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Potential new drugs to help both cancer and diabetes patients

With Worldwide Cancer Research funding, scientists have created new molecules that they hope can become drugs for both cancer and diabetes. Their findings are published this week in the Journal of Medicinal Chemistry.

The chemical compounds reduce the growth and proliferation of colon (bowel) cancer cells, and increase glucose uptake into fat cells meaning they could also help diabetes patients manage their disease.

The research team from Cancer Research at Bath (CR@B), working with colleagues at the University of Oulu in Finland, designed and made two molecules to specifically stick to and switch off enzymes called tankyrases, which are involved in an important cellular process called Wnt/β-catenin signalling.

Nearly all bowel cancers, and several other cancers, are encouraged to grow through a malfunction of the Wnt signalling system, where it is permanently switched “on”, like a foot on an accelerator. As the enzyme tankyrase is an important part of the Wnt system, the researchers realised switching it off could block the Wnt/β-catenin signalling pathway, like taking the foot off the accelerator, and stop the bowel cancer cells from growing. High levels of Wnt/β-catenin signalling is also observed in many inflammatory diseases including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. In lab experiments their custom built tankyrase inhibitors significantly reduced Wnt/β-catenin signalling and slowed down growth and proliferation of bowel cancer cells.

They also showed that targeting tankyrases results in increased uptake of glucose into fat cells. Potent and selective inhibition of tankyrases could therefore also be useful for patients with Type II diabetes to help manage their disease, and possibly reduce the amount of insulin administered to patients with Type I diabetes.

Dr Amit Nathubhai, from the University of Bath’s Department of Pharmacy and Pharmacology, said: “It’s early days but our new set of molecules are a great starting point towards the development of new drugs that target the tankyrases and Wnt signalling to treat cancer, diabetes and inflammatory diseases.

“We have shown they are potent and selective and we see enhanced glucose uptake and a marked reduction of bowel cancer cell proliferation using our molecules.

“The next phase of our research is to further optimise our molecules and evaluate them further in other biological models of diabetes and obesity. We hope to reveal the underlying mechanism(s) that link cancer, fibrosis, diabetes and obesity, which remains unclear.”

The team plan to develop 3D models using cells from patients with diseases such as bowel cancer, prostate cancer, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis to better understand the effects their Tankyrase/Wnt signalling inhibitors may have on these conditions.

Better treatment of bowel and gastic cancers could benefit over 4,500 patients and save the NHS £24 million.

The research was funded by grants from Worldwide Cancer Research, Medical Research Council and the Academy of Finland.

This article was first published by the University of Bath.

Photo - The new molecules bind to tankyrase enzymes. Credit: Dr Lari Lehtiö

A new way to prevent bowel cancer?

Scientists have found a potentially new way to help prevent bowel cancer before it starts.

The findings, published in Nature Communications earlier this year, suggest that blocking a molecule called BCL-2 in bowel cells before they become fully cancerous might derail these cells from their destructive path.

Worldwide Cancer Research funded scientist Dr Louis Vermeulen and his team in the Netherlands helped lead the research, together with Dr Douglas Winton at the University of Cambridge.

“With this new research we show for the first time that inhibiting BCL-2 prevents formation of bowel cancer in the lab.” Said Dr Vermeulen.

Now the researchers want to test their findings further. “The next stage is to validate our findings in human cells. We then want to see if we can develop a way of using BCL-2 inhibitors to help individuals who are at a higher risk of developing bowel cancer because of their genetic predisposition.”

“All in all we expect it will take at least another 5 to 10 years before we know if our strategy will really pay off; but this latest research is certainly an exciting start.”

Read more about this new research on our blog.

Studying the stem cells involved in the start of bowel cancer

Stem cells are the engine room of a tissue - unique starter cells with the potential to develop into a whole host of new cell types. The stem cells in the gut work hard, because the normal intestine replaces it's entire cell lining every 5-7 days. Strict control over these stem cells is therefore vital and is provided by chemical messages secreted by cells surrounding the stem cell. If this control is lost in the bowel, new growths such as colonic polyps and cancers can arise.

Dr Leedham explains “It has long been believed that the accumulation of mutations in the DNA of the stem cell itself was the sole cause of this loss of control. However, we have shown that misregulation of the chemical messages can also cause aberrant stem cell activity. It can even induce other cells to behave like stem cells. We believe that it is this alternative mechanism that is responsible for tumour development in some types of polyps and cancers which may explain differences in the way some cancers behave, including their response to treatments.

In this project a whole team of clinicians and scientists are testing this hypothesis using biological mouse models to mimic the changes seen in early tumour formation. We believe this work will allow us to explore the complex and fascinating relationship between a cancer cell and its surrounding environment and lead to a better understanding of tumour development and growth. It may also help determine whether measuring pathway disruption may predict a patient's risk of cancer and highlight potential target areas for anti-cancer treatment.”

Taking two new chemotherapy drugs towards clinical trials

Dr Juan Carlos Morales is trying to develop new and improved treatments for bowel cancer. He told us “Our aim is to evaluate the scope of two potential chemotherapy drugs, MAR-308 and MAR-320, designed to work against a new cancer drug target called a DNA G-quadruplex. Preliminary studies of the drugs have shown an extremely high efficiency against breast and bowel cancers grown in the lab. The drugs also showed very low toxicity against healthy cells. This high selectivity could reduce their side effects if given to patients. The selectivity seems to be due to the entrance of the drugs through glucose transporters that are highly expressed on tumour cells but not healthy ones.

We propose to translate these lab based findings into a potential cancer treatment by studying the effects of the drugs in animal models of bowel cancer. Furthermore, we will evaluate whether they have the right chemical properties to be a future drug. Finally, we will study in detail the exact way MAR-308 and MAR-320 work inside cells in order to redesign these compounds and increase their chances of success.”

Breaking down bowel cancer

In a ground breaking decision leading experts recently agreed that bowel cancer should now be considered as four entirely distinct diseases.

But what does this mean for patients? In our latest blog post we talk to Worldwide Cancer Research funded scientist and clinician Dr Louis Vermeulen, who was one of the experts involved in this key piece of work.

“Until now we have been largely diagnosing and treating bowel cancer as one disease, but this classification really helps show that this is not the case.” Says Dr Vermeulen. “With this new clearer picture of bowel cancer I hope it will become easier to generate new treatments. If an experimental treatment only works in some patients there is now a clear basis for why this is likely to be the case, and the researchers shouldn’t consider it a failure.” “Ultimately I expect it will really help us and other scientists develop new therapies which can effectively treat all bowel cancer subtypes, even the types which are most aggressive and resistant to our current therapies. This will take time but the recognition of the various distinct diseases is a real breakthrough.”

“The funding from Worldwide Cancer Research really helped ensure we were able to take part and contribute meaningfully to this important decision.” Dr Louis Vermeulen is a lab leader at the Academisch Medisch Centrum in the Netherlands. You can read our interview with Dr Vermeulen in full on our blog.

Read about his latest project with Worldwide Cancer Research here.

Search our database of latest research projects.

 

Can we stop bowel cancer before it starts?

April is Bowel Cancer Awareness Month and throughout the month we’ll be focusing on some of the hottest  most talked about topics in bowel cancer research.

Bowel cancer is the world’s third most common cancer and it's also one of the most preventable. Over half of all bowel cancer cases in the UK could be prevented each year and the vast majority of these avoidable cases are linked to lifestyle. But what about drugs? Chemoprevention research focuses on finding and developing drugs to prevent cancer before it starts. And when you're talking about chemoprevention of bowel cancer, most people think of aspirin.

The idea that aspirin can prevent bowel cancer has been around for years. So what does the latest research show? Our first blog post for Bowel Cancer Awareness Month asks if aspirin really can prevent bowel cancer. We also look at other simple ways to help reduce your bowel cancer risk.

You can also read our recent blog about processed meat and bowel cancer risk here.

See our current and past bowel cancer research projects here.

 

Learning how bowel stem cells develop into tumours

All normal tissues within our bodies have a tiny population of stem cells. Stem cells are a kind of 'starter cell' which can multiply and change into a wide variety of other cells depending on where they are located in the body. Stem cells from the bowel have been isolated in order to study their role in bowel cancer, thanks to a molecule on the surface of these stem cells. This molecule can also be found within the tumour in bowel cancers.

Professor Batlle and his research group have recently discovered that the types of genes that can be found in bowel stem cells predict whether patients with bowel cancer will relapse after treatment. These results point towards a link between bowel stem cells and bowel cancer. With the new Worldwide Cancer Research grant Professor Batlle will analyse and compare normal bowel stem cells and bowel cancer stem cells to learn how new tumours occur after treatment, or when it spreads to different parts of the body.

Investigating the genes involved in age-related cancer risk in Lynch Syndrome

When people talk about a person's risk of developing cancer, genes are often a factor. Sometimes it is only one specific gene that makes the difference, other times it is many small changes to lots of genes. DNA is constantly being unzipped and copied in order to produce millions of new cells each day, but this means that there are many opportunities for the biological assembly line, which makes new DNA, to be broken.

This is called mismatch, like a shirt where the buttons are not lined up; the result is not the same as when the shirt is buttoned up correctly. A series of genes exist to fix these mismatches. Lynch Syndrome is a disorder where the genes that normally fix these mismatches are no longer able to do their job. People who have Lynch Syndrome are much more likely to get cancer, but the age at which this happens varies greatly from one person to the next. While people with Lynch Syndrome experience extensive surveillance to catch potential cancers early, both the patients and healthcare professionals would benefit if it was possible to predict at what age people would be more likely to get cancer.

Professor Dunlop has collected samples from a large group of people who suffer from Lynch Syndrome and will use his Worldwide Cancer Research grant to test for genes that could control the age at which people might develop cancer. This will also be compared with samples from the general population and be used to develop age-specific risk prediction, to be used for the clinical management of Lynch Syndrome.

The role of the MYO5B protein in bowel cancer

The cells that line our intestines have lots of finger-like extensions that help us absorb food, which make the cells look like a brush. This brush-like border disappears as tumours in the bowel grow, although scientists think that this is a result of the tumour rather than a cause. MYO5B is a protein that helps this brush border to take shape. Research has recently shown that, when this protein is no longer present in these cells, the brush border is damaged. The gene for the MYO5B protein is found in the area of a chromosome that is usually missing in bowel cancer. The MYO5B protein is also linked to tumour formation in stomach cancer and acute lymphoblastic leukaemia.

Dr Arango and his team have found that in cases of bowel cancer, a part of the MYO5B gene has an additional molecule attached to it, which affects how the gene works. They will use their Worldwide Cancer Research grant to study how MYO5B affects cancer progression, by studying the genetic changes that delete the protein from bowel cancer cells, and looking at how the presence of the protein might stop tumours from growing. They also plan to study the link between MYO5B and survival of patients at different stages of the disease. This work will hopefully teach us more about what happens within cancer cells at the early stage of development and to see whether the presence or absence of the MYO5B protein can be used as a way to test for bowel cancer.

Understanding the link between obesity, the immune system and bowel cancer

Bowel cancer is one of the most common types of cancer and around 1.24 million new cases were diagnosed around the world in 2008. There is an established link between obesity, the immune system and bowel cancer. Recent evidence has suggested that the molecule leptin, produced by fat cells, could be involved in this link between obesity and bowel cancer as its levels are higher in obese people and it is reported to encourage the growth of bowel cancer. The activity of the immune system is controlled by specific immune system cells called dendritic cells which determine whether or not the immune system responds to cancer cells. These dendritic cells also make leptin and they can carry certain types of fat around the body.

Professor Knight is using her Worldwide Cancer Research grant to study a pre-cancerous condition called familial adenomatous polyposis (FAP) which goes on to develop into bowel cancer. It is not currently known what role leptin plays in FAP and what type of fat that the dendritic cells carry. She will therefore be investigating how obesity, leptin, fat and dendritic cells are all involved in the progression from FAP to bowel cancer. Professor Knight hopes that her results could help with the development of a therapy that could potentially prevent bowel cancer by increasing the immune system's ability to fend off the disease before the onset of cancer.