Therapy considerations in neuroendocrine prostate cancer: what next?

Abstract

Lineage plasticity and histologic transformation to small cell neuroendocrine prostate cancer (NEPC) is an increasingly recognized mechanism of treatment resistance in advanced prostate cancer. This is associated with aggressive clinical features and poor prognosis. Recent work has identified genomic, epigenomic, and transcriptome changes that distinguish NEPC from prostate adenocarcinoma, pointing to new mechanisms and therapeutic targets. Treatment-related NEPC arises clonally from prostate adenocarcinoma during the course of disease progression, retaining early genomic events and acquiring new molecular features that lead to tumor proliferation independent of androgen receptor activity, and ultimately demonstrating a lineage switch from a luminal prostate cancer phenotype to a small cell neuroendocrine carcinoma. Identifying the subset of prostate tumors most vulnerable to lineage plasticity and developing strategies for earlier detection and intervention for patients with NEPC may ultimately improve prognosis. Clinical trials focused on drug targeting of the lineage plasticity process and/or NEPC will require careful patient selection. Here, we review emerging targets and discuss biomarker considerations that may be informative for the design of future clinical studies.

Keywords: biomarkers; epigenetics; lineage plasticity; neuroendocrine prostate cancer; prostate cancer.

Figure 1.

Schematic of the lineage plasticity process in prostate cancer.

Figure 2.

Representation of relative abundance of features and patient-based studies and models along the continuum from localized prostate cancer (PCa) to castration resistant adenocarcinoma (CRPC-Adeno) to androgen receptor (AR)-independent CRPC. The schematic includes the frequencies of relevant genomic and epigenomic aberrations associated with neuroendocrine prostate cancer and the relative number of patient - based studies and models that exist to study each of these disease states, evidencing the yet modest availability of tissue based and liquid biopsy-based studies in the setting of AR independent CRPC, where disease control is especially limited.

Figure 3.

Gene expression of specific targets (EZH2, AURKA, DLL3) in CRPC and NEPC metastatic tissue biopsies, annotated by genomic tumor suppressor loss, NEPC-associated features informed by DNA methylation changes, and AR signaling. Epigenetic and genomic signal might be indicative of non-genomic based NEPC relevant targets/pathways.