Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

In North America, one in seven men will be diagnosed with prostate cancer. Many of these patients will undergo therapy to shut down the activity of a protein in the prostate called the androgen receptor (AR). Though widely used and initially highly effective, suppression of the hormone testosterone, which activates AR, uniformly leads to an aggressive and fatal cancer state called castration-resistant prostate cancer (CRPC). While new drugs, the most notable being one called Enzalutamide, have been developed to shut down hyperactive AR in CRPC their effect is short-lived; tumors can develop resistance to these drugs and grow back, sometimes stronger than before. This is because tumors can learn to shed their dependence on AR signaling leading to uncontrolled growth and dissemination within 6 to 12 months. Our laboratory has recently identified an ominous and possibly widespread way for prostate cancer to progress after treatment with Enzalutamide. It turns out that cancer cells can be re-educated and emerge as 'stem cells' that do not require AR signaling for proliferation and survival. We identified a protein called Wnt5a that we suspect causes a cascade of changes that creates cancer stem cells. We will begin by validating Wnt5a as a target for reduces cancer stem cells using extensive molecular biology and biochemistry techniques. We will also be comparing our findings from clinical trials in North America and Europe using data from patients that are progressing into Enzalutamide resistant prostate cancer. Following this we will use computer modeling software in an attempt to re-purpose known drugs to target the Wnt5a proteins in order to avoid the lengthy and expensive drug discovery process. We have been successful using this method for inhibiting the function of other proteins in the past. Ultimately, our research should help us understand how prostate cancer cells escape therapy so we can improve patient survival.