Targeting CBP/p300 and its Downstream Transcriptional Machinery in Advanced Pca

RITM0030757
Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in the US. The androgen receptor (AR), a hormone-activated transcription factor, plays vital roles in the development and progression of PCa. Thus, androgen-deprivation therapy (ADT) is a standard-of-care first-line therapy for metastatic PCa. Resistance to ADT leads almost uniformly to lethal disease, termed castration-resistant prostate cancer (CRPC). As such, there is a largely unmet clinical need to identify and develop novel strategies, that work either alone or in concert with AR-directed therapeutics, to combat CRPC. The highly conserved histone acetyltransferases CBP/p300 are potent co-activators for AR, and high p300 expression is associated with locally advanced disease and castration-resistant AR function. This study shows that CBP and p300 are highly expressed and correlate closely with AR gene expression and AR activity score in primary PCa and CRPC. Thus, it will be critical to determine the role of CBP/p300 in PCa in order to potentially develop novel therapeutic targets for precision medicine to enhance patient outcome. By employing clinically relevant PCa models, the clinical significance of CBP/p300 expression in PCa patients as well as mechanistic evaluation of CBP/p300 transcriptional reprogramming and DNA damage response pathways have been undertaken. Lastly, the molecular response to CBP/p300 inhibition will be assessed to discern novel metrics for precision medicine for PCa patients to improve therapeutic efficacy. Previous studies have relied on non-specific compounds and genetic silencing to target CBP/p300 and its associated transcriptional machinery. CCS1477 is a first-in-class bromodomain inhibitor designed by Cell Centric and targeted to inhibit CBP/p300 mediated bromodomain activity, and thus regulate cell survival. The IC50 values of CCS1477 in hormone therapy-sensitive and CRPC cell lines were determined to demonstrate effective inhibition in growth and