Researchers in NUI Galway are using a magic-bullet approach, which tells cancer cells to commit suicide, writes Claire O'Connell
The Holy Grail of cancer research is to find treatments that kill tumours while leaving healthy cells unharmed. Now researchers at NUI Galway are homing in on a group of "magic bullet" molecules that lock on to "death receptors" on cancerous cells and tell them to die, meanwhile sparing normal cells.
If further tests go well, the specially engineered molecules could be polishing off tumours in patients within a few years.
It all started about ten years ago when scientists discovered Trail, a defence molecule produced in the body, explains Dr Afshin Samali, a research director at the National Centre for Biomedical Engineering Science. Although Trail could bind to receptors on the outer surfaces of both tumour and normal cells, it triggered the tumour cells to die through a controlled process called apoptosis, he adds.
Trail kills the tumour cells by binding to special death receptors that sit on their surface. But the problem with the natural or "wild-type" form of Trail is that it also docks on to other receptors that do not induce death.
"It is promiscuous, it can bind to five different receptors," says Dr Samali. "And only two of these receptors can activate apoptotic pathways in the tumour cells, these are the death receptors. The other three are decoy receptors."
So Dr Samali and his 18-strong team in Galway have been working with colleagues in Germany and the Netherlands to create new, improved versions of Trail that zone in on death receptors more specifically, thereby offering a more targeted approach to killing tumour cells.
Using computer software, the group examined the structure of Trail and its various receptors and worked out a number of ways to tweak the Trail molecule to make it bind more selectively to death receptors. Next they altered the wild-type Trail gene and inserted the engineered versions into bacteria, which worked like "little factories", pumping out the new versions of the Trail proteins.
Samali and his team then tested the new Trail molecules on cancer cells in the lab, and discovered the precision-engineered killers could indeed wipe out cancer cells more effectively. "It doesn't have any effect on normal cells and its killing potential for tumour cells has been increased between 10- and 100-fold depending on the cancer cell type," he says. The group recently published their findings in the prestigious Proceedings of the National Academy of Sciences of the USA.
While the new Trail was particularly good at killing off ovarian and colon cancer cells, leukaemia cells proved more resistant, because the cells could block the cell death process that Trail triggered. But Samali's team found that adding a non-lethal pinch of arsenic coaxed the resistant leukaemia cells back into being killed by Trail.
The project, which receives funding from the European Union, Enterprise Ireland and Cancer Research Ireland, will now start pre-clinical trials of engineered Trail molecules, and, all going well, the first human clinical trials could start within three to five years, says Dr Samali.
Ultimately he sees a role for Trail in combination with other anti-cancer treatments such as chemotherapy and radiotherapy, where Trail could finish off tumour cells that have not been killed by the other regimes. "It also helps you reduce the amounts of drugs you are pumping into patients because you can use lower amounts of drugs and still be sure you will kill the tumour," he says.
He is excited about the potential of these promising molecules and how they could help people who need them: "That's the main driving force behind our activities at the moment," he says.