Project 1 focuses on the transition of advanced PCa to lethal AR-indifferent disease. Lineage plasticity, where differentiated cells acquire alternative lineage programs, is increasingly recognized as a mechanism of resistance to therapy in multiple cancers. For PCa, this plasticity can manifest as histologic transformation from an AR-driven prostate adenocarcinoma to an AR-independent small cell neuroendocrine carcinoma or NEPC.

Although NEPC tumors arise clonally from prostate adenocarcinoma and share genomic alterations, there is significant epigenetic dysregulation that occurs during the lineage plasticity process. The goal of this project is to develop effective, biomarker-driven therapeutic strategies for patients with advanced prostate cancer and untreatable NEPC. The objective is to determine if specific epigenomic reprogramming plays a role in 1) driving the transition from adenocarcinoma towards NEPC and 2) maintaining the NEPC phenotype. The overarching hypothesis of this project is that specific molecular alterations facilitate lineage plasticity during acquired resistance to AR-therapies through epigenetic reprogramming (DNA methylation and EZH2 activity) leading to transformation to NEPC.

Aim 1. Elucidate the relationship between DNA methylation and EZH2 activity during the progression to NEPC.

Aim 2. Develop biomarkers that identify AR independence and precede the progression from an AR-driven CRPC to NEPC.

Aim 3. Assess the therapeutic potential of DNMT inhibition in combination with EZH2 inhibition to block the transition to or maintenance of NEPC.