Epigenetic cross-talks and novel therapeutic strategies to prevent disease progression in ERG fusion positive prostate cancer
Cancer of the prostate is a leading cause of cancer death in men worldwide. While localized prostate cancer is highly curable, nearly all patients with metastatic disease progress to castration-resistant prostate cancer for which there are presently limited treatment options. Thus, there is high need to develop selective, context-dependent therapeutic strategies to manage metastatic prostate cancer. The identification of the pathways that, in a specific tumor context, lead to disease progression and metastasis is an important step in developing more effective treatments based on the tumor molecular and biological characteristics. The overall goal of this SSAJRP application is to combine and integrate the expertise of the participating groups at two leading Institutions in Switzerland (IOR) and in South Africa (ICGEB) to improve the current understanding of the molecular mechanisms involved in tumor progression and to discover novel therapeutic approaches for a specific subtype of prostate cancers, ERG fusion positive tumors. The participating teams have long term experience in prostate cancer biology, genomics and experimental therapeutics and, along with the excellent facilities and resources available in the respective Institutions, constitute an unique work environment to perform this project with high relevant basic, translational and clinical implications. Furthermore, this bilateral project will provide an ideal platform and framework for training students and young scientists in an international setting in both countries. Gene fusions involving the ETS transcription factor ERG are found in about half of prostate cancers. The gene fusion determine overexpression of full length ERG in prostate epithelial cells. Pre-clinical and clinical data sustain the notion that activation of multiple oncogenic pathways cooperating with ERG is required for progression of ERG fusion positive tumors. However, the molecular details of these interactions are not defined yet. Understanding these mechanisms would be important for the development of more effective therapies. We have recently discovered a novel mechanism leading to aberrant activation of ERG and contributing to prostate cancer progression. We identified EZH2, a key epigenetic effector, as an important element enhancing the oncogenic activity of ERG and at the center of cross-talks between ERG and the PTEN/PI3K/AKT pathway in prostate cancer. We found that EZH2 enhances ERG transcriptional activity, forms with ERG co-activator and co-repressor complexes, and thus contributes to transcriptional reprogramming and acquisition of tumorigenic and metastatic properties. Notably, the genes co-occupied and co-regulated by ERG and EZH2 constitute a gene signature predictive of adverse prognosis and highly enriched in metastatic prostate cancers. Furthermore, we showed that antagonizing the ERG and EZH2 interaction with EZH2 targeting agents could be highly effective to treat patients with aggressive ERG positive tumors. The studies proposed in this application will address the role of ERG in orchestrating and remodeling the transcriptional and epigenetic landscape in prostate tumors by examining the network of co-regulatory factors co-opted by the ERG/EZH2 complexes to activate the pro-tumorigenic and pro-metastatic program. To this end, we plan to integrate molecular, genomic and functional studies in vitro and in vivo with human patient data to understand the events involved in the cross-talks between ERG, EZH2 and transcriptional co-regulators and to examine the biological and clinical consequences. Furthermore, we will examine strategies aimed at reversing ERG pro-tumorigenic/pro-metastatic program by targeting the key components of the ERG-orchestrated epigenetic network. Accordingly, the specific aims of the present applications are: Aim 1. To understand the molecular mechanisms of the ERG-orchestrated transcriptional reprogramming and tumor progression in ERG positive prostate cancer. Aim 2. To explore therapeutic approaches to reverse ERG-dependent reprogramming and progression in prostate cancer. Collectively, the combination of genomic, molecular and functional in vitro and in vivo studies proposed in this SSAJRP application will lead to a deeper understanding of the biological mechanisms leading to transformation and progression in ERG-dependent prostate cancers. Furthermore, these studies will reveal therapeutically actionable pathways whose modulation could have a broad impact on the management of prostate cancer.