Targeting the survival tactics of chronic myeloid leukaemia

Cancer cells will do anything to survive. Dr Vignir Helgason is exploiting weaknesses in their methods, to improve treatment for chronic myeloid leukaemia and help more people live for longer.

Chronic myeloid leukaemia (CML) is often treated with drugs called tyrosine kinase inhibitors, or TKIs. They are an effective treatment for many people, keeping their CML controlled and in remission.

However, TKI treatment does not get rid of all leukaemia cells and for some people CML may become resistant to treatment. Eventually, the cancer may progress from the slow-growing ‘chronic phase’ into the ‘blast phase’, where the cancer multiplies rapidly and becomes more aggressive.

Understanding how cancer cells resist treatments like TKIs is a key aim of research into CML. The goal is to find new options for people whose cancer becomes resistant, to keep their cancer at bay and ensure they can live for longer.

One researcher investigating how CML cells become drug-resistant is Dr Vignir Helgason at the University of Glasgow. Vignir has been studying a seemingly peculiar method a cancer cell can use to survive – eating itself.

Eating itself to survive

Autophagy – literally ‘eating oneself’ – might seem a desperate measure, but it’s something every cell does, and involves the cell destroying parts of its insides. “It is a housekeeping mechanism, in the sense that it keeps the cell clean and tidy by recycling waste,” Vignir explains. “But under stressful conditions, such as starvation or lack of nutrients, it becomes a survival mechanism.”

The cancer environment is inherently stressful. Energy-hungry cells multiplying out of control quickly use up the available resources, like oxygen and glucose and other nutrients. So cancer cells are known to increase autophagy to avoid starvation.

After Dr Vignir Helgason first moved to the University of Glasgow, he and his collaborators showed that CML cells increased autophagy to resist TKI treatment and survive. They speculated that blocking autophagy might make TKI drugs more effective.

Vignir and his colleagues tested this principle in a small clinical trial, using an anti-malarial drug called hydroxychloroquine. They found that combining it with a TKI was safe, but unfortunately the doses of hydroxychloroquine needed to block autophagy were far too high to give to people with CML. What was needed were more specific, more targeted ways to kill CML cells via blocking autophagy.

So Vignir applied to Leukaemia UK for a John Goldman Fellowship to continue this work, and was successful. “I was obviously very pleased that I managed to convince the panel that I was worthy of the fellowship, and that they saw the potential of the research.”

Stopping CML from coming back

During his John Goldman Fellowship, Vignir tested more specific autophagy inhibitors against leukaemia stem cells (LSCs). LSCs are the cells which are responsible for cancers like CML coming back. Killing LSCs is the ‘holy grail’ of any leukaemia treatment, but they are often very resistant to existing drugs.

Vignir and his team found that the LSCs have naturally high levels of autophagy, which meant the specific autophagy inhibitors were particularly effective against them. The drugs caused the LSCs to stop being stem cells and become more like mature leukaemia cells, which are much more easily killed by existing treatments like TKIs.

Vignir’s work confirmed that a combination of specific autophagy inhibitors and TKIs could make an effective treatment for people with CML, and help reduce the chances of their cancer coming back.

His autophagy research then led down a new avenue which could bring new treatments to people sooner.

Reusing existing drugs

When targeting LSCs, researchers need to make sure that the treatment doesn’t affect normal blood-producing haematopoietic stem cells (HSCs). To do this, Vignir looked at the differences between LSCs and HSCs in their metabolism – the chemical reactions happening inside all cells.

One key aspect of metabolism is nutrient uptake and energy production, which happens in mini-organs in the cell called mitochondria. Intriguingly, Vignir found that the mitochondria in LSCs make energy in a particular way which makes the cells vulnerable.

Vignir and his team tested whether targeting mitochondria in leukaemia stem cells might make an effective treatment. One drug which can stop mitochondria working properly is tigecycline – a cheap antibiotic drug used all over the world. Vignir and the team found that combining the TKI imatinib with tigecycline eradicates CML LSCs – both in the lab and in mice with CML. What’s more, the treatment leaves the normal blood stem cells relatively unscathed.

Vignir and his team have continued to search for existing drugs which could be used to target LSC metabolism, and have found anti-fungal drugs and anti-migraine treatments which have similar effects. ‘Repurposing’ existing drugs in this way could mean their research could progress to clinical trials much quicker than having to design a drug from scratch – meaning it could benefit people with CML much sooner.

Finding better treatments for CML – and other cancers

As for autophagy, Vignir and the team are now working with even more specific inhibitors of autophagy which block a molecule called ULK1. It’s possible that these ULK1 blockers and other autophagy inhibitors could also be used to treat other cancers, including bowel cancer and pancreatic cancer.

“So if we can provide the concept, provide the experimental data and support the development of these inhibitors, which Pharma can roll out for other cancers, that’s also a huge impact in the cancer field.”

Funding for this work has come from many sources, including a major £1.4 million award from Cancer Research UK – which Vignir believes is all thanks to the work carried out during the Leukaemia UK John Goldman Fellowship.

Vignir’s research began with trying to find better ways to treat CML, and overcome resistance to TKIs. His work has shown that combinations of drugs, centred around targeting autophagy and cancer cell metabolism, has great potential for targeting the leukaemia stem cells responsible for relapse.

His aim is to identify the best combinations of these treatments and get them into clinical trials – and ultimately keep CML at bay for longer or ideally, allow CML patients to stop treatment without a relapse. “There is more optimism about the potential use of autophagy inhibitors in combination with other cancer therapies. It’s really happening now.”

The difference Leukaemia UK funding has made

Since he was awarded the fellowship from Leukaemia UK, Vignir’s research and his team has expanded. Though funding for his work has always come from a variety of different sources, he believes the John Goldman Fellowship from Leukaemia UK played a crucial role in his early career. “It provides someone who is starting with this initial funding to establish themselves, this extra support at the fragile beginning, which they can build on.”

The fellowship has also been central to building his own team of researchers in Glasgow, who then will go on to do even more research in various related fields. Vignir believes the research will make a huge difference to people with CML.

“I can’t stress more the importance of research into leukaemia, because it clearly works”, he says. “There is progress being made every month in the lab, and some of this is translated into improvements in treatment. It happens very gradually, but I know it’s very important.”

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