Targeting the p300/CBP Axis in Lethal Prostate Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Castration-resistant prostate cancer (CRPC) often exhibits resistance to androgen receptor (AR) blockade due to sustained AR signaling, including AR splice variants (AR-SV).
• Transcriptional coactivators like p300 and CBP play crucial roles in regulating AR activity and are thus attractive therapeutic targets for advanced prostate cancer.

Purpose of the Study:

• To validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer.
• To introduce and evaluate CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain, for its efficacy in prostate cancer models and early clinical studies.

Main Methods:

• Inhibition of cell proliferation in prostate cancer cell lines.
• Assessment of AR- and C-MYC-regulated gene expression.
• Evaluation of antitumor activity in AR-SV-driven models.
• Analysis of early clinical data, including modulation of KLK3 blood levels and CRPC biopsy biomarker expression.

Main Results:

• CCS1477 effectively inhibits prostate cancer cell proliferation and downregulates AR- and C-MYC-driven gene expression.
• The drug demonstrates antitumor activity in AR-SV-driven models by modulating AR and C-MYC signaling.
• Early clinical findings indicate that CCS1477 can affect KLK3 blood levels and alter CRPC biopsy biomarker expression.

Conclusions:

• Targeting p300/CBP with CCS1477 is a promising therapeutic strategy for patients with advanced prostate cancer, including CRPC.
• CCS1477 demonstrates efficacy in preclinical models by inhibiting growth and AR activity, and shows potential in clinical settings by modulating relevant biomarkers.