Grant: Project Grant

It is estimated that in 2020 adenocarcinoma of the prostate will be diagnosed in 23,300 Canadian men and 4200 will die from it. New potent therapies such as abiraterone, enzalutamide, and apalutamide are effective at controlling the disease but ultimately progression to castrate-resistant prostate cancer (CRPC) is universal. It is now known that these potent drugs can cause normal CRPC to turn into a lethal neuroendocrine cancer (NEPC) in 15-25% of patients. This is called neuroendocrine transdifferentiation (NEtD) and there are no effective therapies to prevent it or treat the subsequent neuroendocrine prostate cancer (NEPC). At the Vancouver Prostate Centre, we transplanted a patient's tumor into mice making a so-called patient-derived xenograft (PDX). This PDX turned out to be a particularly valuable and clinically relevant model of the neuroendocrine transdifferentiation (NEtD) for identifying mechanisms of NEtD and drug targets. Recently we applied a powerful new technology called single-cell RNAseq to this PDX model. All expressed genes are sequenced in thousands of individual tumour cells simultaneously. This allowed us to monitor NEtD at single-cell resolution and to identify the very first NE-like cells to emerge. Importantly, in these cells, we identified genes that act very early in NEtD and we confirmed them to be present in multiple NEPC patient cohorts. We will inactivate these in our PDX model to try and block NEtD. If this works the genes will form the basis of novel therapeutic targets for abrogating NEtD. In addition, we found that the emerging LTL331 NEPC has a metabolic weakness - dependence on an external supply of arginine - an important amino acid. We propose to test if this can be exploited to block NEtD. If successful, it will open a radically novel approach to NEPC prevention and/or treatment via dietary changes.