Temporal Evolution of N-Myc Signaling and Early Targeting of the Neuroendocrine Phenotype in Prostate Cancer
Abstract
While therapies targeting the androgen receptor (AR) have significantly improved outcomes for men with advanced prostate cancer, it has beenincreasingly recognized that a subset of castration resistant tumors lose dependence or escape AR signaling which is associated with epithelial plasticity,loss of AR mRNA and protein expression, and the development of neuroendocrine features. Castration resistant neuroendocrine prostate cancer (NEPC) isclinically aggressive and median survival is less than one year. The poor prognosis of NEPC can be accounted for, in part, by late diagnosis and anincomplete understanding of the molecular events underlying its pathogenesis. Over the last 7 years, our groups have co-led extensive molecular analysesof NEPC, elucidated mechanisms of clonal evolution, and have identified the oncogenic transcriptional factor N-Myc as a key driver of the neuroendocrinephenotype (Beltran, Rickman et a, Cancer Discovery 2011; Dardenne, Beltran et al, Cancer Cell, in press). Notably we found that NEPC is clonally derivedwith an origin traceable back to a prostate adenocarcinoma precursor, providing new potential opportunities for early detection and potentially earlyintervention. Through the development of multiple N-Myc-overexpressing prostate cancer preclinical models, we have found that N-Myc drives NEPC byinducing a profile enriched with pro-metastatic, dedifferentiation and Polycomb Repressive Complex 2 (PRC2) dysregulated genes and dramaticallyreducing AR signaling.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1202184
Entities
People
- David Rickman
- Himisha Beltran
Organizations
- Cornell University