Probes for imaging enzyme activity

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Background. The spread of cancer from a primary tumor to a distant location, a process termed metastasis, is the cause of death in 90% of patients. A critical step in the progression of cancer is the remodeling of the local environment with which tumours begin to invade. This remodeling is thought to occur primarily through molecular machines called proteases, enzymes that digest the tumour environment providing a permissive space for cancer cells to invade. However, the exact mechanisms and the specific proteases that help cancers spread are not well understood. We propose to design and develop new chemical agents that can reveal the activity of specific proteases operating in the tumour and the tumour environment using positron emission tomography (PET). Proposed Work. PET produces pictures that represent metabolic information within a person's body. It requires the injection of a minute amount of a radioactive PET tracer, using isotopes produced in a cyclotron facility, that will accumulate in metabolically active tissues. We will design and prepare new PET tracers that become activated by proteases and accumulate in the tumour environment of aggressive breast cancer. Importantly, the advancements made over the course of this program may be used to PET image protease activity in diseases other than cancer including cardiovascular disease, arthritis and atherosclerosis. Impact. New and improved PET molecular imaging methods could be used as an important research tool for identifying proteases that help cancer spread. Once a specific protease has been determined to promote tumour invasion, it would become a high priority therapeutic target. Eventually, this work could also lead to a clinical test capable of simultaneously detecting cancer (diagnosis) and assessing the aggressiveness of the discovered tumour (prognosis). Career Opportunities of Students Trained. A global shortage of people trained in PET radiochemistry has been identified as a threat to PET imaging science in a report submitted to the U.S. National Academy of Sciences in 2007. Since then, the shortage has been exacerbated by the expanding number of cyclotron facilities. Indeed, 8 new Canadian cyclotron sites including facilities in BC Cancer, Saskatoon, Winnipeg, Thunder Bay, University Health Network, Sunnybrook Research Institute, London and Halifax are now operational. In addition, established facilities installed additional cyclotrons in Sherbrooke, Hamilton, Montreal and Edmonton. This proposal will help train the next generation of radiochemists thus allowing the rapidly expanding Canadian sites to operate at their desired capacity and provide excellent careers opportunities for students trained from this NSERC grant.