Mapping the epigenetic dynamics of prostate cancer progression: integrating liquid biopsies and single-cell epigenomics for early detection of lineage plasticity and clinical decision-making - PROJECT SUMMARY/ABSTRACT Transcriptional dysregulation and loss of differentiated cell identity are fundamental cancer traits. Genome-wide analyses have profoundly informed our understanding of these features, allowing investigators to broadly survey tumorigenic alterations, classify tumors, and understand responses to perturbations. While most genome-wide or ‘-omic’ studies have focused on genetics and transcripts, tools and methods have recently matured enabling epigenome-wide studies on clinically annotated primary specimens. The overall goal of this proposal is to utilize the power of innovative epigenomic methods and signatures to inform our understanding of lineage plasticity, including treatment-emergent neuroendocrine prostate cancer (NEPC), a highly lethal cancer as well as to use epigenomic signatures to predict enzalutamide resistance. Over the past decade potent androgen receptor (AR) signaling inhibitors (ARSIs) have been developed for the treatment of castration resistant prostate cancer (CRPC). These therapies effectively extinguish AR signaling and prolong patient survival. However, a hormone insensitive and lethal form of the disease ultimately emerges, rendering AR-targeted therapies ineffective. ARSI-resistant prostate is invariably deadly and NEPC is an increasingly common ARSI resistance phenotype in this setting. NEPC arises through lineage plasticity, a process in which epigenetic programs are rewired, permitting transdifferentiation into an alternate cellular identity. This neuroendocrine differentiation allows the cell to escape dependence on the AR. NEPC also presents a diagnostic dilemma. As prostate cells achieve independence from AR, the established marker (e.g., PSA expression) is often low and becomes decoupled from its typical association with disease burden. NEPC is currently diagnosed by biopsy and pathologic analysis, yet there is a lack of consensus regarding the pathological features for identifying NEPC. Moreover, metastatic biopsy samples are not always representative of patients’ overall disease due to intrapatient and intratumoral heterogeneity. To address this shortcoming, our work has discovered a novel epigenomic signature in NEPC cells that is highly distinct from adenocarcinoma cells. This proposal leverages recent advances in highly sensitive epigenomic signatures to detect NEPC and as a predictive biomarker for enzalutamide resistance. Aim 1 will endeavor to identify clinically relevant phenotypes in plasma, including NEPC and using a pre-defined epigenomic signature as a predictive biomarker for enzalutamide resistance in clinically annotated samples. Aim 2 will employ novel single cell assays to determine if rare subpopulations of aggressive NEPC clones pre-exist in primary tumors. Aim 3 will create an epigenomic classification of metastatic castration resistant prostate tumors to lay the foundation for earlier diagnosis, earlier intervention, and innovative treatments for advanced prostate cancer, ultimately leading to improved outcomes for this lethal disease.
