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Cancer protein ‘can be disarmed’

leukaemiaScientists have found a way to disarm a protein thought to play a key role in leukaemia and other cancers. The breakthrough raises hopes of a new type of therapy that could treat cancer and other diseases.

Previous attempts to neutralise the protein had failed, leading experts to conclude it was effectively “undruggable”.The study, carried out by the US Dana-Farber Cancer Institute, features in the journal Nature.

The protein is one of the body’s transcription factors, which turn genes on or off and set in motion genetic cascades that control how cells grow and develop. They also help fuel the growth of tumours.

The transcription factor targeted in the latest study is a protein called Notch. The gene responsible for manufacturing the protein is often damaged or mutated in patients with a form of blood cancer known as T-cell acute lymphoblastic leukaemia (ALL).

As a result the gene is switched on all the time, driving the uncontrolled cell growth characteristic of cancer. Similar abnormalities in Notch also underlie other cancers, including lung, ovarian, pancreatic and gastrointestinal tumours.

Examining the structure of Notch closely, the researchers isolated a potential weak spot in its structure. They employed a state-of-the-art technique using chemical braces to mould protein snippets called peptides into specific three dimensional shapes.

These “stapled” peptides are readily absorbed by cells, and are so tiny they can be deployed to alter gene regulation at specific sites. After designing and testing several synthetic stapled peptides, the researchers identified one that was able to disrupt Notch’s function.

When tested in mice it was found to limit the growth of cancer cells. Analysis showed that activity was depressed in genes both directly and indirectly controlled by Notch.

The researchers hope the technique could also be used to target other transcription factors with a similar structure. Researcher Professor Greg Verdine said: “Stapled peptides promise to significantly expand the range of what’s considered ‘druggable’.

“With our discovery, we’ve declared open season on transcription factors and other intractable drug targets.” Dr David Ish-Horowicz, head of developmental genetics at Cancer Research UK’s London Research Institute, described the research as “very interesting”.

He said: “There is already considerable work by scientists into ways to block Notch to try and reverse the effects of ALL, but the current drugs have some serious side-effects.

“This study describes the design of a new chemical that blocks the mechanism in a different way. “The new chemical has only been tested in mice so far, and so we don’t know how it will behave in humans.

“But, long term, it may lead to alternative drugs and better treatments for this kind of leukaemia and maybe other cancers.”

Source: BBC

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