Targeting p300/CBP axis in lethal prostate cancer
Jonathan Welti, Adam Sharp, Nigel Brooks, Wei Yuan, Christopher McNair, Saswati N Chand, Abhijit Pal, Ines Figueiredo, Ruth Riisnaes, Bora Gurel, Jan Rekowski, Denisa Bogdan, William West, Barbara Young, Meera Raja, Amy Prosser, Jordan Lane, Stuart Thomson, Jenny Worthington, Stuart Onions, Jonathan Shannon, Silvia Paoletta, Richard Brown, Don Smyth, Gareth W Harbottle, Veronica S Gil, Susana Miranda, Mateus Crespo, Ana Ferreira, Rita Pereira, Nina Tunariu, Suzanne Carreira, Antje J Neeb, Jiang Ning, Amanda Swain, David Taddei, Stand Up to Cancer-PCF International Dream Team, Matthew J Schiewer, Karen E Knudsen, Neil Pegg and Johann S. de Bono
Abstract:
Resistance to androgen receptor (AR) blockade in castration resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of the AR (AR-SV). Inhibitors of transcriptional co-activators that regulate AR activity, including the paralogue histone-acetyltransferase proteins, p300 and CBP, are attractive therapeutic targets for lethal prostate cancer (PC). Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal PC, and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in PC cell lines and decreases AR and C-MYC regulated gene expression. In AR-SV driven models CCS1477 has anti-tumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced PC.