Grant: Ontario Women's Health Council / IGH Mid-Career Award

Ovarian cancer is the fourth most common cancer in women and is the most lethal gynecologic cancer. Epithelial ovarian cancer (EOC) comprises 90% of all ovarian tumours. As in other solid tumours, the growth and development of ovarian cancer is reliant on the formation of new blood vessels through a process called angiogenesis. Without angiogenesis, a tumour cannot grow beyond 1-2mm. Blood vessel formation is regulated by a balance between pro- and anti-angiogenic factors and a disruption of this balance can contribute to numerous pathologies. One potent anti-angiogenic factor is thrombospondin (TSP)-1. TSP-1 is an endogenous inhibitor of angiogenesis and elicits its effects through a number of different mechanisms such as initiating endothelial cell apoptosis, reducing endothelial cell migration and binding and sequestration of pro-angiogenic factors such as vascular endothelial growth factor (VEGF). Due to its large size (450kDa), native TSP-1 would likely not be a suitable therapeutic agent. Recently however, smaller TSP-1 mimetic peptides have been generated that replicate the anti-angiogenic domain of TSP-1. Our laboratory has generated an orthotopic, syngeneic model of human epithelial ovarian cancer and preliminary results demonstrate that TSP-1 mimetic peptides may be very potent inhibitors of epithelial ovarian cancer. We hypothesize that TSP- 1 mimetic peptides can inhibit or prevent the formation of epithelial ovarian cancer and combined with traditional chemotherapeutic agents may be able to reduce and eliminate established ovarian tumours. The impact of these results will be very significant as currently there is a very low 5-year survival rate of EOC. Development of potent anti-tumour therapies will significantly increase the quality and quantity of life of women suffering from ovarian cancer.