Abstract 3054: Investigating novel players involved in AR cistrome reprogramming

Abstract

Abstract Advancements in the treatment of aggressive prostate cancer (PCa) have led to the development of second-generation AR-targeted therapeutics for advanced PCa. Unfortunately, many patients who initially respond to these treatments develop resistance and progress. Several mechanisms of resistance are being studied. We have focused on the roles of a reprogrammed AR cistrome from a canonical to a non-canonical cistrome in resistant disease. The premise of this study is based on previous studies by others and studies in our lab that suggest enrichment in non-canonical AR activity and adaptation to enzalutamide in advanced PCa cell lines and patient-derived xenografts. We aim to develop an ecosystem map of canonical and non-canonical AR activity to understand the drivers of therapeutic resistance and their vulnerabilities. We hypothesize that through combined transcriptomic/chromatin accessibility profiling at single-cell resolution and proteomics studies, we can holistically capture non-canonical AR activity. To provide invaluable information, as PCa is highly heterogeneous and not all cancer cells may be contributing to the resistance pathway that is of interest, we use castrate-resistant PCa (CRPC) and enzalutamide-resistant CRPC patient-derived xenograft (PDX) models and patient tissue samples as our disease models on our multi-omic assay platform to capture and study dynamic interplays and novel players driving a non-canonical AR cistrome and treatment resistance. Our preliminary data revealed potential transcriptional factor (TF) candidates that may modulate non-canonical AR cistrome. We verified the enrichment of these TF in PDX models of treatment-resistant PCa at the gene and protein level. Integration of our ongoing global proteomic studies will provide a holistic view of the contributions of the TF to the AR non-canonical switch. Citation Format: Ephraim Jeremiah Gardner. Investigating novel players involved in AR cistrome reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3054.