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Could drug repurposing be the key to successful treatment of endometriosis?

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Published: 25 Aug 2021
By Sarah Hesse

The chances are that you know someone, or multiple people living with endometriosis. But what is this chronic condition that affects at least 1 in 10 people assigned female at birth? Endometriosis is the growth of tissue similar to the uterine lining on the pelvic peritoneum – a protective layer covering all organs and walls of the pelvis. Sometimes these lesions can even grow through the protective layer into the walls of the organs. Symptoms can vary drastically between people from debilitating periods, that are painful, heavy or highly irregular, over  constipation,  diarrhoea, bloating, pain with or after sex and pain when passing urine, up to infertility, fatigue and depression. Currently, the only way to definitively diagnose the disease is by surgery and patients frequently have to wait almost a decade for a diagnosis – often doctors dismiss their symptoms for years as part of a ‘normal period’. Problematically, even then treatment options are usually not helpful in the long-term and can be quite invasive.

The development of new treatments from scratch usually takes years. Scientists have to identify a drug target and complete extensive in vitro and in vivo preclinical studies before a compound can even be tested in small clinical studies in humans. Drug repurposing can provide a great opportunity to speed this process up. Repurposed drugs have already passed safety checks and have been thoroughly tested and used to treat other health conditions. If a research team identify a specific target in a disease and then finds that a pre-developed drug can target it, they could be in luck. In the case of dichloroacetate (DCA) for the treatment of endometriosis, researchers are already thinking about repurposing a drug candidate that is still in clinical trials for tumour cells.

But what do tumour cells have to do with endometriosis? Researchers realised that in patients with endometriosis, cells of the protective peritoneal lining – peritoneal mesothelial cells – have an altered metabolism like most solid tumours (Young et al., 2017; Horne et al., 2019). Usually, cells undergo glycolysis in the absence of oxygen, or glucose oxidation in the presence of oxygen. Regardless, glucose first gets converted to pyruvate. Usually, in the absence of oxygen, glycolysis takes place with pyruvate yielding low energy levels and lactate. In the presence of oxygen, the enzyme pyruvate dehydrogenase encourages entry of pyruvate into the mitochondria starting the process called glucose oxidation, yielding much more energy.

However, similar to some cancer types, this process can be disrupted in peritoneal mesothelial cells of people with endometriosis. Even in the presence of oxygen, glycolysis takes place yielding much less energy than the alternative process. To make up for the lower energy production, enzymes have to convert more glucose, which is used at much higher rates. In line with this, a research team from Edinburgh found lower enzymatic activity of pyruvate dehydrogenase, which activates glucose oxidation, as well as higher overall levels of glycolysis and lactate secretion from peritoneal mesothelial cells of patients with endometriosis (see Figure 1). Interestingly, in tumour cells, lactate is thought to drive immune suppression and angiogenesis. In endometriosis, lactate could possibly have similar effects on the growth of lesions. In these cancer cells, DCA shifts the cell metabolism back to a more normal state. DCA works by inhibiting pyruvate dehydrogenase kinase (PDK), which usually keeps pyruvate dehydrogenase (PDH) in its phosphorylated, inactive state. Therefore, DCA allows more active PDH to be present, enabling conversion of pyruvate to Acetyl-CoA. This ultimately encourages mitochondria based glucose oxidation.

In the lab, the research team then grew peritoneal mesothelial cells from endometriosis patients in co-culture with an endometrial stromal cell line. This cell line consists of the cells that normally make up the largest proportion of cells in the uterine lining. When DCA was added to the co-culture, the amount of lactate and growth of endometrial cells were reduced. Even more excitingly, in an endometriosis mouse model, treatment with DCA reduced the size of the lesions.

Figure-1.PNG

Figure 1. In patients with endometriosis, glucose is more frequently than usual converted to lactate despite the presence of oxygen via glycolysis. Preclinical studies suggest that treatment with DCA can reduce the amount of lactate produced by kickstarting the enzyme pyruvate dehydrogenase and hence glucose oxidation in mitochondria.

Encouraged by these promising preclinical results, scientists are currently running a small exploratory clinical trial with 30 participants (Leow et al., 2021; ClinicalTrials.gov identifier NCT04046081). Results are expected in 2021.

DCA has been used in clinical trials for different conditions for several decades, which means that approval for its use in endometriosis might be granted a bit quicker than for a new drug. Though this will depend on how possible side effects compare to the benefits DCA could provide for anyone living with endometriosis. This is an exciting example of how drug repurposing can begin even whilst a drug is still in clinical trials for other conditions, thereby increasing both the potential uses of a specific compound and how fast it can potentially benefit patients. Drug repurposing could mean enormous savings in both time and cost, which are currently a major limiting factor in drugs actually reaching the market and being able to reduce patient suffering. Long term this could also mean less abandoned drug research products caused by ineffectiveness in their target condition and more so-called orphan drugs, which are drugs for conditions so rare that there is little financial incentive to invest in developing treatments for them. Overall, drug repurposing holds the opportunity to help patients with conditions that are currently underfunded and underresearched, such as in the case of endometriosis.

If you are affected by endometriosis or think that someone close to you might be, Endometriosis UK has great resources ranging from getting diagnosed, local support groups throughout the UK, treatment options and a helpline.

Short interview with Professor Andrew Horne, a pelvic pain and endometriosis specialist based in Edinburgh

Why is research on endometriosis important?

Endometriosis is a chronic and incurable condition associated with debilitating pain and subfertility that affects approximately 176 million women worldwide. Despite being such a common condition, there is an estimated diagnostic delay of 7-8 years, and available treatments are not always helpful and can come with risks or side effects. More research is urgently needed to identify a non-invasive test for endometriosis and better treatments.

What can we all do to help people living with endometriosis?

There are steps that we can take to significantly reduce diagnosis times and improve the treatments women are offered. We can raise awareness of menstrual health and what’s normal, so no-one puts up with years of pain and other problems thinking “it’s normal”. We can also fundraise to support research so we find some answers about what causes endometriosis and how it can be treated effectively.

Could you provide an update on the clinical trial with DCA or is it still too early to tell?

We have completed recruitment to the DCA trial, but we will not be able to analyse the data for another three months when the last participant has completed the trial.

Is there anything else that you think would be important to mention?

I strongly believe that research efforts are more likely to succeed now that endometriosis researchers have started to work with non-traditional research partners, such as pain biologists/ specialists and data scientists, to better understand this complex disorder so that new knowledge can be applied for patient benefit.

 

Quotes from people living with endometriosis

What do you wish other people knew about endometriosis?

“I wish that people, especially doctors and medical staff, had more knowledge of endometriosis and the impact it can have on someone’s life. I wish people knew that it isn’t just ‘period pains’ or ‘IBS’ and would investigate further rather than prescribing painkillers and sending you back home in pain again.”

“I wish other people could see my pain. I find it hard when people chat away to me and I nod and smile whilst I’m in agony. I find it hard that people don’t notice or can’t see how much pain I’m in.”

“I am a single mum of two small children so as you can imagine, I am on the go non-stop. Endo affects my everyday life in all aspects whether it is having to suddenly stop and fall to the ground with shooting pains in my belly and back whilst on a walk or not being able to run around in the garden and chase my kids because the pain is so horrendous that I can barely walk never mind run.”

“I wish people knew that this is a whole body disease. It’s not just a bad period…the biggest thing for me however, is that very young girls who have had their periods can have this condition just as much as older women. I have suffered since the age of 10 and was told I couldn’t have the condition at that age, and now I wish someone had taught me in primary school/high school that this could be what’s wrong with me. If I’d known, I wouldn’t have spent my entire academic life feeling like there was no way out of how awful I was feeling.”

“I wish doctors would take women more seriously and not just brush off “women’s problems”. Actually doing proper investigations rather than prescribing some painkillers, yoga and meditation would also help to get people diagnosed more quickly.”

How does endometriosis affect your daily life?

“It’s not knowing what to actually expect each day.”

“I was lucky enough to have twins via IVF in 2014 with my symptoms returning within four weeks. Please tell them having children does NOT cure endo, if anything my symptoms intensified. I eventually had a hysterectomy in 2015 only for endo to return with a vengeance and now I’m awaiting further surgery but they aren't even sure if it will make a difference because of where it is. So I would like to highlight that hysterectomy is in no way a cure.”

“I think the hardest part about living with endometriosis is it’s present throughout every moment of your life, even when you try not to let it become a part of your identity. It’s the type of clothes you put on in the morning to ensure you can be comfortable, when maybe the uncomfortable outfit made you feel more powerful…most of all I think it’s subconsciously doing all of these things quietly and under the radar so that no one thinks you’re a nuisance, because the guilt of letting people down even slightly has scarred you from all the times you’ve had to reschedule or cancel. The pain is always there, but the loneliness of this condition can be just as, if not more, painful.”

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Published: 25 Aug 2021
By Sarah Hesse

About the author

Sarah Hesse


 

Sarah is a PhD student at the Centre for Translational Pharmacology, University of Glasgow, supervised by Sophie Bradley and Andrew Tobin. Her project focuses on targeting the M1 muscarinic receptor in neurodegeneration. Outside of juggling endometriosis flare ups with her project, Sarah enjoys public engagement activities and is involved in equality, diversity and inclusion work within her research institute. Sarah is also an editorial board member of Pharmacology Matters.

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