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.
Cancer discovery. 2021 Jan 11 [Epub ahead of print]
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, Jian Ning, Amanda Swain, David Taddei, Stand Up To Cancer-Pcf International Dream Team, Matthew J Schiewer, Karen E Knudsen, Neil Pegg, Johann S de Bono
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research., Prostate Cancer Targeted Therapy Group, Institute of Cancer Research., Translational Science, CellCentric Ltd., Cancer Biomarkers, Institute of Cancer Research., Cancer Biology, Thomas Jefferson University., Cancer Biology, Sidney Kimmel Cancer Centre, Thomas Jefferson University., Drug Development Unit, Royal Marsden Hospital., Cancer Biomarkers Team, Institute of Cancer Research., Division of Clinical Studies, Institute of Cancer Research., Institute of Cancer Research., Clinical Trials & Statistics Unit, Institute of Cancer Research., CellCentric Ltd., Sygnature Discovery Ltd., Sygnature Discovery Services., Bioscience, Sygnature Discovery Ltd., Axis Bioservices Limited, Axis Bioservices Limited., Chemistry, Sygnature Discovery Services., Clinical Studies, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust., Section of Medicine, Institute of Cancer Research., Cancer Research UK Cancer Therapeutics Unit, Institute of Cancer Research., Clinical Studies, Institute of Cancer Reseach., Radiology Department, The Royal Marsden Hospital & The Institute of Cancer Research., Clinical Studies/Cancer Biomarkers, Institute of Cancer Research., The Tumour Profiling Unit, Institute of Cancer Research., Chemistry, Sygnature Discovery Ltd., University of Michigan Medical School., Cancer Biology, Sidney Kimmel Cancer Center at Jefferson., Depts of Cancer Biology, Urology, Medical Oncology, and Radiation Oncology, Sidney Kimmel Cancer Center at Jefferson Health., R&D, CellCentric Ltd., Institute of Cancer Research .