Scientists ushered in “a new era for cancer therapeutics” when they took a step towards developing a new drug to treat a rare blood disorder called myeloid leukemia.
Cambridge University researchers have described a new approach to cancer treatment that targets enzymes that play a key role in converting DNA into proteins and which could lead to a new class of cancer drugs.
Genetic code is written in DNA, but in order to make proteins – molecules vital to the functioning of living organisms – DNA must first be converted into RNA.
The production of proteins is controlled by enzymes that cause chemical changes to the RNA.
Occasionally, however, these enzymes are improperly regulated and produced in abundance.
In a study published in 2017, a team led by Professor Tony Kouzarides of the Milner Therapeutics Institute and the University of Cambridge’s Gurdon Institute showed how one such enzyme, METTL3, plays a key role in the development and maintenance of acute myeloid leukemia.
It is overproduced in certain cell types, which leads to disease.
Acute myeloid leukemia (AML) is a blood cancer in which the bone marrow produces abnormal white blood cells known as myeloid cells.
These usually protect the body from infection and from the spread of tissue damage.
AML grows rapidly and aggressively, usually requires immediate treatment, and affects both children and adults.
Around 3,100 people in the UK are diagnosed with the disease each year, most of whom are over 65 years of age.
Now, Prof. Kouzarides and colleagues from the University of Cambridge, Storm Therapeutics, a Cambridge spin-out associated with his team, and the Wellcome Sanger Institute have identified a drug-like molecule, STM2457, that can inhibit the effects of METTL3.
In tissue cultured by people with AML and in mouse models of the disease, they showed that the drug could block the cancer effects caused by overexpression of the enzyme.
Prof. Kouzarides said: “So far, no one has targeted this essential process as a means of combating cancer. This is the beginning of a new era for cancer therapeutics. “
The researchers tested the drug on cell lines from patients with AML and found that it significantly reduced the growth and proliferation of these cells.
According to the study published in the journal Nature, it also induced apoptosis – cell death – and killed the cancer 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 extended the lifespan of the mice.
It also reduced the number of leukemia cells in the mouse bone marrow and spleen while showing no toxic side effects, including no effect on body weight, the study said.
Dr. Konstantinos Tzelepis of the University of Cambridge’s Milner Therapeutics Institute and the Wellcome Sanger Institute said, “This is a brand new area of research in cancer and the first drug-like molecule of its kind to be developed.
“The success in killing leukemia cells and extending the lifespan 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 – targeting these enzymes – could be used to treat a wide variety of cancers, potentially offering us a new weapon in our arsenal against these terrible diseases.”
The research was supported by Cancer Research UK, the European Research Council, Wellcome, the Kay Kendall Leukemia Fund and Leukemia UK.