Targeting p300/CBP axis in lethal prostate cancer.
International Dream Team, SUTC-P
de Bono, JS
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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.
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Prostate Cancer Targeted Therapy Group
License start date
Cancer discovery, 2021