- The technique worked on a range of human forms of the disease and mice with bowel and blood cancer
- The team at the University of Pennsylvania report the finding in a new study published today
- There are already drugs that block the chemical called ATF4 – offering hope of the fast-tracking of a revolutionary therapy
Scientists have identified the Achilles’ Heel of cancerous tumors, forcing the disease-spreading cells to over-stress and self-destruct.
Experiments showed blocking a specific protein that fuels tumors kills them off.
The technique worked on a range of human forms of the disease and mice with bowel and blood cancer.
What’s more there are already drugs that block the chemical called ATF4 – offering hope of the fast-tracking of a revolutionary therapy.
For years scientists have been trying in vain to target a gene called MYC. It’s known to drive cell growth and allow cancer to take over if it’s mutated or over-expressed. Now Dr Koumenis, an oncologist at Pennsylvania University, and colleagues have found ATF4 controls a chemical pathway that works in tandem with the gene
Co-senior author Professor Constantinos Koumenis said: ‘What we’ve learned is we need to go further downstream to block tumor growth in a way that cancer cells can’t easily escape, and our study identifies the target to do just that.’
His team said it ‘may be its Achilles’ Heel’.
Every day millions of our cells ‘kill’ themselves,helping protect us from potentially harmful ones.
Cancer cells, on the other hand, ignore our immune system’s cell-death signals. Finding a way to stop this is the ‘Holy Grail’ of cancer research.
Dr Koumenis did this by homing in on ATF4 in human bowel, breast and lymphoma cells grown in the lab – and rodents genetically engineered to develop lymphoma.
For years scientists have been trying in vain to target a gene called MYC. It’s known to drive cell growth and allow cancer to take over if it’s mutated or over-expressed.
Now Dr Koumenis, an oncologist at Pennsylvania University, and colleagues have found ATF4 controls a chemical pathway that works in tandem with the gene.
Stopping it in its tracks causes cancer cells to produce too much protein and die, say the researchers.
The findings published in Nature Cell Biology could open the door to a completely fresh approach.
Inhibitors that cease production of ATF4 (activating transcription factor 4) already exist. It has been linked to a host of diseases including Parkinson’s and Alzheimer’s.
Lead author Dr Feven Tameire said: ‘This shows us the potential impacts of targeting ATF4 in MYC-dependent tumors – something we’re already studying.
‘We’re also working to confirm this approach will not cause any serious off-target effects.’
Normal versions of MYC control healthy cell growth. But when it is mutated – or there is too much – it sets off a chain reaction that helps tumors develop and spread.
There is currently no specific way to target it so the focus has increasingly been on other ways to stop the process indirectly.
Dr Koumenis’ team found in some tumors ATF4 is activated by an enzyme known as PERK.
But blocking this protein does not always work because MYC actually controls a second enzyme called GCN2 that can function in parallel – making PERK redundant.
The alternative approach is to target ATF4 itself since it’s the point where both these signal pathways converge.
This means there’s less built-in protection to allow cancer to survive, explained Dr Koumenis.
The study also showed ATF4 turns on the genes MYC needs for growth and also controls the rate at which cells make specific proteins called 4E-BP.
When the researchers knocked out ATF4 in cells or mice they found tumors continued to increase the amount of 4E-BP – and eventually died from stress.
This stopped lymphomas and bowel tumors growing in the mice. In the human tumors driven by MYC, both ATF4 and and 4E-BP were also overly expressed.
This is further evidence suggesting the approach will be successful in patients, said Dr Koumenis.
Future studies will also focus on continuing to investigate why ATF4 works the way it does – shedding light on other potential targets in the chain, said the researchers.
The International Agency for Research on Cancer estimates about 18 million people a year are diagnosed with the disease – which claims around 10 million lives annually.