet on it, you would probably suspect me inhibitors might be better. >> So, you know, so I guess what I'm saying is why would you say somebody has to have chemo before you give them a drug that might be better? >> Yeah. you know, but and so so basically it's up to whoever writes the trial to not necessarily put that in as an inclusion criteria. >> And you think well given given that um most of the community are working together, I think there's a good chance that that can actually happen, right? >> Yeah.

Yeah. Yeah. Exactly. And so just thinking about recurrence and if you've gone through you know surgery hormones standard chemo mech inhibitors what's next what what are we going to do for patients after that I mean there's it's sort of a heroic effort but is there something that that we can do after that >> so this is where we really need this platform study because we the platform study is not going to mandate prior lines.

Now, you know, we're not going to say you can you can only have x number of prior lines. >> That's not going to be because we want it to be permissive. We want it to allow access for patients. Now, I realize the platform study is not here yet. And so, we need something now. But what I would say would be a good strategy would be if patients can get on phase one studies of drugs that could potentially be beneficial. And so drugs that might fit that are things like antibbody drug conjugates that target folate receptor alpha or antibbody drug conjugates that target MOK 16.

So there are there are um you know there are trials out there or if or if it's possible to get a CDK46 inhibitor plus a neuron. It obviously depends which part of the world you live in because in some countries you can the the oncologist is allowed to prescribe off label and so they could prescribe a breast regime for low gradede cirrus. But in other places, you can't do that. >> Got a a couple of really interesting questions around the use of a GLP1 inhibitor um to help manage weight gain and joint pain from letol.

Have you had any experience with that? >> None whatsoever. So yeah, I don't think I could comment on that, but that sounds very interesting. >> It does, doesn't it? That's what I thought as well. It's um yeah um >> obviously obviously if you control weight gain well I guess the whole point of let is it's meant to block the production of estrogen in fat tissues regardless of >> but I'm not sure so I'd have to claim ignorance regarding the impact the GLP1 would have on that but but it sounds a very interesting concept I can't say much about it sorry Um okay.

So another really interesting question about the um EGFR targeted drug and um or drugs and about uh you know personalization of of of that is is there anything on the horizon um for you know I guess a biomarker or something like that do that you know about? Well, so it's funny you say that because Dane cheese DNE's recent study um showed that EGFR expression is a potential biomarker. So, you know, so I think there is a possible biomarker out there.

Now, it's not been validated in a clinical trial. >> That paper was only out in August, I think. So it's only a month or two old and so um you know but I think there is the possibility that that could be a biomarker but it need to be looked at a bit in a bit more detail and you know we need to set up studies of these EGFR inhibitors because it's funny because they got to the same place with their drug screen that we got to with ours which is actually really reassuring.

It makes you think there's really something in it. >> And so, so we need to and those drugs are out there. Those drugs are used for other cancers. So, we need to we need to get them going in low gradede serious surveillance cancer studies and also look at the possibility that EGFR might be a biomarker. >> Would you do them together? Would you test the biomarker alongside the um the treatment to, you know, bundle it all up? >> Well, you potentially could.

I mean, you know, historically when you try to so there's two ways you can do it. You can either test for the biomarker and only put patients in who've got the biomarker. But sometimes when you do that, it turns out you don't understand the biology as well as you thought you did. And therefore sometimes what you're best to do is put is allow everybody access to the treatment and then do a retrospective analysis based on the biomarker status. >> Yeah, we look forward to seeing that.

That's gonna be great. >> Yeah. No, we must we must we must really push on with that. Yeah. >> Um and then just thinking about some of the other I mean uh I guess ADCs but also the bicep specifics and um you touched on the um MUK 16 bicep specific. Do you want to speak any more about that? Um do you want to explain to us what a bio specific is and how that works? Well, this well, this is an antibbody that hits more than one target and brings two targets together, you know.

So, if you've got a target on the cancer cell and you might bring another cell into close proximity with it by using a biopec, you know, I think there's a lot of excitement round about Mach 16 bi specific. I'm probably need to be a little bit careful what I say um because some of it is in confidence. So, but you know, but um as a target, MOK 16 looks really good in low-grade cirrus, whether it's a bicep specific or an antibbody drug conjugate.

Um you know, and I can tell you that from our own work in the lab that Joanna's doing that low grade MK 16 looks like one of the best targets in low grade ser. >> Yeah. >> In terms of it expression on the cell surface, you know. >> Yeah. Yeah. I mean, it's such an exciting field. Um, and as as we get better at making making antibodies, it's really it's just exploding. Um, so it's really cool to hear right at the very cutting edge.

This is this is what we're seeing in the lab and we we see a downstream um use for this. It's really um quite amazing. So, I I I'll let you off the hook in a couple of minutes, Charlie. >> Yeah, that's no problem. No problem. Um so one one question around taking let is it worth taking let indefinitely? When when do you call it? >> So that is a difficult question because >> in breast cancer they did lots and lots of trials because there obviously been literally millions of women with breast cancer.

Yeah. And they've done all these huge trials and they've looked at five years versus 10 years. five years then switching to a different one and you know so they've done all these trials we simply don't have that information so right now the best we can do is sort of I guess expert opinion and there is a a paper that's going to come out um in the next few months the next consensus the low gradede serving cancer consensus and when we discussed is you know even all the people who treat low grade around the world a lot of low grade around the world couldn't really agree um I think the consensus is going to say 10 years I'm not sure I think it's a bit of a personal discussion with the patient >> and my instinct is if they're diseasefree at five years then I might be tempted to stop it but it would be a discussion with individual patient a discussion of the uncertainties a discussion also of the risk of it of continuing on it osteoporosis >> and a consideration of how it's impacting the rest of their life if it's causing a lot of joint pain and things >> because they're not without toxicity you see so so it's it's difficult but I think the guidance is going to say 10 years.

Is the owners true? >> Yeah, it's a it's a really tricky conversation to have when you're in the maintenance setting and there's so much uncertainty, really difficult to study, too. >> Um, >> there's a really interesting question here. I'm just going to read it out so that I get all of all of the nuances of it. So given the low gradede cirrus progression to small intestine and bowel obstruction with bypass surgery not possible and currently dependent on TPN and gastric drainage.

Could cancer treatments such as tranatma shrink the tumor enough to relieve the obstruction? What other options should we consider? >> Yeah, so that's that's a really tough one. Um because if somebody has bowel obstruction, you've got to kill a lot of cells to try and relieve that. I mean, I'll be honest and say I have tried it with tmetanip, but that's only it wasn't particularly successful in that case. it wouldn't necessarily mean it wouldn't be successful in another case.

I think you have to take each case on its merits. Um, obviously the the weakness of that strategy is that tmet is an oral therapy >> and if somebody's got bile obstruction, you'd rather give an intravenous therapy rather than an oral therapy. >> Yeah, >> it is quite well absorbed though. So it's quite quickly absorbed. Um but hopefully if we can get an antibbody drug conjugate that's effective in the near future, that might be a strategy because you know the percentage of patients who respond to chemo isn't really enough to use that as a strategy.

Um it's a very difficult situation is the honest truth. I I will say I have used I have used tremenum in that situation. Actually when I think about it I think I've done it twice now actually. >> Mhm. I've done it twice. Yeah. >> Yeah. Cool. Thanks so much. Okay. This is this is for the UK patients. Um so can patients in the UK ask to have their tumor um evaluated for mutations if they haven't already? What's what's the pathway for that? >> Yeah.

So I think that depends a little bit on your local pathologist. >> Yeah. >> So we're very lucky and our local pathologist essentially does it routinely. If it's low >> he does biraff and nras. He does the three genes. Um so that's the least you would like and I think you should ask for that to be honest. They might say no but I think I think there's a reasonable case for asking for that. Now, of course, in England, some ovarian cancer patients can get whole genome sequencing, and that's amazing. >> So, if they get that, they should definitely ask for that because that that can tell you a lot about the cancer. >> And then also also for people in in the UK, um how are they able to request second opinions with you? >> Yeah.

No. So I mean yes so it's a little bit tricky because I don't do any private practice and um but I do like to see second opinions particularly low grade serious like to see any second opinion um and the only problem is that my health board um they want to get some sort of recompense for it. It's not money for me, it's money for them. And so they ask that if somebody refers so that we say we get referral from an NHS trust in Liverpool, they will ask that that NHS trust in Liverpool agrees to pay for the consultation and it's not very expensive.

It's only about 90 and it goes to NHS Lotheian which is the health board. But the problem is that it creates an extra hurdle because they have to get cuz my my health board won't let me see them until we get agreement from the trust in England that they will pay for the consultation and it's there sometimes quite difficult to get that agreement even though we say it's not going to be expensive. Um, but they won't let me do that without that because otherwise they're scared that I'll see lots and lots of patients from everywhere and NHS Lotheian will end up paying the bill for everybody's patients.

So anyway, but we we're hoping to make it easier. So I'm working with one of the managers and I think we're going to try and make a website so that it says what's required for the referral etc etc. So we are trying to make it easier. But essentially if somebody gets a letter from their oncologist to my secretary then that's probably the best way of starting. >> That's that's fantastic. So there you go all you lucky people in the UK. >> There will be a pathway eventually. >> Yes. >> Um listen I I I will wrap it up because we're we're getting on a bit.

But I also have this really lovely message from one of your patients which I will actually pass on to you privately after this so that it's not all all on record. Um but just to say that you know a long list of people lining up to thank you for your care and and all the work that you're doing which is really impactful for this you know small but very strong community. Um, so it's absolutely our pleasure to have the opportunity to get your name out there and and hear from you.

Um, and also support you in whatever way we can. So, thank you so much, Charlie, for all the work that you're doing. We really, really appreciate it. Um, and and thank you everybody for joining us today. Um, it's been an amazing conversation and we really appreciate you all. So, thanks. >> Thanks. Thanks for the opportunity.