[00:00] Egle: Hello everyone, my name is Egle and I'm the host of UEG Podcast, an educational and hopefully fun dive into the GI world and beyond. And today we're talking about very exciting new avenues in the management of pancreatic adenocarcinoma and the basic science behind it that drives it.

And our guest today is an amazing scientist, a passionate researcher focusing on the discovery and validation of cancer-associated biomarkers for the early detection of pancreatic cancer and cholangiocarcinoma, junior group lead and senior research fellow at UCL: Pilar Acedo. Welcome to UEG Talks, Pilar.

[00:35] Pilar: Hi, Egle, hi everyone. Thank you for the invite. It's a pleasure to be here.

[00:40] Egle: We're very, very excited to have you, a superstar in the UEG stratosphere and previous Young Talent Group lead. And we're very happy to talk about what's new and maybe give some hope to our patients in the future.

So, we do know that PDAC is one of the most devastating diagnoses that we can give a patient, and half of the patients are diagnosed at a metastatic stage. What are the emerging developments in blood-based biomarkers? Can we combine certain newer approaches, such as circulating tumour DNA or microRNAs, with the traditional ones, like CA 19-9? And what could it offer for screening and early detection of PDAC?

[01:26] Pilar: Yeah, I totally agree. I think things are needed, and tools, right? In the AI world, it's impressive that we don't yet have a real early detection or diagnosis tool for these patients. But a lot of things are happening; the field is moving really quickly. And I think some of the findings that I am going to mention now are promising. So hopefully, yes, we can give some hope. Things are slow, right? Maybe in some years, but things are moving forward.

So, as you mentioned, CA 19-9 is the biomarker that is clinically used, right? But it's not an amazing biomarker. Specificity and sensitivity are not fantastic, but this is what we have. And I am still impressed, as a scientist; we have amazing technologies, and still we keep coming back to CA 19-9. As you know, CA 19-9 can also give us positive results, so it can be up in patients without cancer but with other GI-related diseases, such as pancreatitis, right? And also it can be negative for patients with pancreatic cancer. So for sure, we need better biomarkers.

And you mentioned circulating tumour DNA. But pancreatic cancer is a really complex disease. We were all hoping that maybe this tumour would be releasing a lot of circulating tumour DNA into the bloodstream and we would be able to detect it in blood, because we have better technologies now than 20 years ago, right? But still, sadly, we cannot detect circulating tumour DNA in early stages of pancreatic cancer. Stage one would be our aim, when patients can get resected, right? Because we know that if patients can get surgery, prognosis is much better. However, this works for some tumours, and some tumours are releasing more circulating tumour DNA into the bloodstream, but the pancreas is not one of them.

In the UK, maybe you've heard about it, we have this ongoing NHS trial, the NHS-Galleri trial. They're screening the general population with this test, and it includes people with pancreatic cancer. But sadly, for pancreatic cancer, the data are not really encouraging. It's still ongoing, and we will see; these studies, including more than 100,000 patients, take many, many years. But it is challenging because of the level, let's say, of circulating tumour DNA.

You also mentioned microRNAs, and there are a few studies ongoing as well, but honestly, I haven't seen a lot of clinical trials ongoing, [just] a lot of publications. You read the publication, everything looks super promising, and then you don't see a lot of follow-up or clinically relevant data. That's not where we want to be, right?

[04:32] Egle: Because pancreatic cancer is so peculiar in its morphology and biology, could it be that the best way to go about early detection is a combination of various biomarkers (DNA, RNA, proteomics, metabolomics), and a combination also maybe including AI to increase specificity and sensitivity?

[04:59] Pilar: Yeah, I think totally. Including different types of biomarkers, because, as you mentioned, biology is super complex. Each patient is different. We see tumour heterogeneity inside the patient, and if you compare tumours from two different patients, they are totally different, or even in one patient, right? Molecularly or biologically different areas of the tumour, as time goes by.

[05:24] Egle: Yeah, yeah. And even when it's detected, sometimes, you know, different areas of the tumour have totally different profiles.

[05:31] Pilar: So I think, yeah, combining proteins, RNA, circulating tumour DNA will be amazing. But we also need to think about whether this is cost-effective, right? Because someone has to pay for it, and we know how important money is, too.

[05:45] Egle: Money is important too.

[05:46] Pilar: So we also need to think: if you are an academic centre or academic hospital, do you have the instruments, the equipment, the knowledge, the staff that you need to do that? And how long does it take to get the results back? Because in this aggressive disease, you want the results back soon. Then there is this meeting where you discuss what is best for a patient. So we need something that is effective, right? Specific, sensitive, but that cannot be super expensive. Because if not, we're going to be reimbursing for this, and we cannot just offer something that is super expensive that only a few people can pay for. I don't think that should be the way of moving forward.

But yes, I think, checking published papers and at conferences, we hear a lot about multi-cancer detection tests, so a test that promises to detect different cancers. But we go back to this problem of pancreatic cancer, where we know we cannot screen the general population for it, right? We need to focus on high-risk patients. Even if we have an amazing test that is super specific and sensitive, the rate of false positives will be really high, and we cannot just tell a patient "maybe you have pancreatic cancer," and then it's a no, right? I mean, this is not the way of moving the field forward. So I think multi-analyte, as you mentioned, including different types of biomarkers, will be the way of moving forward.

[07:27] Egle: Yeah. Regarding recent publications, it's been all over PubMed, Twitter, whatever you have: KRAS mutations and the new drugs targeting KRAS mutations. And we do know that pancreatic cancer is particular in that in more than 90% of patients you can detect a KRAS mutation. Could you explain the biological significance of this mutation and how it could be utilised in PDAC screening and treatment?

[08:00] Pilar: Yeah. So, as you just mentioned, I think it's super exciting, right? It's everywhere. It's also really important for people to understand, and it has been in the news, and I think it's super exciting. Finally, some good news for everyone, especially patients. So, yes, as you just mentioned, KRAS is mutated in around 90% of pancreatic cancer patients, right? So the opportunity is there.

And just to better understand: KRAS works like a switch that can be on or off, right? When it's on, it's promoting growth of cancer cells. So we have this really beautiful data now with this molecular glue, that I cannot even pronounce, in the new drug. I don't know.

[08:43] Egle: That's what I said!

[08:44] Pilar: Well, you were practicing before the podcast, right?

[08:48] Egle: Yes, yes, yes. I still cannot say it.

[08:51] Pilar: But yeah, it's really promising, because it binds to something else, and then altogether they bind to KRAS when it's on. And this is a new approach, right? It's been there for many, many years, but suddenly someone thought it was a good idea.

[09:03] Egle: And the data are there, right? Overall survival much better than with standard chemo. Twice.

[09:09] Pilar: Yeah. So I think what we also need to understand is the complexity of KRAS. There is not only one mutation, right? We can have patients with wild-type KRAS, not a lot, but they are still there.

[09:22] Egle: Ten percent.

[09:24] Pilar: 10%, yeah. And this new drug also affects wild-type KRAS. There are side effects that we also need to consider and understand, right? And things need to be improved. We can maybe chat about it later, but we need to understand that there are different mutations, the majority of them in codon 12, but there are different ones, right? This new drug is a pan-RAS inhibitor, which is really cool, because if we know the patient has mutant KRAS or has this mutation, then we can use it. But there are side effects.

So I think the important thing to understand is also that KRAS is present in premalignant lesions. People having PanINs and IPMNs already present, in the majority of cases, KRAS mutations.

[10:14] Egle: And it's one of the questions, very early on.

[10:16] Pilar: Yeah. It's a gain-of-function mutation, so it's promoting cancer cell growth. It's a really bad one. It's the main one, and one of the earliest. So there is a window of opportunity for us in this regard. Also, cancer cells then are really dependent on this KRAS mutation, right? Because they are getting all these growth signals. So I think it's super promising.

[10:47] Egle: Let's see the new trials.

[10:51] Pilar: I'm really, really hopeful. But also, I think that PDAC is a very smart tumour that can upregulate, downregulate, circumvent these pathways. And if other pathways can be activated, that's one of the problems that is arising: tumours are smart, and they change their biology.

[11:13] Egle: Yeah, they are. How can we prevent it?

[11:18] Pilar: Oh, well, if I had the answer to that... Something interesting in the study is that they mentioned all the good news, that overall survival almost doubled compared to standard chemo. But they also mentioned that some patients were developing resistance, and we need to understand now how. And whether there are patterns, so we can anticipate this relapse, right? And I think in the new trial they are going to be combining the KRAS inhibitor with different other drugs. I'm a little bit concerned regarding the side effects, right? Because we already see skin rashes and some side effects on the GI tract in general that were moderate and mild, but some patients were, you know, not great. So let's see what happens when we combine the inhibitor with other drugs.

[12:20] Egle: Yeah, because it's not only the single mutation that drives it, right? And there is also, because it's not only cell proliferation but also the microenvironment of the tumour. There are many paths by which a KRAS mutation affects the development of cancer. So if we could target different pathways and have a synergy of drugs, maybe.

[12:42] Pilar: Totally. I think it gets super complex, because this is a pan-RAS inhibitor, right? So they will need to include enough patients with different specific mutations. Are patients with G12D responding the same, or having the same resistance patterns, as patients with [G12V] or patients with wild-type KRAS? What is going on there? And then maybe it's not only the cancer cells, right? What is happening with the stroma in the tissue, but also in blood? You know, when cancer cells are dying, they are releasing things into the bloodstream, and this can also affect the immune cells, for example. So what is going to happen? I really hope that in the new studies they will be getting biopsies and also blood samples, and then we will better understand the biology of the tumour. I think understanding what is going on in the disease is going to be really key to understand which real patients could benefit from this therapy, because I am guessing it's not cheap, right? And then also how we can predict relapse, or patients who are not going to respond, right?

[13:58] Egle: Yeah, tailoring, targeted medicine. If the dream is to never diagnose PDAC, through screening, early detection, vaccines and things like that, but if currently we are still diagnosing PDAC, from the basic scientist's perspective, should comprehensive tumour and/or even germline molecular profiling become routine for every patient? Because we do know that biology is different and the response to treatment is different, and there is an increasing number of targetable alterations involving KRAS, BRCA1 and 2, and homologous recombination deficiencies. So should we do genetic profiling more often?

[14:46] Pilar: Yeah, I think it should be routine, to be honest. Because, as you said, the disease is really complex. How can we know otherwise? Targeted therapies or personalised medicine are expensive, but it's the way of giving a patient better chances to respond, right? I think you will know better than I do. I thought that sequencing is part of the guidelines now for pancreatic cancer patients, or should be, or is, depending on the country.

[15:17] Egle: The newest guidelines should be coming up soon. I'll just say, we'll see. But at least in my country, it's definitely not routine practice.

[15:27] Pilar: Oh, yeah, I see. This is also, I mean, usually, as I was mentioning before, right, it can be a challenge for academic hospitals or places that are not a reference centre for these technologies, with the equipment and the staff who need to get the samples, analyse the samples and also understand the findings, right? But I think we need to understand the germline mutations, right? Because it's up to 10% of patients who are going to have these familial cases, but this can tailor therapy, right?

[16:09] Egle: Yeah, there are different responses to chemo.

[16:11] Pilar: Yeah. And I think nowadays we have different drugs that we could try, even if they are not routine for pancreatic cancer, right? But we need these studies to understand whether people will benefit, and then also to offer them something rather than chemo that isn't working. And if we could also do sequencing of the tumour, then a small proportion of patients are going to have mutations that can be targeted. But we need to know, right? This has been changing the way other cancer patients are treated and their prognosis, but I think there are also limitations or challenges, let's say.

So first of all, if we need to get a piece of tumour to do the sequencing, right, you were mentioning before the complexity of the tumour stroma. So I don't know, but usually when I work in the lab with pancreatic cancer tissue, the biopsies are really tiny. So you need to ensure that the person taking the biopsy has the instruments or the things needed to get a proper piece of tumour, enough to do this sequencing. Because it's not just DNA; sometimes we are talking about RNA sequencing, and who is going to cover the cost? We go back again to all these problems. And then also, when you get the biopsy, you need to ensure this is tumour tissue and not the stroma only, right? And then you also need to ensure that the results come back on time for the patient.

[17:50] Egle: Yeah, because it progresses so fast. So if we do not have it fast, what's the prevention or treatment worth if it's not in good time?

[17:58] Pilar: Yeah, yeah, yeah.

[18:04] Egle: So, coming back to prevention: on a similar timeline to the trial on daraxonrasib, there was also data on the first-in-human testing of a mutant KRAS vaccine for pancreatic cancer interception in high-risk cohorts, patients at higher risk of developing pancreatic cancer. Can you explain in somewhat simpler terms how the vaccine works, and whether we have first hopes of never diagnosing PDAC?

[18:35] Pilar: I got so excited when I saw the data, and I was lucky enough to also be, yeah, I was in London at a pancreatic cancer conference organised by Cancer Research UK, and I was lucky enough to see one of the corresponding authors presenting the data. I was like, wow, it's so beautiful, it's so clever.

[18:55] Egle: Yeah, yeah. And it's US data, as usual. You cannot compete.

[19:03] Pilar: No, luckily we need to collaborate. So it's amazing that they are moving the field forward, but it will be really important to do validation studies, right? And also move away from the US and bring all the cool things.

[19:19] Egle: It's only 20 people. But it's really exciting.

[19:25] Pilar: Indeed.

[19:25] Egle: So can you explain how does it work?

[19:28] Pilar: So this is made of amino acids; I think it's synthetic, so it's peptides that correspond to the most common mutations that we were mentioning before for KRAS. So the cells are then going to be expressing these antigens, and because this is something that shouldn't be there, our super clever immune cells are going to recognise the antigen, the mutant protein. I think it's super interesting, and it makes total sense, right? Because this is going to be interception, so kind of prevention-interception, which is totally different from early detection. But it's something that is coming out now, and I think it's impressive.

So it's really clever that they are focusing on familial cases, people at high risk, or people with high risk because of these [dilations] in the pancreas. These people were getting this vaccine; if I remember well, because I read the article some weeks ago, it's a subcutaneous injection. So they were getting the injection and then going back to the hospital for follow-up, and they were following up the patients, also with different doses of the vaccine. So they wanted to prove whether this is safe, right? And whether there is an immune response to the vaccine.

[20:55] Egle: Yeah. So, as you mentioned, 20 patients. But I am sure, you know, we say "just 20 patients," but getting these 20 patients, the group will be like, "What are you talking about, 20 patients?"

[21:07] Pilar: Yeah, it takes a while to enroll 20 people. Also because, you know, you need to think, these people don't have cancer. I mean, if you think about it, if you have cancer, you want to try any therapy, you want to continue living, you want something that is making your tumour disappear. But here you are high risk; maybe you never develop the disease, right? So you need to enroll and get a vaccine that you don't know if it's going to work, if it's safe, if it's going to make the disease worse. But luckily it was safe.

[21:43] Egle: Good immunological response.

[21:46] Pilar: Yeah, yeah, yeah.

[21:48] Egle: 80% sustained?

[21:49] Pilar: Yeah, around 90% of the patients generated memory [T cells], which I thought was really nice. And I thought something really shocking was that they also followed some of these patients up to two years, and they still saw this immune response, right? So it's maintained.

[22:10] Egle: Yeah, it's sustained. It's really impressive.

[22:14] Pilar: And also, okay, getting access to tissue is always difficult, so trying to understand what is going on in the tissue will be more complex. But I think they also have imaging data, and they saw that the cystic lesions were smaller, were shrinking. So this is also really important, right? Because if you have a cystic lesion and it's smaller, the risk of progression will be less. So I think it's really encouraging.

[22:44] Egle: It's really nice. We covered screening and some prevention techniques, some biology of the cancer, and I think it's a good note to end this first part, with a lot of excitement for the future that is held by PDAC research. What do you think, Pilar?

[23:03] Pilar: Yeah, I think it's really exciting times for people working on pancreatic cancer, right? And I am looking forward to seeing the new data. I think it's a really clever approach, and looking forward to seeing if we can give something better to our patients.

[23:20] Egle: Indeed. Thank you, Pilar. And we will talk about the treatment options in pancreatic cancer in the second part. See you then.

[23:28] Pilar: See you, bye.