Endocrine Abstracts

Lineage plasticity has been postulated to contribute to the failure of targeted- and immuno-therapies. In prostate cancer (PCa), the discovery that advanced metastatic castration-resistant PCa (CRPC) classified as adenocarcinoma remains fueled by the androgen receptor (AR) has ushered the development of potent AR pathway inhibitors (ARPIs), notably abiraterone and enzalutamide undoubtedly benefiting the survival of patients with advanced disease. However, a subset of patients (~20%) relapse with tumors that are no longer dependent on AR activity and, instead, activate lineage programs including stem cell and neuronal pathways. These tumors, termed treatment emergent neuroendocrine prostate cancer (tNEPC), are particularly aggressive in that no targeted therapeutic strategies exist, leading to a poor prognosis with an overall survival of only 1 year. Managing NEPC patients and developing novel therapeutic strategies have so far proven challenging due to knowledge gaps in the underlying molecular mechanisms governing tumor cell plasticity and neuroendocrine differentiation. Despite similar genetic profiles, CRPC and NEPC are distinguished by extensive transcriptional landscape rewiring. To begin addressing this, we integrated genomic, transcriptomic, epigenomic, and proteomic data that has informed us that ARPI therapy can activate a lineage switch owing to dynamic and reversible epigenetic regulations. The changes in the epigenetic landscape create an favorable environment for transcription factors to be “reprogrammed”. In particular, we uncovered new androgen receptor (AR) binding sites that allow AR to flow between alternative binding profiles and identified the neuronal determinant factor ASCL1 to facilitate phenotypic switching guided by the epigenetic modifier EZH2. This cross talk between lineage determinant transcription factors creates an opportunity to targeting EZH2 in lineage plasticity. Hence, these pre-clinical data have guided the initiation of a new arm in the Genomic Umbrella Neoadjuvant Study and other Biomarker Trials (NCT04812366) using EZH2 inhibitor.