Dr. Robert Britton firmly believes every molecule is important. This chemist doesn't want any molecule sitting unused on a laboratory shelf or in a fridge. This project would develop carbohydrate mimics to assist cancer therapies.
"I want every molecule to have a purpose that's my ethos for our lab," says Britton, a GlycoNet network investigator, and professor at Simon Fraser University. With that spirit in mind, Britton has embarked on an ambitious project to develop carbohydrate mimics to assist cancer therapies by making them more selective in how they target and kill cancer cells.
In the 80s and 90s, it was recognized that traditional chemotherapies were limited as a result of the high systemic toxicity associated with targeting rapidly dividing cells. Researchers began to look at alternative approaches to specifically targeting cancer cells, including the development of antibodies which recognized and bound to proteins expressed on cancer cells.
Identifying the antibodies
This research led to the development and approval of the first two monoclonal antibodies (mAbs) for use in cancer therapy: rituximab (Rituxan) for non-Hodgkin's lymphoma in 1997 and trastuzumab (Herceptin) for breast cancer in 1998.
Herceptin changed HER2+ breast cancer from a fatal disease where patients had a small chance of survival to one that is highly treatable Britton's work focuses on the binding of the antibody to the cancer cell which leads to the recruitment of Natural killer cells and results in Antibody-Dependent Cell-mediated Cytotoxicity (ADCC).
However, researchers have now identified that when antibodies have fucose molecules attached (i.e., are fucosylated), they have lower levels of ADCC as the antibody's ability to attract immune cells is impeded, and studies have shown that removal/prevention of the fucosylation from antibody therapeutics elicits high ADCC.
"The challenge in creating these molecules is that, while some companies are successful in inhibiting the transfer of fucose to the antibody, the inhibitor itself becomes attached to the antibody which may represent an immunogen and presents significant drug consistency risks," said Britton.
Britton explains the goal of his project is to develop fucosylation inhibitors that do not transfer themselves to the antibody. These molecules, fucosylation inhibitors, are what Britton and his research group are trying to identify and create. GlycoNet funding will provide the means to develop this set of inhibitors in the form of a Catalyst grant.
"These aren't simple molecules to make," said Britton. "They take real expertise, so GlycoNet funding allows us to hire highly qualified personnel to work on this project for one year. We couldn't do this without GlycoNet, it takes a lot of time, energy and expertise."