Emerging data suggest that a subset of late-stage prostate cancer can progress to a predominantly neuroendocrine phenotype. Project 2 team members previously discovered over-expression and gene amplification of both AURKA (encoding Aurora kinase A (Aurora-A)) and of MYCN (chromosome 2p24, encoding N-Myc) in neuroendocrine prostate cancer (NEPC) as compared with prostate adenocarcinoma. They found that N-Myc and Aurora-A interact to form a stabilizing complex that can be disrupted by allosteric inhibitors of Aurora-A (e.g., MLN8237). This led to a WCM-initiated Phase 2 clinical trial for NEPC patients (NCT#01799278, PI Beltran). Preliminary human tumor, in vitro and in vivo data–including a novel mouse model–support the role of N-Myc as a key driver of NEPC.
NEPC is associated with low or absent AR expression, suppressed AR signaling, retention of early genomic mutations from its adenocarcinoma precursor, and acquisition of distinct genomic and epigenomic alterations. The development of novel therapeutic approaches for patients with NEPC represents a clinical unmet need. This project will focus on first-in-class observations that nominate the N-Myc/Aurora-A pathway and specific epigenetic modifiers (e.g., EZH2) as targets driving NEPC.
Project 2 posits that N-Myc cooperates with both Aurora-A and EZH2 to drive the neuroendocrine phenotype and that characterizing this driving role will lead to more effective targeting strategies for this tumor entity.
AIM 1: Characterize the interaction between the EZH2 and N-Myc signaling in driving NEPC;
AIM 2: Develop novel allosteric compounds that target the N-Myc/Aurora-A complex;
AIM 3: Develop clinical biomarkers to predict response to targeting N-Myc and EZH2 in advanced prostate cancer.