Breast cancers over-expressing the human epidermal growth factor receptor-2 (HER2) represent a molecular subtype of very aggressive cancers associated with poor patient survival. We were the first to note a correlation between the over-expression of HER2 on breast tissue and that of an adhesion signalling molecule called Junctional Adhesion Molecule-A (JAM-A). We were subsequently the first to show that protein levels of JAM-A can regulate those of HER2 via a pathway putatively involving HER2 proteasomal stability. Together with other evidence that JAM-A regulates tumorigenic signalling, this suggested that JAM-A functional antagonism could represent a novel and innovative strategy to reduce cancer progression. We therefore designed a novel peptide inhibitor of JAM-A signalling, KB3. Preliminary testing has revealed that KB3 exerts anti-proliferative and anti-migratory effects on breast cell lines in vitro, and that it can reduce tumour size in an in vivo mouse model of breast cancer. This proposal will therefore adopt a rigorous patient-focussed approach towards testing the potential efficacy of KB3 in models of HER2-dependent breast cancer. Aim 1 will utilise breast cancer patient-derived primary cultures to test the anti-proliferative and anti-migratory properties of KB3 (alone/ in combination with HER2 antagonists) in the cell biological setting which best recapitulates the heterogeneity of human tumours. Aim 2 will establish the efficacy of KB3 (alone/in combination with HER2 antagonists) in an in vivo mouse model of HER2-dependent breast cancer. Finally Aim 3 will use an innovative patient-derived xenograft approach towards determining the efficacy of KB3 (alone/ in combination with a HER2 antagonist) on the growth of HER2-positive human tumours in immunocompromised mice. Taken together, successful outcomes from our studies would position JAM-A inhibitors such as KB3 as a new generation of anti-cancer drugs ready to progress rapidly to the Phase I clinical testing arena.
