Health and Medicine
PUBLISHED
A class of anti-cancer drugs that have worked great in the lab only to be disappointing in human trials may be about to get a renaissance, as scientists believe they may have figured out why they haven't fulfilled their potential. With this knowledge, it’s possible some tweaks could be made to future approaches to achieve better clinical outcomes.
The rest of this article is behind a paywall. Please sign in or subscribe to access the full content.The drugs at the center of all this are called BET inhibitors. They target bromodomain and extra-terminal domain (BET) proteins, which many cancer cells rely on to help activate the oncogenes that drive their uncontrolled growth. Therefore, blocking the activity of these proteins should theoretically help put the reins on cancer progression.
Over the last decade and more, cancer scientists saw that this checked out – at least, it did in the lab. Where BET inhibitors would often show success at slowing down tumors in preclinical trials, once they were tried in the human body it was a different story. Clinical trial results have been disappointing, side effects have been a problem, and it proved hard to predict which tumors would even respond to the treatments at all.
One suggestion has been to use BET inhibitors in combination with other drugs. Some have said that the domains targeted by these drugs just aren't enough to completely prevent their oncogenic activity.
But now, a team led by scientists at the Max Planck Institute of Immunobiology and Epigenetics have hit on another theory.
Current BET inhibitors tend to target two proteins simultaneously, BRD2 and BRD4. However, study lead Asifa Akhtar and colleagues have found that these two proteins actually do very different jobs, and targeting them in a blanket way may not be the best plan.
“Think of gene activation like stage production,” Akhtar explained in a statement. “BRD2 sets up the stage: assembling the props, costumes and actors to ensure preparations run smoothly. BRD2 then gives BRD4, the actor, the ‘start’ signal to begin with the performance. Previous studies had been focused almost entirely on the performance. Our data shows that the setup work happening before is just as critical for gene activation.”
So, while prior work had focused mostly on BRD4, it’s actually BRD2 that may be the more interesting in terms of cancer treatment.
The team found that BRD2 is highly responsive to a form of molecular “tagging” called histone acetylation on chromatin – the stuff that chromosomes are made of. This is an epigenetic change, meaning it can affect how genes work without altering their actual DNA sequence. In this case, the presence of the tag attracts BRD2 to bind, where it can begin its "stage manager" duties and promote the activation of oncogenes.
An enzyme called MOF places these chemical tags on the chromatin. Without that, the authors observed, BRD2 won’t bind to the chromatin, and won’t start promoting gene activation like usual. Other BET proteins aren’t affected, but BRD2 pretty much stops doing its job.
“The findings support a model in which acetylated chromatin creates a platform that allows regulatory proteins like BRD2 to concentrate and prepare the transcription machinery for when it will be needed,” said first author Umut Erdogdu.
They also discovered that removing only a part of BRD2 prevented it from gathering together all the different cellular components needed to start gene transcription.
The authors therefore suggest that rather than blanket targeting of both BRD2 and BRD4, looking more specifically at their particular roles and how to stop them could be the way forward, setting the stage for – hopefully – some happier endings in future human trials.
The study is published in the journal Nature Genetics.
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