Project 466690

Prostate cancer (PCa) is the most commonly diagnosed cancer in male Canadians, yet resistance to radiation treatment leading to metastatic progression is still a cause of significant morbidity and mortality in patients. A recent study of our radioresistant PCa cell line DU-145 found a significant increase of lysyl oxidase-like 2 (LOXL2), an extracellular matrix (ECM) cross-linking enzyme. LOXL2 has previously been associated with radioresistance, as well as promoting metastasis and fibrosis through ECM remodelling. Aptly, two LOXL2 inhibitors have already passed phase I clinical trials for fibrotic disease. I hypothesize that increased LOXL2 promotes radioresistance and metastasis in PCa cells, and its pharmacological inhibition can be used therapeutically to target these processes.My first aim will be to confirm that targeting LOXL2 sensitizes PCa cells to radiation. I will perform clonogenic assays with radioresistant DU-145 cells to determine whether genetically or pharmacologically inhibiting LOXL2 sensitizes these cells to radiation. I will also perform these assays on clinically-relevant patient-derived cells. My second aim evaluates the metastatic potential of DU-145 PCa cells using the CAM assay, which measures the extent to which metastatic cells injected into the blood vessel of a chick egg chorioallantoic membrane (CAM) can exit the vessel to invade nearby tissue. The third aim of my project will use a preclinical mouse model injected with DU-145 cells to evaluate the therapeutic efficacy of the clinically approved LOXL2 inhibitors in sensitizing PCa cells to radiation.The proposed research will elucidate the mechanisms of LOXL2 radioresistance and metastasis, while paving the way for the use of approved LOXL2 inhibitors to treat PCa in clinical trials.