Ensuring the cure is nowhere near as bad as the disease

Chemotherapy can be debilitating for even the strongest of patients, but it can be particularly hard on children who have to cope with both an illness they barely understand as well as the often toxic effects of the treatment.

This is a field which particularly interests Dr Kyle Matchett of the Northern Ireland Centre for Stratified Medicine (NICSM) at Ulster University; he is leading a number of promising research projects aimed at finding new and kinder ways of treating children suffering from acute myeloid leukaemia (AML).

Matchett has focused on cancer research throughout his career, and his PhD looked at genetic involvement in ovarian cancers. Following that, he made an important discovery into how oestrogen is metabolised in certain forms of breast cancer, and this was published in the prestigious Cancer Research journal. That saw him win the inaugural Prof John Fitzpatrick prize awarded by the Irish Association for Cancer Research (IACR). He was also awarded EU FP7 programme funding for research into the role of erythropoietin (EPO) in breast cancer.

His focus then turned towards developing novel therapeutics for paediatric and adult acute myeloid leukaemia. “I wanted to do something more translational,” he recalls.

Real hair wigs

Matchett’s work on leukaemia has been recognised by a number of grants and awards internationally, including from the Little Princess Trust, a British charity which provides real hair wigs free of charge to children and young people who have lost their own hair due to cancer treatment and other conditions. In addition, the organisation has given grants of £2.8 million (€3.15 million) to childhood cancer research since its foundation in 2006.

“I was giving a talk at a conference and someone from the Little Princess Trust was there,” Matchett recalls. “They approached me and said they were really interested in what I was doing in finding a less toxic treatment for cancer and I was encouraged to apply for a grant.”

One of the attractions is that NRAS is one of most commonly mutated genes in AML

He took up his current role as a staff member at the School of Biomedical Sciences at Ulster University in October 2018, and is based at NICSM's Clinical Translational Research and Innovation Centre (C-TRIC).

He is currently leading three separate research projects. The first is what can best be described as a piece of detective work to find the Achilles’ heel vulnerability of the NRAS gene which has been found to have an involvement in a high proportion of AML cases.

“One of the attractions is that NRAS is one of most commonly mutated genes in AML,” Matchett explains. “This could apply to 30 to 40 per cent of AML cases.”

The project will see Matchett and his team take the genome of a blood cell and painstakingly knock out each gene until one is found that NRAS is dependent on. “We are going to go through every gene in the genome of the NRAS-mutated cell to see which one kills the cell,” he says.

Targeted therapies

The removal of that gene will therefore induce cell death. The next step will be to find drugs which target only that specific gene and use these to kill off the NRAS-mutated cells whilst leaving other cells unaffected. Targeted therapies like those are much less toxic and difficult on the patient than many of the alternatives.

“We will start work on this four- or five-year project early in the new year,” says Matchett.

We are looking at every gene in the genome to see which ones are changing in response to the drug

The second project is looking at existing drugs to see which ones have potential to be repurposed for the treatment of childhood AML. “We screened about 800 drugs already approved by the FDA and tested them on cells at very low concentrations,” he explains. “If we find a drug that’s really interesting, we can potentially get it to patients much more quickly because it’s already used for something else.”

The screen produced 38 hits for drugs which looked exciting and interesting and potentially effective for adult or childhood AML or both. Twelve of these are already used for blood cancers today while 14 were completely novel for this use.

‘Highly effective’

“We are working on a few of them and one of them is proving to be highly effective in childhood myeloid leukaemia in the lab,” says Matchett.

This also involves detective work. “We are looking at every gene in the genome to see which ones are changing in response to the drug and then looking for the mechanism involved. We hope to go for publication and clinical trials in possibly four or five years.”

The other study is into the BCL-2 gene, a member of the family of proteins that regulate cell death. The research is looking at Venetoclax, a BCL-2 inhibitor used to treat chronic lymphocytic leukaemia which has been approved for elderly patients with advanced AML. The aim is to find another drug which can be used in partnership with Venetoclax to make it more effective.

“The focus is always on the patient,” Matchett concludes. “It’s fantastic to make breakthroughs in the lab, but the focus has to be completely on the patient.”

For more information contact Ulster University at enquiry@ulster.ac.uk