Grant: Operating Grant

Cancer is the leading cause of death in the developed countries including Canada. To reduce mortality rate, new tools for early diagnosis and characterization of cancer, and new specific and effective treatment options are urgently needed. Bradykinin B1 receptor (B1R) is a protein often overexpressed on membranes of cancer cells but not on normal cells. This makes B1R an excellent diagnostic marker and therapeutic target for cancer. Since the binding of endogenous ligands to B1R induces tumor growth and facilitates metastasis, potent drugs to block the activation of B1R by endogenous ligands have been developed, and their abilities to inhibit the growth of B1R-positive human cancer cells and their xenografts in mice have been demonstrated. In spite of potential application of B1R-targeting drugs for cancer therapy, there is no technology currently available for identifying B1R-positive cancer patients who can benefit from emerging B1R-targeted therapies. To solve this problem, we propose here to develop radiolabeled B1R-targeting probes for non-invasive imaging of B1R expression in cancer. We will design and synthesize potential B1R-targeting probes amenable for radiolabeling. We will measure their binding affinity to B1R expressed in human cancer cells, select high affinity B1R-targeting probes for radiolabeling, and determine their biodistribution profiles in normal mice. For promising radiotracers that have high binding affinity to B1R and preferred pharmacokinetic patterns, we will evaluate their suitability as cancer imaging agents in mice bearing B1R-positive human cancer xenografts. The success of this proposed research will generate radiotracers suitable for early diagnosis and characterization of prostate, lung and breast cancers that often overexpress B1R. These radiotracers will facilitate the development of B1R-targeting drugs and optimize their therapeutic dosage based on the blockade of B1R in the tumours.