International Medical Conference Endometriosis 2025:
Endometriosis 2025: Your Mother Should Know, Your Doctor Should Know Better!
Understanding Peritoneal Endometriosis - Towards New Medical Treatment - Andrew Horne, MD
I'd like to introduce our next speaker, Dr. Andrew Horn from Edinburgh, Scotland. He's a professor of Gynecology and Reproductive Sciences at the University of Edinborough. He's currently the director of the PEC Center for Pelvic Pain and Endometriosis and has more than 200 peer reviewed scientific articles. He currently is the President elect of the World Endometriosis Society. Andrew,
Thanks very much indeed for the introduction and thank you Dr. Martin and Dr. Second for the invitation to speak at this meeting. I've really enjoyed all of the lectures and discussions so far. It's a real pleasure to be here in New York. These are my potential conflicts of interest. So as you've heard, I'm based at the University of Edinburgh and I work with the Expect Team, which is a group of clinicians, data scientists, discovery scientists and trialists who all work together with the aim of trying to improve the care of people with endometriosis. And we set up the Expect Group around 10 years ago together with my colleague, professor Philip Saunders in Edinburgh. And one of the first things that we did was that we set out to establish the research priorities in endometriosis. We carried out this a number of national surveys of patients and clinicians and using a three-step Delphi process identified a top 10.
And these priorities have really informed our research over the last 10 years or so. We also established a large biobank of tissue samples from patients with endometriosis. We've also been looking at patient specific changes using wearable technology such as smart watches and sensors. We've been piloting home collected samples to allow us to seriously sample blood and other bodily specimens from patients in their own home. You heard yesterday we've established an animal model of endometriosis and also a cell model, which I'll talk about shortly. But I think importantly what we've done is we've been able to take some of our discoveries in the laboratory through to early phase clinical trials, and we also carry out larger multicenter trials comparing, for example, surgery to some of the medical managements we use today. But for the purpose of my talk this morning, I want to talk about some of the work that we've been doing trying to understand peritoneal endometriosis, particularly focusing on changes in the peritoneal mesothelial cells and also some work that we've been doing looking at the peritoneal microenvironment with focus on the immune cells.
And we've heard quite a lot about the importance of the role of macrophages in the lectures yesterday. So first of all, in order to look at the peritoneal mesothelium, we established this tissue resource. So for patients undergoing surgery in our center, whether that be diagnostic or treatment surgery, they all with their consent, we collect samples of the endometriosis lesion, the peritoneum, we collect brushings of the mesothelial cells and also samples of peritoneal fluid. We've also, as I said, and I'm a bit ashamed to show this model after Linda Griffith's very sophisticated models yesterday, but set up this very simple co-culture model which we use to look at the interactions of peritoneal mesothelial cells isolated from patients with stromal cells, and in particular look at the impact of various investigatory drugs. And then we also have this mouse model of induced endometriosis. This is a syngen mouse model. We required, first of all, to induce menstruation in a mouse. Most of you, I'm sure are aware that mice don't menstruate far less spontaneously develop endometriosis. So we have this donor mouse, which in which menstruation is induced, and then that menstrual tissue is then injected into the pelvis of a recipient mouse. And these mice then go on to spontaneously develop endometriosis, which looks very similar to the endometriosis we see in our patients. And this work was led by Aaron GREs and my colleague Phillip Saunders in Edinburgh.
So using first of all the tissue resource, we demonstrated that there was altered energy metabolism in the peritoneum of women with endometriosis. And this cartoon summarizes some of the work that was carried out largely by a variable PhD student of mine, Vicki Young. So you've got the pelvic peritoneal mesothelial cell on left, the peritoneal fluid in the middle and the lesion on the right. And what we've been able to show is that there's an increase in the metabolic drivers of aerobic glycolysis, not only in the lesion but also in the peritoneal mesothelial cell. But I think most importantly we've shown that there's an increase in the levels of lactate in the pelvis of patients with endometriosis compared to patients without the condition. And this lactate is produced by the peritoneal mesothelial cells. And we know that lactate is extremely important for some of the crucial steps in the development of endometriosis, AEs and invasion and angiogenesis.
And this is largely from work looking at cancer. And this work has been confirmed by other groups. A group I showed you a paper from Taiwan and another one from Estonia in subsequent studies to ours. So having established that there was altered energy metabolism in the peritoneum, we wondered if we could target lactate as a treatment for endometriosis. We used this drug repurposing approach. So we searched the literature for drugs that have been used preclinically in early trials and in clinical practice for targeting lactate. And we've focused all of our efforts on one that's been used in clinical practice for a number of years now to treat rare metabolic disorders in children. And this is di chloro aate. And the first thing that we did was that we tested chloro acetate in our vitro model of endometriosis. And you can see here to summarize, we've shown that DCA reduces the amount of lactate produced by the peritoneal mesothelial cells.
And this altered lactate production has an impact upon endometrial stromal cell proliferation. So potentially in a very crude way, suggesting that it might reduce the amount of endometriosis that we see. And so we then went on and tested dilu acetate in our mouse model of induced endometriosis, comparing it to control. And just some of this work is summarized on the right hand side. You can see in blue the mice that have been treated with endometriosis compared to in red the control mice. And you can see that DCA seems to reduce the burden of disease in these mice. So we then felt that we had sufficient preclinical data to then take this into an early phase clinical trial. And this was a very simple single arm open label exploratory trial. It's important to bear in mind that both the patients in the trial and the clinicians looking after the patients were aware that they were taking the drug treatment.
And this trial essentially recruited patients with peritoneal disease. We asked them at the start of the trial to complete pain scores and quality of life questionnaires such as the EHP 30 questionnaire. They then took initial treatment with DCA for six weeks, and then they were allowed to double the dose if they wished after that first six weeks say on the same dose or of course stop the dose if they felt they had side effects or if it wasn't impacting upon their symptoms. And we collected the same raft of questionnaires at the midpoint and at the end of the trial and included an acceptability questionnaire a month later. You can see we had a very modest target of recruiting 30 participants, but we hadn't counted upon the covid pandemic when we started recruitment. And as many of you'll know, this really hindered the recruitment to non-malignant clinical trials.
But we did reach our primary outcome measures for recruitment and retention. But although this study wasn't powered for efficacy, what we found, which was most interesting to us, was that it did seem to have an impact upon patients' symptoms. So chloro acetate improved pain scores by two out of 10 on a zero to 10 rating scale, reduced EHP 30 scores by around 50%. And what I think is most interesting in two thirds of the trial participants, they reported using significantly less pain medication by the end of the trial. We also looked at safety and tolerability and police report. There were no serious adverse events, but patients did have side effects from this treatment and particularly some of them reported this tingling or numbness in their fingers, which was transient during the course of the trial. So we looked at this in a bit more detail and what we found was that the patients who experienced this transient peripheral neuropathy had much higher levels of DCA in their blood.
And this is important because dilu acetates metabolized by an enzyme called GST Z one, and this enzyme has five haplotypes and one haplotype confers fast metabolism of DCA and the other four are slow metabolism of DCA. So you can actually genotype patients to determine whether or not they're going to be slow or fast metabolizers. And if you look at the patients in our study in more detail, for example, a patient who completed the trial with good effect and no side effects, you can see a fast metabolizer low levels of DCA in their blood, whereas two patients who had side effects slow metabolizers, much higher levels of DCA. So we've now managed to secure funding to do a second trial. And this is a larger randomized double-blind placebo controlled trial to look at dilu acetate. This has a similar design to the first trial in terms of a treatment period of 12 weeks with the option to increase the dose after six weeks.
And we're using the same pain and quality of life questionnaires. We're recruiting in two centers, Edinburgh and London. And our aim is to target a hundred participants. But the big difference here is that we're going to be genotyping our patients at the start of the trial in order to decide on what dose to give these patients. This has been quite a long time, the funding and getting this study set up, but we're going to be starting recruiting in the next couple of months. So I also said that we were interested in the peritoneal microenvironment and the immune cells, in particular macrophages. And we heard some really great work yesterday from ASCI FBA and also from Hugh Taylor looking at macrophages in the context of endometriosis. This is some work from one of my PhD students, Chloe Hog. She like others, has confirmed their abundance of macrophages in lesions and the peritoneal fluid that they promote lesion growth and vascularization.
They appear to be important in the development of pain symptoms. But most importantly, they exist in this different phenotype in the context of endometriosis, a pro repair rather than a pro-inflammatory phenotype. And this is important because these macrophages have parallels with tumor associated macrophages. So these tumor associated macrophages promote tumor growth and inhibits phagocytosis. So there if you like, conserving the tumor. And this happens similarly in endometriosis. And of course the cancer field is much, much further ahead than us in the endometriosis field. And so there are multiple anti-cancer strategies which involve macrophage repolarization. So once again, we've looked at repurposing some of these anti-cancer strategies. So we did a search of FDA approved treatments that alter the macrophage phenotype. And we identified this drug treatment here called NSIs tone or RRX 0 0 1. And it's a drug that's been tested in over 300 participants to date in phase one to three clinical trials largely for head and neck cancer.
And it's an interesting drug because as well as repolarization the macrophages and altering the inflammatory profile, it has differing activity in normoxic and hypoxic environments. So it tends to be more active in a hypoxic environment such as a tumor or for example, an endometriosis lesion. So again, together with Aaron Greaves, we've tested this drug in the mouse model of induced endometriosis. If you look in the top left hand panel, you can see that Aaron's labeled the endometriosis showing up nicely in in the control mice who've not had the treatment. And you can see along the bottom in the mice who've received RRX 0 0 1, the endometriosis is almost completely resolved even by day seven of treatment. And this is reflected graphically in the panels below. And Erin also did some fairly primitive pain behavioral studies and showed that the treatment attenuates evoked like pain responses. So we're now in the position to start our trial, and I think this is going to be possibly the first trial of an immunotherapy treatment for endometriosis.
This is again, a small trial, 36 participants, and it's largely a dose finding trial and also a trial to look at potential side effects and tolerability. And we'll be starting at the first cohort of patients on two milligrams, increasing to four and eight milligrams during the course of the trial. And it's quite a high burden trial for participants. They have to have a two hour infusion of the treatment once a week for six weeks. So we're going to obviously be trying to work out whether this is something that patients would tolerate. We'll be collecting information about safety, but also of course, pain scores, symptom control, quality of life, and analgesic use. We also have an embedded mechanistic study, particularly to look at endometrial function and the impact of the drug on that. So lastly, I'd just like to finish with a project which is really close to my heart, and any of you who are on social media hopefully have been following this project.
So this is a research project embedded in an endometriosis awareness campaign and a fundraising campaign to allow for the sustainability of this project. So the Endo 1000 project is a longitudinal cohort study. So we're aiming to recruit a thousand people with endometriosis associated symptoms and work with them really closely over a period of at least two years. During that two year period, we're going to get the patients to document their symptoms, their behaviors. So for example, if they take up self-management strategies, any treatments that they have, whether that be a medical management or surgical management, and information about any changes to their health. So we'll collect that information on a bespoke end 1000 app. We're going to get them to wear smart watches to look at their physical activity and their sleep patterns. And then we're going to get them to collect biological samples in their home.
So samples of saliva to look at their genetics, samples of blood to look at their inflammatory profile and samples of urine and feces to look at their microbiome and their metabolome. And the idea is that once we've collected all of this information, analyzed the samples that will collate the information and together with support from data scientists, we'll look for patterns using machine learning and AI that may help us with diagnosing endometriosis, but I think more importantly, help us predict response to existing medical and surgical treatments. So if you like moving much more towards precision medicine care for endometriosis, we also want to look at self-management strategies as well in this context. And if you're interested in hearing more about the study or reading more about the study, please scan the QR code if you're interested in supporting it as well. There's information there about how you can get involved.
So lastly, I'd just like to acknowledge, obviously this work is a team science approach, so I'm really grateful to all of my team in Edinburg, my collaborators, our funders, and of course the patients and their organizations who support us and like others, I'd just like to finish by inviting you all to the worlds Congress in endometriosis, which is being held in Sydney in May, which I think will be a great opportunity to hear about more emerging research and have these discussions like we've been having over the last couple of days. So thank you very much for your time.
