Researchers at UCC are studying the complex protein signalling involved in cancer in the hope of finding ways to block the disease, writes Cormac Sheridan
A group led by Rosemary O'Connor, principal investigator in the BioSciences Institute at University College Cork has uncovered new insights into an important molecular signalling mechanism that enables cancerous cells to grow and invade other tissues.
O'Connor and colleagues - Patrick Kiely and Denise O'Gorman of UCC and collaborators Ken Luong and Dorit Ron at the University of California, at San Francisco - have identified a key step in cancerous cells that enables them to migrate within the body.
It involves the insulin-like growth factor-I receptor (IGF-IR), an emerging therapeutic target for anti-tumour drug development. A clutch of pharmaceutical and biotechnology firms, including Pfizer, Amgen, Schering-Plough, Centocor, Novartis and Sanofi-Aventis, have development programmes in this area, several of which have already entered early stage clinical trials.
The general aim is to develop monoclonal antibodies that would bind to IGF-IR in a highly specific fashion, and block its effects. Animal experiments already indicate that the approach is highly promising.
"On paper, it's an ideal target because it should inhibit the growth of a lot of tumours," says O'Connor, who is an associate professor of biochemistry. That's because IFG-IR is ubiquitous in tissues throughout the body.
Proper triggering of IFG-IR plays an important role in normal growth and development, both before and after birth. In cancerous cells, however, the same molecular switch is turned permanently to the "on" position.
The latest work, which is funded by the Health Research Board, was published in the June issue of the journal Molecular and Cellular Biology. It builds on more than a decade of research O'Connor has undertaken in cell signalling, at the US biotechnology company ImmunoGen and, since 1997, as a member of UCC's biochemistry department.
Her group has found how a previously identified protein called RACK1 plays a key role in determining whether the IGF-IR signal is turned "on" or "off". It does so via its ability to simultaneously associate with IGF-IR and with one of two other proteins.
It's a delicate form of molecular choreography, which can have very damaging consequences. This association "is abundantly detectable in transformed (cancerous) cells and is not detectable or only occurs transiently in normal cells", O'Connor says.
Her group is now dissecting IGF-IR signalling pathways in cancer further, with a view to finding new biomarkers and signal modulators to aid drug development, diagnosis and treatment. Through a project funded by Science Foundation Ireland, it has identified around 15 novel genes that appear to be associated with the IGF-IR pathway. It is now in the process of understanding their physiological role.
O'Connor's work is part of a wider global effort to decipher the molecular signatures of all cancers. "Now we're actually figuring out the molecules that are necessary for enabling cancer cells to thrive," O'Connor says.
The advent of new cancer therapies such as Herceptin, Avastin and Gleevec exemplifies this approach. Each acts in a highly precise, targeted fashion on specific cancers, whereas classical cancer treatment is based on what O'Connor calls a "slash-and-burn" approach, which involves the use of cytotoxic drugs that kill any cell that is actively growing and dividing.
"We're getting more sophisticated," she says. Because they target the cancer directly, these newer drugs tend to have less side-effects than their older counterparts.