How we can reduce cancer risk in IBD patients

Inflammatory bowel disease (IBD) is an umbrella term mainly used to describe disorders that cause chronic inflammation of your digestive system. Its most often used to refer to two conditions: Crohn’s disease and ulcerative colitis.

Under normal circumstances, inflammation is a good thing. For example, if you have an infection, inflammation is a sign that your immune system is fighting off the bacteria or virus that’s caused it.

However, when inflammation persists for long periods of time without cause, like in IBD, it can cause symptoms like pain, cramps or swelling in the tummy, recurring or bloody diarrhoea, and extreme tiredness.

Inflammation is also linked to cancer, and people with IBD have an increased risk of developing bowel cancer than those without it.

Therefore, if we can find ways to prevent or reduce the inflammation caused by IBD, we can in theory kill two birds with one stone. We could treat this debilitating condition and reduce the risk and incidence of bowel cancer amongst these people simultaneously.

The problem here is that current treatments for IBD aren’t always effective, and often involve high doses of drugs such as steroids, that suppress the immune system, leaving patients susceptible to infections, or in some cases, several other types of cancer outside of the bowel.

So, if we’re to reduce the risk of bowel cancer in people with IBD, we’re going to have to find a more effective treatment.

And Dr Maike de la Roche, group leader at our Cambridge Institute, and her team’s research, funded by us and recently published in Nature Communications, may have done just that.

IBD is a huge problem in healthcare because it’s chronic, lifelong and really debilitating, and the incidence is rising.

In IBD patients, cancer can develop really, really fast. And so currently, we have patients that are not only extremely sick for a long time with IBD, but a lot of them are at high risk of developing cancer.

– Dr Maike de la Roche, group leader at our Cambridge Institute

Targeting the root cause

There is no cure for IBD, and we don’t know exactly what causes it, though we do know it is down to a combination of factors, including genetics and problems with the immune system.

One of these problems with the immune system involves a specific type of immune cells called T-helper 17 (Th17) cells.

Th17 cells produce a type of molecule called a cytokine, which causes inflammation in the body. Normally, this inflammation begins as part of a normal immune response to infections, but in IBD the cytokine produced by Th17 cells, called IL-17, results in the chronic inflammation we see in the gut.

“Th17 cells were discovered to be the one of the main drivers of IBD a long time ago, so there’s a huge interest in finding inhibitors of the pathways that lead to the development of these cells,” says de la Roche.

T-helper cells come in several types, like Th1, Th2, and Th17 for example. Each type of these cells has a slightly different function, but they all start out as the same type of cell, known as a naïve T-cell.

The differentiation into one of these specific types happens later on and is activated by an ancient signalling pathway in our bodies called Hedgehog signalling.

What’s Hedgehog signalling?

Hedgehog signalling is an essential pathway in developmental biology and occurs in all animals that have a symmetrical left and right side, like humans.

It is the pathway that allows the body to form correctly as an embryo, ensuring that the parts of the body meant to be on the left, right, front, back, top and bottom of the body are all growing in the right place.

But later on, as de le Roche’s new research has revealed, Hedgehog signalling plays a role in the immune system. It’s how cells like naïve T-cells ‘know’ what type of cell they should become.

Therefore, if specific Hedgehog signals can be inhibited, we can prevent naïve T-cells from differentiating into one particular type of cell, like Th-17 cells. And that’s exactly what we want to do in people with IBD.

That may sound like we’d need to try and develop a completely new treatment, which is a very time consuming, not to mention expensive, process.

But the good news is a drug that inhibits Hedgehog signalling already exists. Even better, this drug, called vismodegib, is already approved for use on the NHS to treat a type of skin cancer called basal cell carcinoma.

Old drugs; new uses

So, once the team had worked out that Hedgehog signalling was responsible for the generation of Th17 cells, and found a drug that could inhibit that pathway, the next step was to test whether it would actually work in practice.

“What we did then is we used a model of IBD in mice,” de la Roche tells us.

“We took the Hedgehog inhibitor that’s already used in the clinic and approved in the NHS, and gave these mice either that, or a placebo.

“And what we found is that the mice that had the inhibitor were doing much better. Their gut was not that sick, and they didn’t produce so many of these disease-causing Th17 cells in the gut.”

When treated with the Hedgehog inhibitor, the condition of these mice improved dramatically.

And whilst at this stage its only in mice, this repurposed treatment could be hugely beneficial to people living with IBD.

“We now think that the discovery that the Hedgehog pathway is important for making Th17 cells, and the knowledge that we can treat IBD in mice, might be very useful for the clinic,” de la Roche tells us.

The potential of Hedgehog inhibitors

Unfortunately, Hedgehog inhibitors can’t be used as a permanent treatment for IBD because they would impact on other cell types, which could be harmful to the patient.

However, de la Roche and her team think that they could be used to slow down the progression of the disease if the treatment was given over short, regular periods.

This could be particularly effective in children or young people with IBD, before the cells in the bowel become permanently damaged by inflammation.

And the applications of this treatment might not stop there.

“We want to do a little bit more work on this, and we want to think a little bit broader too.

“Because Th17 cells are the drivers of IBD, but they are also drivers of other many other autoimmune diseases, like rheumatoid arthritis or psoriasis, which are also debilitating for the patients and maybe they would benefit from this treatment as well.”

So, whilst Hedgehog inhibitors might not represent the cure to IBD in the long term, their efficacy in treating inflammation makes them great candidates for lowering the risk of bowel cancer in IBD patients and opens up a whole host of possibilities for the treatment of autoimmune diseases.

Jacob

Dr Maike de la Roche

Maike de la Roche is a group leader at the Cancer Research UK Cambridge Institute. She completed her veterinary degree in Germany before pursuing her interest in immunology. Her group’s research aims to understand the roles of the Hedgehog signalling pathway in immune cells, with the long-term goal of modulating these signals to improve immune responses in the context of cancer, infection, autoimmunity and vaccination.