LAUSR

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in the US. 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. 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. 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. CCS1477 (inobrodib) is a first-in-class bromodomain inhibitor developed by Cell Centric and targeted to inhibit CBP/p300 mediated bromodomain activity, and thus regulate cell survival. Inhibition of the CBP/p300 bromodomain resulted in significant downregulation of AR-FL, AR-V7, and its targets’ mRNA expression, as well as inhibition of associated factors such c-MYC and its downstream targets, in multiple PCa models. Transcriptomic analysis indicated that both CBP and p300 expression correlate with expression of genes involved in double strand break (DSB) DNA repair process including homologous recombination (HR) and non-homologous end joining (NHEJ) in both primary PCa and CRPC models. CCS1477 directly impacted DNA damage response and repair dynamics, as shown via delay in time to resolution of DNA damage foci formation, including RAD51 and γH2AX foci. Inhibition of CBP/p300 activity decreased tumor cell proliferation, blocked CRPC xenograft growth in vivo, and decreased proliferation ex vivo in patient-derived prostate tumor explants. Importantly, CBP/p300 expression correlated with HR genes in human prostate tissue samples in different cohorts. Lastly, inhibition of CBP/p300 activity also decreased HR gene expression in patients further supporting the essential role CBP/p300 plays in DNA repair. In sum, CBP/p300 inhibition mediates HR repair and impacts patient outcome. In conclusion, these studies identify CBP/p300 as a driver of PCa tumorigenesis through coordinated control of critical transcriptional events and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed therapies. Combined, these studies have the capacity for significant near-term impact in the prevention and/or management of metastatic disease. Citation Format: Sumaira Sardar, Lakshmi Ravindranath, Christopher McNair, Saswati Chand, Wei Yuan, Denisa Bogdan, Jon Welti, Adam Sharp, Matthew Schiewer, Lisa Butler, Johann DeBono, Kris Frese, Nigel Brooks, Neil Pegg, Karen Knudsen, Ayesha A. Shafi. Targeting CBP/p300 and its downstream transcriptional machinery in advanced PCa [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B074.