Several TCD departments are combining efforts in the fight against breast cancer by helping to identify powerful new drugs to treat the disease, writes Dick Ahlstrom
A great deal of advanced technology and scientific expertise have been brought to bear on a research project aimed at finding new treatments for breast cancer. The goal is to find novel drugs that can help block the cancer and stop it spreading.
The project makes use of the very latest computing power and imaging technology available at Trinity College Dublin's Institute for Information Technology and Advanced Computing (IITAC).
Pharmaceutical chemists and biochemists can view three-dimensional images of candidate drugs and pre-selected promising compounds on the basis of their physical shape, explains Dr Mary Meegan, a senior lecturer in the school of pharmacy.
Pharmaceutical chemist Meegan leads the Health Research Board-funded project which focuses on the oestrogen receptor. She points out, however, that the work required a team effort that involved expertise at IITAC and other Trinity departments, including biochemistry.
"In breast cancer one of the main targets is the oestrogen receptor," she says. "Oestrogen doesn't cause the breast cancer, but its activity can promote the development of cancer."
Oestrogen circulating in the bloodstream binds to the receptor causing it to change its shape. This in turn allows other proteins to link to the site and further changes to take place. "It sets off a downstream cascade of events that lead to cancer proliferation," she says.
The goal is to find agents that can inhibit this cascade by binding to the receptor and keeping oestrogen at bay. Protein, drug and receptor interactions are all dependent on the physical shape of these molecules, so it is extremely valuable to know the shape if you are looking for a useful drug, Meegan explains.
This is where the IITAC facility comes into play. It received €19 million under the Higher Education Authority's Programme for Research in Third-Level Institutions, allowing it to purchase supercomputer facilities and an advanced visualisation system, explains IITAC principal investigator and head of Trinity's Centre for High Performance Computing, Prof Graeme Watson.
It also has X-ray equipment that can determine the shape of proteins, he says. "It allows you to see structures in three dimensions. In the cancer project you can actually look at the oestrogen binding site."
Knowing the shape of the receptor helps Meegan identify candidate drugs that can interact with the receptor. "I am interested in the shape of the drugs and their activity. To understand how they work we need to know in three dimensions how they bind to the receptor," Meegan explains.
There are huge databases of drugs which provide information about their shape, and Meegan and her team can use high throughput computerised screening to find promising candidates.
"What IITAC allows us to do is to screen agents that are known to have very good binding to the receptor site," she says. A scoring system is used to find the ones with the greatest promise. "We can select the molecules that give us a good score." Once candidate agents are identified their efficacy can be tested in the biochemistry lab, she adds.
The use of IITAC in a biological context is a relatively recent departure, says Watson. "It is primarily computational but we are developing ways to use it in other areas. We are talking to a lot of people about how to exploit the 3-D visualisation system," he says.
There are already seven schools at Trinity involved in IITAC, including maths, physics and chemistry, computer science, biochemistry, immunology, microbiology and pharmacy, he says. "It involves a huge number of people."