Scientists have hailed “a new era for cancer therapeutics” as they take a step towards developing a new drug for treating a rare blood disorder, myeloid leukaemia.
University of Cambridge researchers have reported a new approach to cancer treatment that targets enzymes which play a key role in translating DNA into proteins – enzymes which can become mis-regulated, being produced in over-abundance and causing cancer.
The new study builds on research published in 2017 by Professor Tony Kouzarides at Cambridge, and could lead to a new class of cancer drugs for the 3,100 people diagnosed with the condition in the UK every year.
How does myeloid leukaemia develop?
Genetic code is written in DNA, but in order to generate proteins – molecules that are vital to the creation of cells and to overall the functioning of living organisms – the double-stranded DNA first needs to be converted into single strands, called RNA.
To do this, the body has enzymes that can 'read' the DNA and create the RNA. Enzymes can also make chemical changes to RNA, impacting the protein that is subsequently made.
While the body uses this process on a regular basis with no problems, if something does go wrong it can lead to cancer.
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Acute myeloid leukaemia (AML) is a particular cancer of the blood in which the over-production of a certain enzyme causes the bone marrow to produce abnormal white blood cells, known as myeloid cells.
The enzyme, called METTL3, changes the chemical structure of the RNA created by the body to make its white blood cells. So while white blood cells normally protect the body against infection and against the spread of tissue damage, in patients with AML, they have been altered and become abnormal.
The resulting cancer grows rapidly and aggressively, usually requiring immediate treatment, and affects both children and adults.
New research could halt cancer in its tracks
Kouzarides and his colleagues from the Milner Therapeutics Institute and the Gurdon Institute at the University of Cambridge showed in 2017 how the METTL3 enzyme played a key role in the development and maintenance of AML.
Now, the researchers have identified a drug-like molecule, STM2457, which can inhibit the cancer-causing action of METTL3.
In tissue cultured from individuals with AML and in mouse models of the disease, they showed that the drug was able to block the cancerous effect caused by over-expression of the enzyme.
“Until now, no-one has targeted this essential process as a way of fighting cancer," said Kouzarides. "This is the beginning of a new era for cancer therapeutics.”
Researchers tested the drug on cell lines derived from patients with AML and found that it significantly reduced the growth and proliferation of these cells.
According to the study, it also induced apoptosis – cell death – killing off the cancerous cells.
The researchers transplanted cells from patients with AML into immunocompromised mice to model the disease.
When treated with STM2457, they found that it impaired the proliferation and expansion of the transplanted cells and significantly prolonged the lifespan of the mice.
It also reduced the number of leukaemic cells in the mouse bone marrow and spleen, while showing no toxic side-effects, including no effect on body weight, the study suggests.
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“This is a brand-new field of research for cancer and the first drug-like molecule of its type to be developed," said Dr Konstantinos Tzelepis, from the Milner Therapeutics Institute at the University of Cambridge and the Wellcome Sanger Institute.
“Its success at killing leukaemia cells and prolonging the lifespans of our mice is very promising and we hope to begin clinical trials to test successor molecules in patients as early as next year.
“We also believe that this approach – of targeting these enzymes – could be used to treat a wide range of cancers, potentially offering us a new weapon in our arsenal against these terrible diseases.”
Kouzarides and colleagues at the University of Cambridge, Storm Therapeutics, a Cambridge spinout associated with his team, and the Wellcome Sanger Institute, published their research in the journal Nature. The research was supported by Cancer Research UK, the European Research Council, Wellcome, the Kay Kendall Leukaemia Fund, and Leukaemia UK.
