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‘New era for cancer therapeutics’ opens with acute myeloid leukaemia drug candidate, says Cambridge’s Prof Tony Kouzarides

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Progress in developing a potential new drug for treating a form of leukaemia has been hailed as the “beginning of a new era for cancer therapeutics” by Cambridge scientists.

For the first time, the process in which our DNA is translated into RNA using enzymes has been targeted as a method of tackling cancer - and clinical trials in patients could begin as early as next year.

At The Gurdon Institute are, from left, Tony Kouzarides, STORM Therapeutics CEO Keith Blundy, and Eric Miska. Picture: Keith Heppell
At The Gurdon Institute are, from left, Tony Kouzarides, STORM Therapeutics CEO Keith Blundy, and Eric Miska. Picture: Keith Heppell

Prof Tony Kouzarides, from the Milner Therapeutics Institute and the Gurdon Institute at the University of Cambridge, and the team at STORM Therapeutics, the biotechnology company he founded, collaborated with the Wellcome Sanger Institute to publish their work in Nature on Monday April 26.

It showed how a drug-like molecule, known as STM2457, had been shown to inhibit the action of an enzyme that plays a key role in the development and maintenance of acute myeloid leukaemia (AML), a rare blood disorder

About 3,100 people are diagnosed with the condition each year in the UK - the majority of whom are over 65 years old. The disease is a cancer of the blood in which bone marrow produces abnormal white blood cells known as myeloid cells, which normally protect the body against infection and against the spread of tissue damage.

AML proceeds rapidly and aggressively, typically requiring immediate treatment. It is an example of how enzymes can sometimes become misregulated and over-abundant. Enzymes usually play a key role in protein production.

Prof Kouzarides explained: “Proteins are essential for our bodies to function and are produced by a process that involves translating our DNA into RNA using enzymes.

“Sometimes, this process can go awry with potentially devastating consequences for human health. Until now, no one has targeted this essential process as a way of fighting cancer. This is the beginning of a new era for cancer therapeutics.”

A team led by Prof Kouzarides showed in 2017 that an enzyme known as METTL3, plays a key role in the development and maintenance of AML, when it becomes over-expressed in certain cell types.

Now, in tissue cultured from individuals with AML and in mouse models of the disease, the researchers have showed that their drug was able to block the cancerous effect caused by this over-production of the enzyme.

Prof Tony Kouzarides, director of the Milner Therapeutics Institute. Picture: Keith Heppell
Prof Tony Kouzarides, director of the Milner Therapeutics Institute. Picture: Keith Heppell

They tested the drug on cell lines derived from patients with AML and found it significantly reduced the growth and proliferation of these cells, while also inducing apoptosis, or cell death, killing off the cancerous cells.

They also transplanted cells from patients with AML into immunocompromised mice to model the disease.

When they were treated with STM2457, it impaired the proliferation and expansion of the transplanted cells and significantly prolonged the lifespan of the mice.

The number of leukaemic cells in the mouse bone marrow and spleen were reduced, with no toxic side effects shown and no effect on body weight.

Dr Konstantinos Tzelepis, from the Milner Therapeutics Institute and Wellcome Sanger Institute, said: “This is a brand-new field of research for cancer and the first drug-like molecule of its type to be developed.

“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.”

Keith Blundy, CEO of STORM Therapeutics, said: “I am delighted to see the publication of our ground-breaking research on STM2457 in a world-leading journal. We are excited to be leading the field.”

While the publication focused on STM2457, STORM has already gone further, announcing last October that it has selected a newer compound - STC-15 - as its first-in-class oral drug candidate targeting this enzyme for development towards the first in-human clinical studies in 2022.

STORM is a University of Cambridge spin-out supported by Cambridge Enterprise and specialises in translating research in RNA epigenetics into the discovery of drugs to treat cancer and other diseases.

The company won Biotech Start-up of the Year at the 2017

Cambridge Independent

Science and Technology Awards.

Prof Kouzarides said: “At STORM we are proud to be leading the field in development of drugs targeting RNA epigenetics and are making rapid progress. This paper has provided comprehensive proof of concept that targeting RNA modifying enzymes represents a promising new avenue for anti-cancer therapy and confirms the findings in our 2017 Nature paper made using genetic approaches.”

Michelle Mitchell, chief executive of Cancer Research UK, said: “This work is yet another example of how our researchers strive to get new cancer treatments into the clinic and improve outcomes for cancer patients.

“Acute myeloid leukaemia is an aggressive form of cancer which grows rapidly. Treatment is required as soon as possible after diagnosis, which means research like this can't come soon enough.

“We look forward to seeing the outcomes of the phase 1 trial and the benefits it may have for AML sufferers and their families in the future.”

The research was supported by Cancer Research UK, the European Research Council, Wellcome, the Kay Kendall Leukaemia Fund, and Leukaemia UK.

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